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Cáncer de mama temprano – terapia loco-

regional
Value of adjuvant radiation therapy in breast cancer patients with
one to three positive lymph nodes undergoing a modified radical
mastectomy and systemic therapy.

Sub-category:
Local-Regional Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
507
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 507)
Author(s):
S. Dawood, A. M. Gonzalez-Angulo, W. Woodward, F. Meric-Bernstam, K. Hunt, A.
Buzdar, G. Hortobagyi, T. Buchholz; Dubai Hospital, Dubai, United Arab Emirates; UT
M. D. Anderson Cancer Center, Houston, TX
Abstract:
Background: Whether adjuvant radiation therapy should be utilized for patients
(pts) with early stage breast cancer with up to 3 positive axillary lymph nodes
treated with mastectomy and systemic therapy is controversial. This retrospective
study was performed to determine if adjuvant radiation therapy had an impact on
survival for this cohort of pts. Methods: 4240 pts with T1-2N0-1 breast cancers,
diagnosed between 1980-2007, who underwent either mastectomy without
adjuvant radiation therapy or segmental mastectomy with adjuvant radiation
therapy were identified. All pts received systemic treatment. Women with >3
positive axillary lymph nodes were excluded. Overall (OS) and distant disease free
survival (DDFS) were estimated using the Kaplan-Meir product method. Cox
proportional hazards were used to determine associations between OS/DDFS and
type of surgery after controlling for pt and disease characteristics.Results: 1336
(18.8%) had T1N0 disease, 1114 (26.27%) had T2N0 disease, 989 (23.33%) had
T1N1 disease and 801 (18.89%) had T2N1 disease. Median follow-up was 54
months.5- year DDFS among women who underwent mastectomy and segmental
mastectomy was 81% (95% 78%-83%) and 86% (95% CI 84%-87%), respectively (p
< 0.0001). In the Cox analysis, pts who had mastectomy without radiation had a
significantly increased risk of distant recurrence (HR = 1.39, 95% CI 1.14-1.70, p =
0.0013) than pts treated with segmental mastectomy and radiation. When looking
at subgroups, no significant difference in DDFS was observed between the two
groups in pts with lymph node negative disease. However, for pts with 1-3 positive
lymph nodes, pts treated with mastectomy without radiation had significantly
increased risk of distant recurrence compared to pts treated with segmental
mastectomy with radiation (HR=1.614, 95% CI 1.198-2.177, p = 0.002). This
difference was most pronounce in the subset of patients with T2N1 disease (HR =
1.794, 95% CI 1.220-2.637, p=0.003). Similar trends were observed for
OS. Conclusions: This study provides provocative evidence for benefit of radiation
therapy among pts with 1-3 positive axillary lymph nodes who are treated with
surgery and systemic therapy.
Impact of omission of completion axillary lymph node dissection
(cALND) or axillary radiotherapy (ax RT) in breast cancer patients
with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in
the sentinel lymph node (SN): Results from the MIRROR study.

Sub-category:
Local-Regional Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA506
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA506)
Author(s):
V. C. Tjan-Heijnen, M. J. Pepels, M. de Boer, G. F. Borm, J. A. van Dijck, C. H. van
Deurzen, E. M. Adang, M. B. Menke-Pluymers, P. J. van Diest, P. Bult; Maastricht
University Medical Centre, Maastricht, Netherlands; University Medical Centre St
Radboud, Nijmegen, Netherlands; Comprehensive Cancer Centre East, Nijmegen,
Netherlands; University Medical Centre Utrecht, Utrecht, Netherlands; Erasmus
Medical Center-DDH, Rotterdam, Netherlands
Abstract:
Background: The Dutch MIRROR study is the largest cohort study on pN1mi and
pN0(i+) in the SN era with long-term follow-up, central pathology review (6th AJCC-
classification), and separate analyses on the use of adjuvant systemic therapy
(AST). In patients not receiving AST, pN1mi and pN0(i+) as final N-stage were
shown to be independent prognosticators for disease-free survival (SABCS 2008,
#23, oral). As a substantial number of patients in the MIRROR study did not undergo
cALND or ax RT, we questioned whether this policy was safe in patients with
pN1mi(sn) or pN0(i+)(sn). Methods: Patients operated for breast cancer in all
Dutch hospitals in the years 1998-2005, having favorable primary tumor
characteristics, and having undergone an SN biopsy without macrometastases as
final N-stage were included. For this present research question, patients were
categorized by their SN-stage. Median follow-up was 4.7 years. The Kaplan-Meier
method was used to estimate 5-year axillary recurrence (AR) rates, and Cox
regression was used to estimate the hazard ratios (HR). In the analyses, the effect
of AST was taken into account. Results: In total, 835 patients with pN0(i-)(sn), 799
patients with pN0(i+)(sn), and 958 patients with pN1mi(sn) were included. AR rates,
and HRs on AR are displayed below. Conclusions:Omission of cALND or ax RT in
patients with pN1mi(sn) resulted in a significantly higher 5-year AR rate, even after
correction for AST, and other patient and tumor characteristics. This indicates that
patients with pN1mi(sn) should undergo cALND or ax RT to prevent AR. Support:
The Netherlands Organization for Health Research and Development (ZonMw) and
the Dutch Breast Cancer Trialists' Group (BOOG).

5-year HR AR
n AR(%) (95%CI)*
pN0(i-)(sn) cALND 11 1.9 1.00
3
pN0(i-)(sn) SN 72 2.2 1.07 (0.23 -
2 4.94)
pN0(i+)(sn) cALND or ax RT 45 1.1 1.00
9
pN0(i+)(sn) SN 34 1.7 2.14 (0.57 -
5-year HR AR
n AR(%) (95%CI)*
0 7.96)
pN1mi(sn) cALND or ax RT 82 1.2 1.00
8
pN1mi(sn) SN 13 6.2 4.45 (1.46 -
0 13.54)
* Corrected for AST, age, (log) tumor size, grade,
hormone receptor status.

Comentario por Mauricio Lema


La Dra. VC Tjan-Heijnen presentó los resultados del estudio MIRROR (Micrometastases and Isolated
Tumor Cells: Relevant and Robust or Rubbish? (MIRROR) study: retrospective, nonrandomized cohort
analysis). El MIRROR es un estudio observacional de una cohorte de 2680 mujeres a quienes se les
practicó biopsia de ganglio centinela axilar por carcinoma de mama temprano seguidas por una mediana
de 56 meses. Específicamente, describe el impacto de la omisión de vaciamiento ganglionar o de
radioterapia axilar en pacientes con micrometástasis (pN1mi) o con células tumorales aisladas (pN0i+)
en esta cohorte.

Definición
N0: Ausencia de células epiteliales en el ganglio centinela.
N0i+: Presencia de células tumorales en ganglio centinela, de menos de 0.2 mm.
N1mi: Presencia de micrometástasis definida como acúmulos de células tumorales de 0.2 a 2 mm.
N1: Acúmulos tumorales metastásicos > 2mm.

Consideraciones metodológicas
Todos los hospitales de Holanda incluyeron a todas la pacientes tratadas con biopsia de ganglio centinela
entre 1997 y 2005 (n=3205). Se excluyeron a las pacientes con macrometástasis, pacientes con pobre
pronóstico por otras variables, y las que no tuvieran resultados de patología disponibles. Se incluyeron
2608 pacientes clasificadas en N0, N0i+ o N1mi. De estas, 1218 no recibieron terapia adicional a la axila,
1314 fueron tratadas con vaciamiento ganglionar axilar (ALND), y 148 recibieron radioterapia a la axila
(AxRT). El desenlace principal fue la probabilidad de recurrencia axilar a 5 años por terapia axilar
adicional estratificada por los resultados del ganglio centinela.

Resultados
El seguimiento mediano fue de 56 meses. La recurrencia axilar ocurrió en 1.7% de las pacientes. La
probabilidad de recurrencia axilar a los 5 años en las pacientes N0 tratadas con ALND o AxRT fue de
1.6% (n=125), comparado con 2.3% (n=732) que no recibieron terapia adicional a la axila. Esta
diferencia no fue estadísticamente significativa.

Las pacientes N0i+ tratadas con ALND (n=396) tuvieron un riesgo de recurrencia axilar a 5 años del 1%.
Las tratadas con AxRT (n=54) tuvieron 0% de recurrencia axilar a 5 años. Las que no recibieron terapia
axilar adicional (n=345) tuvieron un riesgo de recurrencia axilar a 5 años del 2%, sin alcanzar
significancia estadística. Análisis multivariado encontró que las pacientes con tamaño grande, grado 3, y
receptores hormonales negativos tenían un riesgo mayor de recurrencia axilar a 5 años, en este
subgrupo de pacientes.

Las pacientes N1mi tratadas con ALND (n=793) tuvieron un riesgo de recurrencia axilar a 5 años de
1.1%. Ninguna de las tratadas con AxRT (n=94) tuvo recurrencia axilar. En tanto que 5% de las 141
mujeres N1mi que no recibieron terapia adicional a la axila tuvieron recurrencia axilar a 5 años.

Conclusión
La Dra. Tjan-Heijnen concluye que la terapia adicional con disección ganglionar axilar disminuye la
probabilidad de recaida axilar en pacientes con micrometástasis en el gangloio centinela. También
concluye que la radioterapia axilar mostró resultados interesantes en este estudio descriptivo, pero el
número de pacientes es demasiado bajo para extraer conclusiones definitivas sobre esta modalidad de
tratamiento. Para pacientes con N0i+, posiblemente se debe reservar terapia adicional a la axila cuando
haya factores adicionales que indiquen pobre pronóstico. Finalmente, para pacientes N0 no se
recomienda terapia adicional dirigida a la axila.

Referencia
Tjan-Heijnen VC, Pepels MJ, de Boer M, et al. Impact of omission of completion axillary lymph node
dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases
(pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR
study. Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology;
May 29 - June 2, 2009; Orlando, Florida. Abstract CRA506
Final 10-year analysis of prospective multicenter Chemo N0 trial for
validation of ASCO-recommended biomarkers uPA/PAI-1 for therapy
decision making in node-negative breast cancer.

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
511
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 511)
Author(s):
N. Harbeck, M. Schmitt, C. Meisner, C. Friedel, M. Untch, M. Schmidt, B. Lisboa, C.
Sweep, F. Jänicke, C. Thomssen, Chemo N0 Study Group; Technische Universitaet
Muenchen, Munich, Germany; Department of Medical Biometry, Universitaet
Tuebingen, Tuebingen, Germany; Department of Obstetrics and Gynecology, Helios
Klinikum Berlin-Buch, Germany; Department of Obstetrics and Gynecology,
University of Mainz, Mainz, Germany; Universitaetsfrauenklinik Eppendorf,
Hamburg, Germany; Department of Chemical Endocrinology, University Medical
Center Sint Radboud, Nijmegen, Netherlands; Department of Obstetrics and
Gynecology, Martin Luther University, Halle, Germany
Abstract:
Background: Based on interim results of the prospective, randomized, multicenter
Chemo N0 trial and an EORTC pooled analysis (n = 8,377), ASCO and AGO
guidelines recommend invasion markers uPA/PAI-1 for risk assessment in N0 breast
cancer. Methods: We present final analysis of the Chemo N0 trial (recruitment
1993-1998; n = 647; 12 centers) with 113 (5-167) months median follow-up.
Patients (pts) with low tumor levels of uPA and PAI-1 (n = 283) were observed. Of
364 patients with high uPA and/or PAI-1, 242 were randomized to CMF
chemotherapy (n = 117) vs. observation (n =125); 122 pts decided for or against
CMF on their own. External quality assurance provided good ELISA standardization
in 5 participating laboratories. Results: The actuarial 10-year recurrence rate
(without any adjuvant systemic therapy) for high uPA/PAI-1 pts in the combined
(randomized and not randomized) observation group was 23.0%, in contrast to only
12.9% in those with low uPA/PAI-1 (p = 0.011, log rank). High-risk pts randomized
for CMF had a 26.0% lower estimated probability of disease recurrence than high-
risk pts randomized for observation (intention-to-treat analysis: HR 0.74 (0.44-1.27);
p = 0.28, log rank). In per-protocol analysis, the treatment benefit was significant:
HR 0.48 (0.25-0.88), p = 0.019, adjusted for tumor stage and grading in Cox
regression for DFS; for OS, HR was 0.64 (0.35-1.19); p = 0.162, adjusted for tumor
stage and grading in Cox regression. Conclusions: Chemo N0 is the first
prospective biomarker-based therapy trial in early breast cancer defining a patient
group achieving good long-term DFS without any adjuvant therapy. This trial
demonstrates that, using a standardized uPA/PAI-1 ELISA, about half of N0 pts,
classified as low-risk, could be spared chemotherapy, while high-risk pts benefit
from adjuvant chemotherapy. These 10-year results validate the long-term
prognostic and predictive impact of uPA/PAI-1 at highest level of evidence (LOE
I) and support their guideline-based routine use for risk-adapted individualized
therapy decisions in N0 breast cancer. The ongoing NNBC-3 trial is evaluating
optimal chemotherapy for uPA/PAI-1 high-risk patients.
The 70-gene profile and chemotherapy benefit in 1,600 breast cancer
patients.

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
512
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 512)
Author(s):
R. A. Bender, M. Knauer, E. J. Rutgers, A. M. Glas, F. A. de Snoo, S. C. Linn, L. J. Van
't Veer; Agendia, Inc., Huntington Beach, CA; Netherlands Cancer Institute,
Amsterdam, Netherlands; Agendia B.V., Amsterdam, Netherlands
Abstract:
Background: The 70-gene expression profile (MammaPrint) is validated as an
independent prognostic indicator for breast cancer patients with T1-2 node-negative
and positive disease regardless of estrogen receptor status. Here we present the
relationship between MammaPrint outcome and chemotherapy benefit in the
adjuvant setting. Methods: We performed a pooled analysis of 1,637 patients with
MammaPrint outcomes (T1-2, node-negative and positive invasive breast cancer
and median FU 7.1 yrs) to determine the chemotherapy benefit of patients treated
with adjuvant chemotherapy in addition to endocrine therapy. Patients were
collected from 7 large datasets at multiple institutions across Europe.Results: In
this meta-analysis, MammaPrint assigned 772 patients (47%) to "low risk" and 865
(53%) to "high risk". In total 349 patients were treated with endocrine therapy
alone, whereas 226 were treated with both chemo- and endocrine therapy. Patients
with poor prognosis MammaPrint profile had a substantial benefit from
chemotherapy: At 5 years, distant disease-free survival was improved from 69% to
88% (HR 0.28 (95% CI 0.14-0.56, p<0.001) when chemotherapy was added to
hormonal therapy. The results remained significant in multivariate analysis
including stratification by standard clinico-pathologic prognostic factors. Patients
classified by MammaPrint as good prognosis ("low risk") had no significant benefit
from chemotherapy (p=0.962). Conclusions: The 70-gene MammaPrint profile is
not only a strong and independent prognostic indicator for patients with early stage
breast cancer, but it may also be predictive for the benefit of chemotherapy. While
MammaPrint "high risk" classified patients demonstrate a clear benefit from
adjuvant chemotherapy added to hormonal therapy, patients classified by
MammaPrint as "low risk" for recurrence do not appear to benefit from the addition
of chemotherapy to hormonal treatment alone.
Breast cancer molecular profiles and tumor response of neoadjuvant
doxorubicin and paclitaxel: The I-SPY TRIAL (CALGB 150007/150012,
ACRIN 6657).

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA515
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA515)
Author(s):
L. J. Esserman, C. Perou, M. Cheang, A. DeMichele, L. Carey, L. J. van 't Veer, J. Gray,
E. Petricoin, K. Conway, D. Berry, I-Spy Investigators; University of California, San
Francisco, San Francisco, CA; University of North Carolina at Chapel Hill, Chapel Hill,
NC; University of Pennsylvania, Pittsburgh, PA; Netherlands Cancer Institute,
Amsterdam, Netherlands; George Mason University, Manassas, VA; M. D. Anderson
Cancer Center, Houston, TX
Abstract:
Background: I-SPY is a multi-center trial designed to identify predictive markers of
pathological complete response (pCR) and survival of women with locally advanced
breast cancers (3cm or greater). Women received neoadjuvant doxorubicin and
cyclophosphamide then paclitaxel. Methods: 237 women enrolled, 216 completed
serial imaging and core biopsies. Pre-treatment assays include: Agilent expression
arrays, MIP aCGH, p53 gene chip and sequencing, IHC and reverse phase protein
arrays (RPMA). Response to therapy was measured by serial MRI, pCR and residual
cancer burden (RCB). Associations among molecular markers, pCR, RCB and
survival were evaluated using chi-square test, Kaplan-Meier curves and log-rank
test. Results: Median tumor size was 6cm, % pCR and RCB 0/1 was 27% and 36%
for the entire study; % pCR rate for the 144 Agilent arrays was 25%. Distribution,
rates of pCR and RCB 0/1 are shown in the Table for molecular and IHC markers.
DFS and OS will be presented. Several molecular subtypes, including NKI 70 gene
low, luminal A, 21 gene set low and IHC HR+, define 15-28% of patients with 3-10%
pCR, yet excellent early survival. Wound healing, most discriminatory for prognosis,
is not predictive of chemotherapy response. By RPMA, patients with pCR had
increased phosphorylation of 4EBP1, eNOS, cAbl, STAT5, EGFR, AKT (p<0.05). In
ER+ patients with poor MR response, pIRS, pIGFR, p706S were activated (p<0.05).
RCB is a more refined way to measure pCR and was more predictive of DFS and OS
(p=0.01) than pCR alone with a mean follow up of 3.9 years. MR volume is highly
predictive of pCR and RCB. For specific subtypes, e.g. basal, RCB is predictive of
DFS (p<0.00001). Conclusions: LABC have aggressive biology. Response to
therapy and outcome can be predicted by many biomarkers. The I-SPY data set
provides a platform to compare, contrast and combine marker signatures to tailor
therapy and demonstrates the power of the neoadjuvant setting. Support: ACRIN
U01 CA079778; CALGB CA31964, CA33601; NCI SPORE CA58207.

Profile rates of pCR and RCB


RCB
Distribut pC RCB p-
ion R 0,1 pCR p-value value
Intrinsic Luminal A 28% 5 14% <0.001 <0.00
Profile rates of pCR and RCB
RCB
Distribut pC RCB p-
ion R 0,1 pCR p-value value
Subtypes LuminalB 21% % 21% . 1
n=144 Basal 31% 13 40% . .
Her 2 15% % 73% . .
Normal 4% 34 67% . .
% .
55
%
50
%
NKI 70 gene Good 15% 10 17% 0.16 0.07
n=144 Poor 85% % 39% . .
27
%
IHC HR+ Her2- 29% 10 21% Effect HR
n=189 HR+ Her2+ 20% % 48% 0.0002
HR- Her2- 34% 28 41% Effect Her2
HR- Her2- 17% % 79% 0.009
36
%
48
%
MIP No Amplification 86% 17 .
n=127 17q 14% % <0.0001
Amplification 61
17q %
p53 Mutation Any Mutation 43% 38 43% .
n=181 MissenseZn- 39% % 100% 0.02
binding 27% 75 53% 0.0003
Null %
57
%
ROR-S Low 22% 6 21% 0.001 0.005
n=144 Medium 38% % 27% . .
High 40% 17 52% . .
%
43
%
Wound Quiescent 49% 19 34% 0.12 0.72
Healing Activated 51% % 38% . .
n=144 31
%
Low 22% 3 12% <0.001 0.002
Intermediate 10% % 20% . .
21 gene set High 68% 0 46% . .
n=144 %
36
%
Genotypic characterization of phenotypically defined triple-negative
breast cancer.
Sub-category:
Local-Regional Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
500
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 500)
Author(s):
J. A. Sparano, L. J. Goldestin, B. H. Childs, S. Shak, S. Badve, F. L. Baehner, N. E.
Davidson, G. W. Sledge, R. Gray, North American Breast Cancer Intergroup; Albert
Einstein Cancer Center, Bronx, NY; Fox Chase Cancer Center, Philadelphia, PA;
sanoti-aventis, Bridgewater, NJ; Genomic Health, Inc. , Redwood City, CA; Indiana
University School of Medicine, Indianapolis, IN; University of Pittsburgh Cancer
Institute, Pittsburgh, PA; Eastern Cooperative Oncology Group, Boston, MA
Abstract:
Background: Triple negative breast cancer (TNBC) is associated with a higher risk of
recurrence and earlier recurrences than other breast cancer phenotypes. We
evaluated the genotypic features of TNBC compared with hormone receptor (HR)-
positive disease, and also evaluated genotypic features associated with recurrence.
Methods: RNA extracted from tumor samples obtained from 764 patients with stage
I-III breast cancer was analyzed by RT-PCR for 371 genes. All patients received
adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial
E2197; HR and HER2 expression were evaluated by immunohistochemistry (IHC) in
a central lab (J Clin Oncol 26:2473-2481). An unsupervised clustering analysis was
performed in all samples (N=764). Cox proportional hazard models were used to
identify differences in gene expression in TNBC versus HR-positive disease, and with
recurrence in phenotypically defined (by IHC) TNBC (N=246) and HR-positive
(N=465) disease. Results: Unsupervised analysis revealed two major clusters that
differed with regard to HR expression by IHC. Supervised analysis comparing the
TNBC vs. HR-positive phenotypes revealed 269 genes (73%) with significantly
different expression (p<0.0001). The top 10% of genes exhibiting higher expression
the TN group included genes associated with nucleosome assembly (CENPA), kinase
activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling
(DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation
(MYBL2). There was increased expression of genes for which inhibitors are currently
being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-
positive disease. AlthoughGRB7 expression was significantly lower in the TN group,
increased expression of GRB7 was the only gene in the TNBC group (but not the HR-
positive group) associated with increased recurrence (p=0.04), and did not
correlate with nodal status, tumor size, or grade. Conclusions: We genotypically
characterized breast cancers that have also undergone rigorous phenotypic
characterization.. There were significant differences in gene expression between the
TN and HR-positive groups, including genes for which targeted agents are currently
being evaluated in the clinic.
Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer
patients.

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
502
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 502)
Author(s):
J. Gronwald, T. Byrski, T. Huzarski, R. Dent, V. Bielicka, D. Zuziak, R. Wisniowski, J.
Lubinski, S. Narod; Pomeranian Medical University, Szczecin, Poland; Sunnybrook
Odette Cancer Centre, Toronto, ON, Canada; Regional Oncology Center, Bielsko-
Biala, Poland; Women’s College Research Institute, Toronto, ON, Canada
Abstract:
Background: Neoadjuvant chemotherapy is administered to control disease, make
surgical resection possible and increase the possibility of breast tissue conservation.
A further advantage of neoadjuvant therapy is that it helps to assess chemo-
sensitivity to a particular agent. Induction of a pathological complete response
(pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a
better disease-free and overall survival. Experimental data suggest that BRCA1
related breast cancer may have increased sensitivity to platinum-based
chemotherapy, but clinical data are limited. The aim of this study was to evaluate
the frequency of complete pathologic response after neo-adjuvant treatment with
cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation.
Methods: Twenty five women with breast cancer and a BRCA1 mutation with stage I,
II, and III breast cancer between December 2006 and December 2008 were entered
into this study. Patients were treated with cisplatin 75 mg/m2 intravenously every
three weeks for four cycles. After chemotherapy, patients underwent surgery and
were assessed for pathologic response in both the breast and axillary lymph nodes.
Complete pathologic response was defined as no residual invasive disease in both
the breast and axilla, however ductal carcinoma in situ was allowed. Results:
Twenty five patients were enrolled in the study. Thirteen patients had tumors of
greater than two centimeters (52%) and seven patients had positive lymph nodes at
diagnosis (28%). Twenty two patients completed four cycles of cisplatin (88%) and
three patients completed two cycles (12%). Clinical complete response was
observed in eighteen patients (72%). Pathologic complete response was observed in
eighteen patients (72%). Conclusions: Platinum-based chemotherapy is effective in
a high proportion of patients with BRCA1-associated breast cancers. Clinical trials
are warranted to determine the optimum treatment for this subgroup of breast
cancer patients.
Cáncer de mama temprano: Hormonoterapia
Risk of breast cancer recurrence in women initiating tamoxifen with
CYP2D6 inhibitors.

Sub-category:
Local-Regional Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA508
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA508)
Author(s):
R. E. Aubert, E. J. Stanek, J. Yao, J. R. Teagarden, M. Subar, R. S. Epstein, T. C. Skaar,
Z. Desta, D. A. Flockhart; Medco Health Solutions, Franklin Lakes, NJ; Indiana
University School of Medicine, Indianapolis, IN
Abstract:
Background: Tamoxifen (TAM) is metabolized to its active form, endoxifen, by
hepatic cytochrome P450 (CYP) 2D6. Diminished CYP2D6 function, both by genetic
variation or concurrent use of pharmacologic inhibitors, can significantly reduce
endoxifen plasma concentrations and may lead to reduced TAM effectiveness.
Methods: We interrogated an integrated research database comprised of de-
identified medical and pharmacy claims (Rx) data for 10.7 million U.S. health plan
members to identify women with breast cancer (BrCa) new to TAM therapy in a 30-
month period from 2003 to 2005, and investigated the risk of recurrent BrCa as a
function of concurrent use of potent and moderate inhibitors of CYP2D6. Inclusion
criteria were: greater than or equal to 24 months of follow-up data and adherence
to TAM (medication possession ratio > 70%) over 2 years (N = 1,298). Disease
recurrence was defined by BrCa ICD-9 codes or CPT codes for mastectomy,
lumpectomy, lymph node dissection, or radiation therapy occurring at least 6
months after the index TAM Rx. Two study groups were identified: TAM alone (N =
945) or TAM + a CYP2D6 inhibitor concomitantly (N = 353). BrCa recurrence rates
were compared using Kaplan-Meier analysis with log-rank test, and univariate
hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox
proportional hazards model. Results: The study groups were similar at baseline.
Median age was 52 years (TAM) and 53 years (TAM + CYP2D6 inhibitor).
Interventions performed in the TAM alone group included mastectomy in 54%,
lumpectomy in 36%, and radiation therapy in 47%, and were 52%, 38%, 46%,
respectively, in the TAM + CYP2D6 inhibitor group. Among women on a CYP2D6
inhibitor, the median duration of overlap with TAM was 255 days. Patients receiving
TAM + a CYP2D6 inhibitor had a 2-year BrCa recurrence rate of 13.9% versus 7.5%
in patients receiving TAM alone (HR 1.92, 95% CI 1.33-2.76, p < 0.001).
Conclusions: Our findings support the presence of a clinically significant drug
interaction between TAM and known CYP2D6 inhibitors. This resulted in a significant
1.9 fold higher BrCa recurrence within 2 years of initiating TAM therapy.
Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage
breast cancer: A pharmacoepidemiologic study.

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA509
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA509)
Author(s):
V. Dezentje, N. J. Van Blijderveen, H. Gelderblom, H. Putter, M. P. Van Herk - Sukel,
M. K. Casparie, A. C. Egberts, J. W. Nortier, H. J. Guchelaar; Leiden University
Medical Center, Leiden, Netherlands; PHARMO institute for Drug Outcomes
Research, Utrecht, Netherlands; Palga Foundation, Utrecht, Netherlands; Utrecht
University, Pharmaceutical Sciences, Utrecht, Netherlands
Abstract:
Background: The use of cytochrome P450 2D6 inhibiting drugs (CYP2D6 inhibitors)
during tamoxifen treatment leads to a decrease in plasma concentration of
endoxifen, the major active tamoxifen metabolite. Concomitant use of CYP2D6
inhibitors, such as the commonly prescribed selective serotonin reuptake inhibitors,
as well as low tamoxifen adherence may negatively impact tamoxifen efficacy in
breast cancer. The objectives were to relate concomitant CYP2D6 inhibitor use and
tamoxifen adherence to breast cancer event free time (EFT). Methods: Data were
used from PHARMO, a pharmacy database, PALGA, a nationwide pathology
database and the Dutch Medical Register in the Netherlands. Breast cancer patients
who were treated with tamoxifen as adjuvant therapy between 1994 and 2006 were
included. A Cox proportional hazards model with a time-dependent definition for the
CYP2D6 inhibitor exposure was used. Results: 1,990 breast cancer patients using
tamoxifen were included, among whom 215 (10.8%) used a CYP2D6 inhibitor during
tamoxifen treatment. No association between concomitant CYP2D6 inhibitor use
and breast cancer recurrence was observed. Poor tamoxifen adherence was
associated with lower EFT. Conclusions: This observational study did not show an
association between concomitant CYP2D6 inhibitor use and breast cancer
recurrence among patients treated with adjuvant tamoxifen. However, this study
shows for the first time that poor tamoxifen adherence is associated with lower EFT.
Cognitive function in postmenopausal women receiving adjuvant letrozole
or tamoxifen in the Breast International Group (BIG) 1-98 trial.
Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
510
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 510)
Author(s):
K. E. Ribi, K. A. Phillips, Z. Sun, A. Stephens, A. Thompson, V. Harvey, B. Thürlimann,
F. Cardoso, A. S. Coates, J. Bernhard; IBCSG and BIG1-98 Collaborative Group, Bern,
Switzerland; IBCSG and BIG 1-98 Collaborative Group, Bern, Switzerland
Abstract:
Background: Hormonal therapy for breast cancer (BC) may affect
cognition. Methods: Post-menopausal women with hormone receptor positive,
early-stage BC were randomized to receive either: A) tamoxifen for 5 years; B)
letrozole for 5 years; C) tamoxifen for 2 years followed by letrozole for 3 years; or D)
letrozole for 2 years followed by tamoxifen for 3 years, as adjuvant endocrine
treatment. During the fifth year of trial treatment, objective cognitive function
(speed of psychomotor function, visual attention, working and verbal memory,
learning) was evaluated by computerized tests. The difference in the composite
score for patients taking letrozole (B+C; N = 65) versus tamoxifen (A+D; N = 55) at
the time of testing was the primary comparison. Scores for each domain were
standardized according to age-specific norms. Two-way ANOVA controlling for
language was used to test the effect of treatment on cognitive function. Self-
reported subjective cognitive function, psychological distress, fatigue and quality of
life were also assessed. Results: Patient characteristics were balanced between
groups. Both groups performed below age norms on most domains. The group
taking letrozole had better overall cognitive function than the tamoxifen group
(difference in mean composite scores = 0.278, p = 0.038, 95% CI: 0.015-0.540) and
outperformed patients on tamoxifen for all domains (n.s.). Comparison of
monotherapy arms A versus B supported better cognitive function among letrozole
patients. Subjective cognitive function, psychological distress, fatigue, and quality
of life did not differ between groups. Conclusions: Although letrozole results in
lower circulating estrogen levels than tamoxifen, in this study BC patients taking
adjuvant letrozole during the fifth year of treatment had better cognitive functioning
than those taking tamoxifen.
Effect of denosumab on bone mineral density (BMD) in women with
breast cancer (BC) and men with prostate cancer (PC) undergoing
hormone ablation therapy.

Sub-category:
Supportive Care
Category:
Patient Care
Meeting:
2009 ASCO Annual Meeting
Abstract No:
9520
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 9520)
Author(s):
M. R. Smith, G. Ellis, F. Saad, T. Tammela, H. Bone, B. Egerdie, C. Ke, S. Jun, R.
Dansey, C. Goessl; Massachusetts General Hospital Cancer Center, Boston, MA;
Seattle Cancer Care Alliance, Seattle, WA; Centre Hospitalier de l’Université de
Montréal, Montréal, QC, Canada; Tampere University Hospital, Tampere, Finland;
Michigan Bone and Mineral Clinic, Detroit, MI; Urology Associates Urologic Medical
Research, Kitchener, ON, Canada; Amgen, Inc., Thousand Oaks, CA
Abstract:
Background: Hormone ablation therapies, including adjuvant aromatase inhibitor
(AI) therapy and androgen deprivation therapy (ADT), improve recurrence-free
survival in patients (pts) with BC and PC, respectively. However, these treatments
increase bone resorption, leading to bone loss and fractures. RANKL is a key
mediator of osteoclast-mediated bone resorption. In this 24 month (mo)
comparison, we investigated the effects of denosumab, a fully human monoclonal
antibody against RANKL, on preserving BMD across both
populations. Methods: Two trials were conducted: a 24-mo BC study and a 36-mo
PC study. Postmenopausal women with low BMD receiving AI therapy for
nonmetastatic BC and men receiving ADT for nonmetastatic PC (with low BMD or
history of osteoporotic fracture if < 70 yrs) were randomized to receive placebo or
denosumab 60mg subcutaneously every 6 mos. All pts in both studies were
prescribed calcium and vitamin D supplements. The primary endpoint was %
change from baseline in lumbar spine (LS) BMD at 12 mos for the BC study and at
24 mos for the PC study. Herein, we present changes in BMD at 24 mos at LS, total
hip (TH), and 1/3 radius from both studies. Power calculations were based on
enrollment of at least 208 patients in the BC study (for primary endpoint only) and
1226 in the PC study (for primary and key secondary endpoints). The actual
numbers randomized were 252 and 1468, respectively. Results: Denosumab
increased BMD of the LS, TH, and 1/3 radius compared with placebo at 24 mos in
both pt populations (Table). In both studies, differences between denosumab and
placebo at each skeletal site were consistent, and the effects of denosumab were
statistically significantly different from placebo as early as 1 month at the LS in both
studies. The overall safety profile was similar to placebo in each
study. Conclusions: Denosumab consistently increased BMD at all 3 skeletal sites
compared with placebo in both women with BC undergoing AI therapy and in men
with PC undergoing ADT.

Difference in % change from baseline BMD at month 24 compared with


placebo
BC Study PC Study
Lumbar spine 7.6 (6.6, 8.6)* 6.7 (6.2, 7.1)*
Difference in % change from baseline BMD at month 24 compared with
placebo
BC Study PC Study
Total hip 4.7 (4.0, 5.5)* 4.8 (4.4, 5.1)*
1/3 radius† 6.1 (5.0, 7.1)* 5.5 (4.5, 6.6)*
*p<0.001; †substudy in PC study; n=309; Results presented as least squares mean
± 95% CI (ANCOVA models adjusting for stratification variables, baseline BMD
value, densitometer type, and baseline BMD value-by-densitometer-type
interaction).

Cáncer de mama metastásico


RIBBON-1: Randomized, double-blind, placebo-controlled, phase III
trial of chemotherapy with or without bevacizumab (B) for first-line
treatment of HER2-negative locally recurrent or metastatic breast
cancer (MBC).

Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
1005
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 1005)
Author(s):
N. J. Robert, V. Dieras, J. Glaspy, A. Brufsky, I. Bondarenko, O. Lipatov, E. Perez, D. Yardley, X. Zhou, S.
Phan; Fairfax-Northern Virginia Hematology-Oncology, Fairfax, VA; Institut Curie, Paris, France; UCLA
TORI, Los Angeles, CA; University of Pittsburgh, Pittsburgh, PA; State Medical Academy, Dnipropetrovsk,
Ukraine; Bashkirian Republican Clinical Oncology, Ufa, Russian Federation; Mayo Clinic, Jacksonville, FL;
Sarah Cannon Cancer Center, Nashville, TN; Genentech, Inc., South San Francisco, CA
Abstract:

Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has
improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase
III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for
MBC.Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) +
chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m² x 14d),
taxane (T) (nab-paclitaxel [260 mg/m²] or D [75 or 100 mg/m²], q3wk), or anthracycline (Ant)-based
chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC
or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no
CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included
overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At
progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T
or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified
log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect
HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in
22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant
cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was
consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based
chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant
improvement in PFS with a safety profile comparable to prior Phase III studies.

Cap (n=615) T + Ant (n=622)


Pl (n=206) B (n=409) Pl (n=207) B (n=415)
PFS, HR (95% CI) 0.688 (0.564, 0.840) 0.644 (0.522, 0.795)
Log-rank p-value 0.0002 <0.0001
Median (months) 5.7 8.6 8.0 9.2
ORR* (%) 38 (23.6) 115 (35.4) 67 (37.9) 177 (51.3)
p-value 0.0097 0.0054
OS, HR ( 95% CI) 0.847 (0.631, 1.138) 1.032 (0.774, 1.376)
Cap (n=615) T + Ant (n=622)
Pl (n=206) B (n=409) Pl (n=207) B (n=415)
Log-rank p-value 0.2706 0.8298
Median (months) 21.2 29.0 23.8 25.2
HR=hazard ratio. * Includes only patients with measurable disease at baseline.
Phase III trial of gemcitabine plus docetaxel (GD) compared to
capecitabine plus docetaxel (CD) with planned crossover to the
alternate single agent in metastatic breast cancer (MBC).

Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
1000
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 1000)
Author(s):
A. D. Seidman, A. Brufsky, R. H. Ansari, J. R. Rubinsak, R. S. Stein, L. S. Schwartzberg, J. F. Stewart, L.
Zhao, J. Gill, D. Tai; Memorial Sloan-Kettering Cancer Center, New York, NY; Magee Women's Hospital,
Pittsburgh, PA; Michiana Hematology Oncology, PC, South Bend, IN; SCRI/Florida Cancer Specialists, Ft.
Myers, FL; Vanderbilt-Ingram Cancer Center, Nashville, TN; The West Clinic, Memphis, TN; Newcastle
Mater Misericordiae Hospital, Sydney, NSW, Australia; Lilly USA, LLC, Indianapolis, IN
Abstract:
Background: GD and CD are efficacious in patients (pts) with MBC. This study compared
safety and efficacy of GD and CD induction regimens, where the alternate, single-agent,
crossover therapy (GD to C or CD to G) was predetermined. Primary endpoint was time to
progressive disease (TTP). Secondary endpoints included toxicities, overall response (ORR),
and overall survival (OS). Methods: This multicenter, open-label, phase III study enrolled
MBC pts with possible prior anthracycline therapy, adjuvant or neoadjuvant taxane therapy,
but no taxane therapy for MBC ≤6 months prior to entry. Enrollment of 442 pts (221 per arm)
was planned with 385 progressions required to achieve 80% power for a 2-month observed
difference in median TTP between arms. Pts were randomized to: GD: G 1,000mg/m2Days 1,
8 plus D 75 mg/m2 Day 1, q21 days; or CD: C 1,000 mg/m2 BID, Days 1-14 plus D 75
mg/m2Day 1, q 21 days. Upon disease progression, pts were given crossover C or G at doses
and schedules identical to induction. ORR was assessed by RECIST. Results: Demographics
of 472 enrolled pts were balanced between arms; 57% had prior anthracycline. GD caused
greater myelosuppression than CD, but without greater febrile neutropenia. Gastrointestinal
toxicities, mucositis, and hand-foot syndrome were greater with CD. More pts in the CD arm
(n=61, 26.2%) versus the GD arm (n=41, 17.2%) discontinued due to toxicity (p=0.023).
ORR, TTP, and OS were not significantly different comparing GD and CD. However, ORR and
TTP were significantly greater for the GD to C crossover monotherapy compared to CD to G.
Post-hoc analysis of crossover pts showed that the TTP sum from induction through crossover
was 6.1 months greater for GD to C. Conclusions: GD and CD had similar efficacy with
toxicity profiles consistent with prior clinical experience. Results suggest that the GD to C
crossover sequence may provide a clinical benefit over CD to G.

p
Parameter GD CD value
G3-4 neutropenia, n (%) 175 (73.8%) 67 (30.0%) <0.00
1
G3-4 thrombocytopenia, n (%) 19 (8.0%) 0 (0.0%) <0.00
1
G3-4 hand-foot syndrome, n (%) 1 (0.4%) 52 (23.3%) <0.00
1
G3-4 mucositis, n (%) 2 (0.8%) 9 (4.0%) 0.032
Induction ORR, n (%) 71 (34.3%) 76 (40.2%) 0.278
Crossover ORR, n (%) 11 (15.5%) 3 (4.3%) 0.043
p
Parameter GD CD value
Induction TTP, months (95% CI) 9.8 (8.1, 9.0 (7.4, 0.494
11.0) 11.9)
Crossover TTP, months (95% CI) 4.6 (2.1, 7.8) 2.2 (2.0, 3.4) 0.031
Induction-crossover TTP sum, months 14.5 (10.4, 8.4 (6.9, 0.039
(95% CI) 17.8) 11.2)
Median overall survival, months 23 (18.8, 23.3 (18.6, 0.704
(95%) CI) 25.7) 25.5)

A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug


conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer
(MBC): Final results.

Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
1017
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 1017)
Author(s):
C. L. Vogel, H. A. Burris, S. Limentani, R. Borson, J. O'Shaughnessy, S. Vukelja, S.
Agresta, B. Klencke, M. Birkner, H. Rugo; Lynn Regional Cancer Center West, Boca
Raton, FL; Sarah Cannon Cancer Center, Nashville, TN; Blumenthal Cancer Center,
Charlotte, NC; St. Louis Cancer and Breast Institute, St. Louis, MO; Texas Oncology
P.A. Baylor Sammons Cancer Center, Dallas, TX; Tyler Cancer Center, Tyler, TX;
Genentech, Inc., South San Francisco, CA; University of California, San Francisco,
San Francisco, CA
Abstract:
Background: T-DM1 is an ADC that combines the biological activity of trastuzumab
(T) with targeted delivery of a potent antimicrotubule agent, DM1, to HER2-
expressing cancer cells. In a phase I study, T-DM1 was administered IV q3w to pts
with HER2+ MBC who had progressed on T + chemotherapy. T-DM1 was well-
tolerated at the maximum tolerated dose (MTD) of 3.6 mg/kg, with no reports of
cardiac toxicity. The confirmed objective response rate (ORR) for the 9 pts with
measurable disease treated at the MTD was 44%. The phase II study described here
further assesses tolerability and activity of T-DM1. Methods:This was a multi-
institutional, open-label, single-arm phase II study, to enroll 100 pts. All eligible pts
had progressed on HER2-directed therapy and had received chemotherapy in the
metastatic setting. T-DM1 was administered at 3.6 mg/kg IV q3w. Primary objectives
were assessment of ORR and of safety and tolerability. Results: As of the August
29, 2008, data-cut, 112 patients had enrolled, with baseline median age 54.5 (range
33-82); ECOG PS 2 or 3, 80%; 68.7% with > 3 sites of metastatic disease; median 3
(range 1-14) prior chemotherapy agents for metastatic disease, median 76.3 weeks
prior T, and 55.4% with previous lapatinib. Due to limited F/U, the median number
of T-DM1 cycles received was 5 (range 1-16), and 19 of the 107 efficacy evaluable
patients had only one post-baseline tumor assessment. Fifty-six pts had
discontinued study treatment. With a median follow-up of 4.4 mos, there were 42
(39.3%) ORs (CR or PR), 29 (27.1%) of which have been confirmed by follow-up
(F/U) imaging. Among the subgroup of pts who had either >6 months F/U or had
discontinued from the study at any time (n = 76) there were 33 ORs (43.4%), 29
(38.2%) of which were confirmed by F/U imaging. The most common grade 3-4 AE
was thrombocytopenia (7.1%). Updated data will be presented at the meeting,
including updated ORR, 6-month clinical benefit rate, ORR by independent review,
progression-free survival, and duration of response. Conclusions: T-DM1 has
single-agent activity in pts with previously treated, HER2+ MBC, and is well
tolerated at the recommended phase II dose.
Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1)
inhibitor, in combination with gemcitabine/carboplatin (G/C) in
patients with metastatic triple-negative breast cancer (TNBC):
Results of a randomized phase II trial.

Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
3
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr 3)
Author(s):
J. O'Shaughnessy, C. Osborne, J. Pippen, M. Yoffe, D. Patt, G. Monaghan, C. Rocha, V.
Ossovskaya, B. Sherman, C. Bradley; Baylor Sammons, Texas Oncology, US
Oncology, Dallas, TX; Cancer Centers of North Carolina/US Oncology, Raleigh, NC;
Texas Oncology Cancer Center, US Oncology, Austin, TX; Kansas City Cancer
Center, US Oncology, Kansas City, MO; BiPar Sciences, Inc., Brisbane, CA
Abstract:
Background: TNBC is an aggressive breast cancer subtype that shares molecular
and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are
sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA
repair, and thus represent a rational target of PARP inhibitor-based cancer therapy.
The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in
combination with gemcitabine/carboplatin (G/C) in subjects with metastatic
TNBC. Methods: Eligible subjects had measurable disease and had ≤2 prior
cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer.
Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000
mg/m2) and carboplatin (AUC=2) were given on days 1 and 8, and BSI-201 (5.6
mg/kg; iv; biweekly) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical
benefit rate (CBR = CR + PR + SD ≥6 months), progression-free survival (PFS) and
overall survival (OS). Results: Analyses of the first 86 of a planned 120 patients
showed that BSI-201 + G/C had improved CBR, median PFS, and median OS,
compared with G/C alone. The frequency and nature of adverse events (AEs) did not
differ between arms.Conclusions: This preliminary analysis demonstrates that BSI-
201 + G/C significantly improves CBR, PFS, and OS, compared with G/C alone. BSI-
201 + G/C was well tolerated, with BSI-201 adding no significant toxicity to G/C.
Updated CBR, PFS, and OS for all 120 patients and exploratory correlative analyses
of PARP expression and clinical response will be presented.

G/C (n = G/C+BSI-201 (n Hazard ratio P


44) = 42) (95% CI) value
CBR, % 12 52 0.001
2
Median PFS, 87 211 0.30 (0.15-0.59) 0.000
days 3
Median OS, 169 >254 0.24 (0.09-0.61) 0.001
days 2
Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient
advanced breast cancer.

Sub-category:
Adjuvant Therapy
Category:
Breast Cancer--Local-Regional and Adjuvant Therapy
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA501
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA501)
Author(s):
A. Tutt, M. Robson, J. E. Garber, S. Domchek, M. W. Audeh, J. N. Weitzel, M.
Friedlander, J. Carmichael; Breakthrough Breast Cancer Research Unit, Kings
College London School of Medicine, Guy's Hospital, London, United Kingdom;
Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer
Institute, Boston, MA; University of Pennsylvania, Philadelphia, PA; Cedars-Sinai
Outpatient Cancer Center, Los Angeles, CA; City of Hope Comprehensive Cancer
Center, Duarte, CA; Prince of Wales Cancer Centre, Sydney, Australia; AstraZeneca,
Macclesfield, United Kingdom
Abstract:
Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP
inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A
phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an
initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510).
The primary aim of this study was to test the efficacy of olaparib in
confirmedBRCA1/BRCA2 carriers with advanced refractory breast cancer. The
secondary aim was to assess safety and tolerability in this population. Methods: In
an international, multicenter, proof-of-concept, single-arm, phase II study, two
sequential patient (pt) cohorts received continuous oral olaparib in 28-day cycles
initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd, a
previously identified PARP inhibitory dose (27 pts). Eligibility criteria included
confirmed BRCA1/BRCA2 mutation and recurrent, measurable chemotherapy-
refractory breast cancer. The primary efficacy endpoint was best objective response
rate (ORR; RECIST) post baseline. Progression-free survival (PFS) and clinical benefit
rate were secondary endpoints. All adverse events were reported using CTCAE
v3. Results: On November 20, 2008, 54 pts exposed to a median of three prior
lines of chemotherapy had been enrolled. 27 pts were dosed at 400 mg bd (18
BRCA1 deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST
assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24)
(400 mg bd). Causally-related toxicity was mainly mild (grade 1-2) in severity; 9/27
pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and 1/27
(4%) had anemia. Causally-related grade 3 or higher toxicities were seen in 5 pts
(19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts were treated in
the subsequent 100 mg bd cohort where no data are currently
available. Conclusions: Olaparib at 400 mg bd is well tolerated and highly active in
advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity
in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers. This
first study with olaparib in BRCA-deficient breast cancers provides positive proof of
concept for high activity and tolerability of a genetically defined targeted therapy.
Cáncer de colon y recto
A quantitative multigene RT-PCR assay for prediction of recurrence
in stage II colon cancer: Selection of the genes in four large studies
and results of the independent, prospectively designed QUASAR
validation study.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4000
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4000)
Author(s):
D. Kerr, R. Gray, P. Quirke, D. Watson, G. Yothers, I. C. Lavery, M. Lee, M. J.
O'Connell, S. Shak, N. Wolmark, Quasar Colon Teams; University of Oxford;
University of Birmingham Clinical Trials; Leeds Institute of Molecular Medicine;
Genomic Health, Inc., Redwood City, CA; NSABP, Pittsburgh, PA; Cleveland Clinic
Foundation, Cleveland, OH
Abstract:
Background: New clinical tools are needed to improve risk assessment and
treatment decisions in stage II colon cancer. Four development studies [Surgery
(Sx) alone: NSABP C-01/C-02 (n=270) and CCF study (n=765); Sx+5FU/LV: NSABP
C-04 (n=308) and C-06 (n=508)] were performed to select the genes for prediction
of recurrence and 5FU/LV benefit. To determine clinical utility of the prespecified
assay, we performed a large, independent, prospectively designed, clinical
validation study in stage II colon cancer pts from the QUASAR trial. Methods: Gene
expression was quantitated by RT-PCR from 30 µm manually microdissected fixed
paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI),
disease-free survival (DFS), and overall survival (OS) were analyzed using Cox
regression. Results:Combined analysis of the four development studies (total
n=1,851; 761 candidate genes) identified 48 genes significantly associated with
recurrence risk and 66 genes predictive of 5FU/LV benefit. Multivariate analysis, in
the context of stage, grade, nodes examined, and MSI status, yielded 18 genes (7
prognostic genes, 6 predictive genes, 5 reference genes) and separate prognostic
recurrence score (RS) and predictive treatment score (TS) algorithms. In the
QUASAR validation study, tumor blocks were collected for 68% of pts; 1,490 pts with
blocks had stage II colon cancer and RT-PCR was successful in 1,436 eligible pts
(711 Sx, 725 Sx+5FU/LV). Median FU=6.6 yrs. In the primary analysis of RFI in pts
following Sx, the RS predicted recurrence risk (HR/25 units=1.58, 95% CI 1.15-2.15;
p=0.004). The RS also predicted DFS (p=0.01) and OS (p=0.04). Recurrence risk
increased monotonically with increasing RS. In multivariate analyses, RS retained
prognostic significance (p=0.008) independent of mismatch repair (MMR), T stage,
nodes examined, grade, and lymphovascular invasion. MMR deficiency (HR=0.31,
95% CI 0.15-0.63; p<0.001) and T4 stage (HR=1.94, 95% CI 1.35-2.79; p=0.005),
together ~25% of pts, also were independently prognostic. 5FU/LV benefit was
significant (p<0.001). However, TS was not validated as a predictor of 5FU/LV
benefit (interaction p=0.19). Conclusions: The colon cancer recurrence score is a
validated, independent predictor of individualized recurrence risk for stage II colon
cancer patients following surgery.
Stage-specific prognostic value of molecular markers in colon cancer:
Results of the translational study on the PETACC 3-EORTC 40993-
SAKK 60-00 trial.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4002
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4002)
Author(s):
A. D. Roth, S. Tejpar, P. Yan, R. Fiocca, D. Dietrich, M. Delorenzi, R. Labianca, D. Cunningham, E. Van
Cutsem, F. Bosman; Geneva University Hospital, Geneva, Switzerland; University Hospital Gathuisberg,
Leuven, Belgium; Lausanne University, Lausanne, Switzerland; University of Genova, Genova, Italy; Swiss
Group of Cancer Research (SAKK), Bern, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne,
Switzerland; Ospedali Riuniti, Bergamo, Italy; The Royal Marsden Hospital, Sutton, United Kingdom
Abstract:
Background: We compared the incidence of molecular markers in stage II (SII) and
III (SIII) colon cancer and tested their prognostic value per stage, using PETACC 3,
an adjuvant trial with 3,278 patients. We included expression of P53, SMAD4,
thymidylate synthetase (TS) and hTERT, mutations of KRAS and BRAF, microsatellite
instability (MSI) and 18qLOH. Methods: 1,564 formalin fixed paraffin embedded
tissue blocks were prospectively collected and DNA from normal and tumor tissue
was extracted after macrodissection. High P53, TS and hTERT expression and
SMAD4 loss were assessed by immunohistochemistry. MSI was studied with 10
markers. KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific
real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs. Prognostic value of
the markers was analysed per stage by Cox regression for Relapse Free Survival
(RFS). Results: marker frequencies and stage specific p-values in prognostic
models in 420 SII and 984 SIII patients are listed in the table. Significant differences
in frequency per stage were found for all markers except KRAS and BRAF. An
interaction test for differences between marker prognostic value for SII and SIII was
significant for MSI (p=0.04) and 18qLOH (p=0.04) in SII. Multivariate analysis
including markers, T stage, N stage (for SIII), Tu grade, age <60, sex, treatment
arm, and Tu site found T stage (p=0.0001) and MSI (p=0.02) as independently
significant clinical predictors in SII; N stage (p<0.0001), T stage (p<0.0001), SMAD4
(p<0.0001) and P53 (p=0.01) in SIII. Conclusions: Molecular markers in colon
cancer have a stage specific prognostic value. The possibility that the stages
represent different diseases, rather than sequential steps in the evolution of a single
disease, needs to be considered.

Marker alteration Prognostic


frequency(%) value*
S II S III p value S II S III
MSI-H 22 12 <0.0001 0.004 0.06
P53 30 37 0.009 0.99 0.02
TS 43 29 <0.0001 0.02 0.03
SMAD 9 13 0.02 0.73 <0.0001
Marker alteration Prognostic
frequency(%) value*
S II S III p value S II S III
4
18qL 63 70 0.04 0.03 0.91
OH
hTER 40 48 0.06 0.32 0.006
T
KRAS 36 37 n.s. 0.79 0.69
BRAF 8 8 n.s. 0.89 0.26

A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus


bevacizumab in stage II or III carcinoma of the colon: Results of
NSABP Protocol C-08.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4)
Author(s):
N. Wolmark, G. Yothers, M. J. O'Connell, S. Sharif, J. N. Atkins, T. E. Seay, L.
Feherenbacher, S. O'Reilly, C. J. Allegra; Allegheny General Hospital, Pittsburgh, PA;
University of Pittsburgh; National Surgical Adjuvant Breast and Bowel Project;
National Surgical Adjuvant Breast and Bowel Project, Allegheny General Hospital;
Southeast Cancer Control Consortium; Atlanta Cancer Care; Kaiser Permanente,
Northern California, Vallejo; All Ireland Clinical Oncology Research Group; University
of Florida
Abstract:
Background: The primary aim of this two-arm randomized prospective study was
to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong
disease-free survival (DFS) compared to mFOLFOX6 (mFF6)
alone. Methods: Between September 2004 and October 2006, 2,672 patients with
follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma
of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m2 IV d1,
leucovorin 400 mg/m2 IV d1, 5-FU 400 mg/m2 IV bolus d1, and 5-FU 2400 mg/ m2 CI
over 46 hrs (d1+2) q14d x 12 cycles) or mFF6+B (same mFF6 regimen +
bevacizumab 5 mg/kg IV q 2 wks x 1 yr). The primary end point was DFS. Events
were defined as first recurrence, second primary cancer, or death. Results: The
median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B
vs. mFF6) was 0.89; 95% CI (0.76-1.04); p=0.15. Data censored at intervals
disclosed an initial benefit for bevacizumab that diminished over time: The
smoothed estimate of the DFS HR over time indicated that bevacizumab
significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year.
There was no evidence that patients receiving bevacizumab had a worse DFS
compared to those receiving mFF6 alone following treatment.Conclusions: The
addition of bevacizumab to mFF6 did not result in an overall statistically significant
prolongation in DFS. There was a transient benefit in DFS during the one-year
interval that bevacizumab was utilized. Consideration may be given to clinical trials
assessing longer duration of bevacizumab administration. Supported by PHS grants
U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from
Genentech, Inc.

3yD
N Ev FS P Yr 1 1.5 2 2.5 3
mFF6 133 31 75.5 H 0.60 0.74 0.8 0.8 0.8
8 2 R 1 5 7
mFF6 133 29 77.4 0.1 P 0.000 0.00 0.0 0.0 0.0
+B 4 1 5 4 4 2 5 8
Use of two-year disease-free survival (DFS) as a primary endpoint in
stage III adjuvant colon cancer trials with fluoropyrimidines with or
without oxaliplatin or irinotecan: New data from 12,676 patients
from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4011
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4011)
Author(s):
D. J. Sargent, G. Yothers, E. Van Cutsem, J. Cassidy, L. Saltz, N. Wolmark, Q. Shi, M.
Buyse, A. de Gramont, The Adjuvant Colon Cancer Endpoints (ACCENT) Group; Mayo
Clinic, Rochester, MN; NSABP Biostatistical Center, Pittsburgh, PA; University
Hospital Gasthuisberg/Leuven, Leuven, Belgium; Cancer Research UK, Glasgow,
United Kingdom; Memorial Sloan-Kettering Cancer Center, New York, NY; Allegheny
General Hospital, Pittsburgh, PA; IDDI, Louvian-La-Neuve, Belgium; Hospital Saint
Antoine, Paris, France
Abstract:
Background: The ACCENT group previously validated DFS with 3 years (yr) median
follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx)
(3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS)
(Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a
stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and
(3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials
due to extended survival following recurrence (de Gramont ASCO 2008). The
relationship between endpoints in more recent trials with oral fluoropyrimidines,
oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr
DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997-
2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2
irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard
ratios (HRs) via weighted least squares (WLS), and concordance between predicted
and actual within-trial HRs, were calculated overall and for stage III
pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced
compared to the prior ACCENT analysis (Table). In stage III pts, the association
between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were
predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction
limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS
HRs.Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-
up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS
and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data
support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that
2yr DFS would also be an appropriate primary endpoint.
Association of HRs for DFS and OS, overall and for stage III pts
All Pts Stage III Pts
Previous Previous
DFS Time ACCENT New Trials ACCENT New Trials
Point 5 yr OS 6 yr OS 5 yr OS 6 yr OS 5 yr OS 6 yr OS 5 yr OS 6 yr OS
2 yr DFS 0.78 0.85 0.59 0.77 0.82 0.89 0.91 0.91
3 yr DFS 0.86 0.91 0.62 0.77 0.88 0.94 0.93 0.89
Table provides trial level R2 from WLS; R2 ranges 0-1; values close to 1 indicate
better agreement
Use of two-year disease-free survival (DFS) as a primary endpoint in
stage III adjuvant colon cancer trials with fluoropyrimidines with or
without oxaliplatin or irinotecan: New data from 12,676 patients
from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4011
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4011)
Author(s):
D. J. Sargent, G. Yothers, E. Van Cutsem, J. Cassidy, L. Saltz, N. Wolmark, Q. Shi, M. Buyse, A. de
Gramont, The Adjuvant Colon Cancer Endpoints (ACCENT) Group; Mayo Clinic, Rochester, MN; NSABP
Biostatistical Center, Pittsburgh, PA; University Hospital Gasthuisberg/Leuven, Leuven, Belgium;
Cancer Research UK, Glasgow, United Kingdom; Memorial Sloan-Kettering Cancer Center, New York,
NY; Allegheny General Hospital, Pittsburgh, PA; IDDI, Louvian-La-Neuve, Belgium; Hospital Saint
Antoine, Paris, France
Abstract:Background: The ACCENT group previously validated DFS with 3 years (yr) median
follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an
endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT
further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in
stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS
association in future trials due to extended survival following recurrence (de Gramont ASCO 2008).
The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and
irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was
examined in 6 randomized phase III trials from 1997-2002. Individual data for 12,676 pts was
analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association
between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance
between predicted and actual within-trial HRs, were calculated overall and for stage III
pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the
prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained
strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts
(within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs
5yr OS HRs.Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are
highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger
for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for
modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint.

Association of HRs for DFS and OS, overall and for stage III pts
All Pts Stage III Pts
DFS Previous Previous
Time ACCENT New Trials ACCENT New Trials
Point 5 yr OS 6 yr OS 5 yr OS 6 yr OS 5 yr OS 6 yr OS 5 yr OS 6 yr OS
2 yr DFS 0.78 0.85 0.59 0.77 0.82 0.89 0.91 0.91
3 yr DFS 0.86 0.91 0.62 0.77 0.88 0.94 0.93 0.89
Table provides trial level R2 from WLS; R2 ranges 0-1; values close to 1 indicate
better agreement
Preoperative fluorouracil (FU)-based chemoradiation with and
without weekly oxaliplatin in locally advanced rectal cancer:
Pathologic response analysis of the Studio Terapia Adiuvante Retto
(STAR)-01 randomized phase III trial.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA4008
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA4008)
Author(s):
C. Aschele, C. Pinto, S. Cordio, G. Rosati, A. Tagliagambe, S. Artale, P. Rosetti, S.
Lonardi, L. Boni, L. Cionini, on behalf of STAR Network Investigators; E. O. Galliera,
Genova, Italy; A.O. S. Orsola Malpighi, Bologna, Italy; S. Luigi Santo Currò, Catania,
Italy; A.O. S. Carlo, Potenza, Italy; A.S.L. 1 , Carrara, Italy; Ospedale Niguarda Ca'
Granda, Milano, Italy; Ospedale Morgagni-Pierantoni, Forlì, Italy; Istituto Oncologico
Veneto, Padova, Italy; Istituto Toscano Tumori, Firenze, Italy; A.O. S. Chiara, Pisa,
Italy
Abstract:
Background: Oxaliplatin (OXA) enhances the efficacy of FU-based chemotherapy in
colon cancer. This randomized phase III trial investigated the effect of adding OXA
to preoperative (preop) FU-based pelvic chemoradiation (CRT) in patients (pts) with
locally-advanced rectal cancer. Methods: Eligibility required a resectable, biopsy-
proven rectal adenocarcinoma within 12 cm from the anal verge with radiological
evidence of perirectal fat or lymphnode involvement. Randomization was between
infused FU (225 mg/msq/day) concomitant to external-beam pelvic radiation (50.4
Gy in 28 daily fractions) (arm A) or the same regimen + weekly OXA (60 mg/msq x
6) (Arm B). Surgery was scheduled 6-8 weeks after completing CRT. Overall survival
was the primary endpoint. A protocol-planned analysis of local tumor response to
preop treatment (secondary end-point) is the object of this report. Results: 747 pts
from 41 Italian centers were randomized between 12/2003 and 8/2008 (arm A/B:
379/368). Pretreatment characteristics in arm A/B: median age 63/62 years;
male:female 2:1; median distance from anal verge 6 cm; T4 16/14%, N+ 63/65%.
Overall grade 3-4 toxicity rates on treated pts (mainly diarrhoea) were 8% and 24%
(arm A/B, p<0.001). 96/90% of pts (arm A/B) received > 90% of the planned RT.
82% of Arm B pts had > 5 oxa courses. 358/342 pts (arm A/B) had surgery at a
median of 52/53 days from the end of CRT, 14 pts in each arm were not operated
(progression 8, death 5, other/unknown 15) and surgery data are not yet available
for 19 pts. Pathologic response data analyzed on the randomized population are
reported in the table. Conclusions: The addition of weekly OXA to standard FU-
based preop CRT significantly increases toxicity without affecting local tumor
response. The reduced pathologic M+ rate suggests a potential effect on distant
micrometastases. Longer follow-up is needed to assess the impact on efficacy
endpoints.

Pathologic Arm A (N=379) Arm B (N=368) Total (N=747) P


stage pts (%) pts (%) pts (%) value
T0N0 60 (16) 57 (15) 117 (16) 0.982
Pathologic Arm A (N=379) Arm B (N=368) Total (N=747) P
stage pts (%) pts (%) pts (%) value
T1-2N0 104 (27) 103 (28) 207 (28)

N1-2 92 (24) 96 (26) 188 (25) 0.568

M1 11 (3) 2 (0.5) 13 (2) 0.014

Randomized multicenter phase III trial comparing two neoadjuvant


chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in
patients (pts) with locally advanced rectal cancer (LARC): Results of the
ACCORD 12/0405 PRODIGE 2.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4007
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4007)
Author(s):
J. Gerard, D. Azria, S. Gourgou-Bourgade, I. Martel-Laffay, C. Hennequin, P. Etienne,
V. Vendrely, T. Conroy, E. Francois, C. Montoto-Grillot; Centre Antoine Lacassagne,
Nice, France; Centre Val d'Aurelle, Montpellier, France; Centre Léon Bérard, Lyon,
France; Hôpital St Louis, Paris, France; Clinique Armoricaine de Radiologie, St.
Brieuc, France; Hôpital St André, Bordeaux, France; Centre Alexis Vautrin, Nancy,
France; FNCLCC-BECT, Paris, France
Abstract:
Background: Following the results of randomized trials FFCD 9203 and EORTC
2291, neoadjuvant CT-RT is considered standard treatment for LARC. The ACCORD
12/0405 PRODIGE 2 trial was initiated to optimize this regimen. Methods: Pts with
T3 or resectable T4 N0-1-2 M0, rectal adenocarcinoma were randomized to arm A:
concurrent RT 45Gy/25f/5 weeks (w) + capecitabine (800mg/m²/bid) or arm B:
concurrent RT 50Gy/25f/5w + capecitabine (800mg/m²/bid/5/7days) + oxaliplatine
50mg/m²/w. Resection with Total Mesorectum Excision was scheduled 6 weeks after
the end of CT-RT. Adjuvant chemotherapy was optional. 590 patients were needed
to show an increase in the pathological complete response (Dworak) rate from 11%
(arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was
defined as the presence of residual cancer cells within 0 to 1 mm from the perirectal
surface. Results:This trial closed in 07/2008 after randomization of 598 pts since
11/2005. Patients characteristics of 586 eligible pts were well balanced: male 66%,
median age 61 years, 66% low rectum, 87% T3 stage. Data base was locked in
March 2009. Results are reported in Table. Conclusions: The RT 50 capox regimen
is compatible with surgery in 98% of cases with no increase in postoperative
complication. In the RT 50 arm, there is a trend in favour of a higher rate of
pathological complete sterilization and lower rate of positive CRM. These data could
contribute to design a new standard preoperative regimen for LARC. 50 Gy/25 F/5
weeks combined with concurrent chemotherapy could be proposed as an efficient
schedule.
Arm A RT 45-Cap Arm B RT 50-
Eligible patients (295) Capox (291)
Preop Grade 3/4 all 32 (11%) 73 (25%) p: < 0.001
toxicity
Surgery performed 289 (98%) 287 (98.6%)
Sphincter saving 218 (75%) 223 (78%)
surgery
Postop death (60 1 (0.3%) 1 (0.3%)
days)
yp M1 (abdomen) 12 (4%) 8 (2.8%)
CRM R1 18 (11%) 9 (6%) p: 0.12
yp CR (Dworak) 40 (13.8%) 54 (18.8%) p: 0.11
Evaluation of the effect of intravenous calcium and magnesium
(CaMg) on chronic and acute neurotoxicity associated with
oxaliplatin: Results from a placebo-controlled phase III trial.

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4025
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4025)
Author(s):
A. Grothey, D. A. Nikcevich, J. A. Sloan, J. W. Kugler, P. T. Silberstein, T. Dentchev, D.
B. Wender, H. E. Windschilt, X. Zhao, C. L. Loprinzi; Mayo Clinic Rochester,
Rochester, MN; St Mary's Duluth Clinic, Duluth, MN; lllinois CancerCare, Peoria, IL;
Creighton Hem Onc, Omaha, NE; Altru Health Systems, Grand Forks, ND; Siouxland
Hematology-Oncology Associates, Sioux City, IA; CentraCare Clinic, St. Cloud, MN
Abstract:
Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which
commonly leads to early discontinuation of oxaliplatin-based therapy in the
palliative and adjuvant setting. We recently demonstrated the protective effect of
CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO
2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative
sNT.Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX
were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre-
and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an
oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires
were used to differentially assess the effect of CaMg on acute (effect on sNT on
days 1-4 after oxaliplatin) and chronic sNT (area between curves over whole course
of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6
FOLFOX4) were available for analysis. Apart from a strong reduction in muscle
cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO
with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold
liquids, throat discomfort) on days 1-4 after oxaliplatin of any treatment cycle. In
contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness
in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers
(p=0.06), and muscle cramps over the course of therapy (p=0.01).Conclusions: In
our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic,
cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires.
No effect was noted on phenomena associated with acute sNT. CaMg can be
recommended as neuroprotectant against oxaliplatin-related chronic sNT,
oxaliplatin's dose-limiting toxicity.
Randomized phase II study of picoplatin in combination with 5-
fluorouracil and leucovorin (FOLPI) as a neuropathy-sparing
alternative to modified FOLFOX-6 as first-line therapy for colorectal
cancer (CRC).

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4026
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4026)
Author(s):
R. Earhart, S. Cheporov, O. Gladkov, M. Biakhov, H. Breitz, R. De Jager; Poniard
Pharmaceuticals, South San Francisco, CA; Regional Clinical Oncology Hospital,
Yaroslavl, Russian Federation; Chelyabinsk Regional Oncology Center, Chelyabinsk,
Russian Federation; Semashko Central Clinical Hospital #2 , Moscow, Russian
Federation
Abstract:
Background: Picoplatin (Pico) was designed to overcome platinum resistance and
has the potential for improved safety compared to other platinum agents. FOLFOX
(5-FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose-limiting oxali-
related neurotoxicity. The incidence of grade (G) 3-4 neurotoxicity with single-agent
Pico across studies was <2%, suggesting that Pico may provide a neuropathy-
sparing alternative to oxali. A Phase I trial identified the Pico MTD at 150
mg/m2 when infused Q4W with Q2W FU/LV. The present study evaluates Pico when
administered Q4W with Q2W FU and LV (FOLPI) vs. modified (m) FOLFOX-6
(FOLFOX) as 1st line treatment for patients (pts) with advanced
CRC. Methods:Each pt received LV and infusional FU per mFOLFOX-6 Q2W. Pts with
no prior chemotherapy for advanced CRC received Pico Q4W (150 mg/m2) or oxali
Q2W (85 mg/m2). Tumor response was assessed by RECIST using CT scans. Adverse
events (AEs) were assessed with CTCAE. Neuropathy was assessed using the FACT-
Neurotoxicity questionnaire and by a neurologist blinded to treatment.Results: 101
pts were randomized (50 to FOLPI, 51 to FOLFOX). Pts have received 213 (median 4,
max 11) 4-week cycles of FOLPI and 414 (median 8, max 21) 2-week cycles of
FOLFOX. Median dose intensity of Pico = 28 mg/m2/wk (range 19-44); mean relative
dose intensity = 77%. Median dose intensity of oxali = 36 mg/m2/wk (range 28-43);
mean relative dose intensity = 86%. Neurotoxicity was observed in 65% of pts on
FOLFOX (10% G 3/4) and 28% of pts on FOLPI (no G 3/4). Most frequent G 3/4 AEs
on FOLPI were neutropenia (60%), thrombocytopenia (40%) and anemia (14%). In
the FOLFOX arm, other than neuropathy, the most frequent G 3/4 AEs were
neutropenia (20%) and thrombocytopenia (12%). Disease control (CR+PR+SD) was
76% for FOLPI and 76% for FOLFOX. In the FOLPI arm there were 1 CR (2%) and 11
PR (22%). In the FOLFOX arm there were no CRs and 13 PR (26%).Conclusions: In
this ongoing trial, FOLPI with Pico Q4W shows comparable disease control as
measured by RECIST compared to FOLFOX. Neurotoxicity was less frequent and less
severe in the FOLPI arm compared to the FOLFOX arm. Pico therefore may be a
neuropathy-sparing alternative to oxaliplatin in CRC.
Cáncer de ano
A randomized trial of chemoradiation using mitomycin or cisplatin,
with or without maintenance cisplatin/5FU in squamous cell
carcinoma of the anus (ACT II).

Sub-category:
Colorectal Cancer (including liver metastases)
Category:
Gastrointestinal (Colorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4009
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009)
Author(s):
R. James, S. Wan, R. Glynne-Jones, D. Sebag-Montefiore, L. Kadalayil, J. Northover,
D. Cunningham, H. Meadows, J. Ledermann, National Cancer Research Institute
(NCRI) ACT II Trial Management Group; Maidstone General Hospital, Maidstone,
United Kingdom; Cancer Research UK & UCL Cancer Trials Centre, London, United
Kingdom; Mount Vernon Hospital, Northwood, United Kingdom; St. James's
University Hospital, Leeds, United Kingdom; St. Mark's Hospital, London, United
Kingdom; The Royal Marsden Hospital, London, United Kingdom
Abstract:
Background: Chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C
(MMC) is standard treatment for anal cancer. This trial addresses two questions:
whether (i) replacing MMC with cisplatin (CDDP) improves the complete response
(CR) rate, and (ii) two cycles of maintenance chemotherapy after CRT reduces
recurrence. Methods: Between 2001 and 2008, 940 patients (pts) were recruited to
a multicenter, randomized factorial trial. Pts received 5-FU (1,000mg/m2/day on d1-
4 and 29-32), radiotherapy (RT) (50.4Gy in 28 fractions), and either MMC (12mg/m2,
d1; n=471) or CDDP (60mg/m2 on d1 and 29; n=469). Pts were also randomized to
receive maintenance therapy (n=448) 4 weeks after CRT (two cycles of CDDP and
5-FU weeks 11 and 14) or no maintenance (n=446). Maintenance randomization
was not considered appropriate in 46 pts. Statistical power was ≥80% to detect a
difference in the CR rate of 5% (CDDP vs MMC), and 30% reduction in recurrence
(maintenance vs no maintenance). Results:Median age 58 yrs; 62% male, 38%
female; tumor site - canal (81%), margin (15%); stage T1-T2 (50%), T3-T4 (43%);
node negative (62%), positive (30%). Median follow-up was 3 yrs. The CR rate was
94% MMC and 95% CDDP (p=0.53). MMC pts had more acute grade 3/4
haematological toxicities (25 vs 13%, p<0.001) but this did not result in an increase
in neutropaenic sepsis (3.1 vs 3.2%, p=0.93). Non-haematologic grade 3/4 toxicities
were similar (61 vs 65%, p=0.22). Preliminary analysis shows no statistically
significant difference in recurrence free survival (RFS) (HR 0.89, 95% CI 0.68, 1.18;
p=0.42) or overall survival (HR 0.79, 95% CI 0.56,1.12; p=0.19) for the
maintenance comparison. The number of pre-treatment colostomies not reversed
were similar between treatments (18 MMC vs 14 CDDP, p=0.65, Maint/No maint,
p=0.23) and only 9 disease-free pts had colostomies performed (5 MMC, 4
CDDP).Conclusions: ACT II is the largest trial conducted in anal cancer. High CR
(95%) and RFS (75% at 3 yrs) rates were achieved with this CRT. This excellent
outcome may have been influenced by the absence of a gap in the RT schedule.
There was no difference in CR rates between MMC and CDDP or in RFS rates with or
without maintenance chemotherapy. 5-FU, MMC with RT remains the standard of
care.
Cáncer de Páncreas
ESPAC-3(v2): A multicenter, international, open-label, randomized,
controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-
FU/FA) versus gemcitabine (GEM) in patients with resected
pancreatic ductal adenocarcinoma.

Sub-category:
Pancreatic Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4505
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4505)
Author(s):
J. Neoptolemos, M. Büchler, D. D. Stocken, P. Ghaneh, D. Smith, C. Bassi, M. Moore,
D. Cunningham, C. Dervenis, D. Goldstein; University of Liverpool, Liverpool, United
Kingdom; University of Heidelberg, Heidelberg, Germany; University of
Birmingham , Birmingham, United Kingdom; Clatterbridge Centre for Oncology,
Wirral, United Kingdom; University of Verona, Verona, Italy; Princess Margaret
Hospital, Toronto, ON, Canada; The Royal Marsden Hospital, London, United
Kingdom; Agia Olga Hospital, Athens, Greece; Prince of Wales Hospital, Sydney,
Australia
Abstract:
Background: Adjuvant 5-FU/FA (ESPAC-1 trial) and GEM (CONKO-001 trial) provide
improved survival for patients with resected pancreatic cancer compared to no
chemotherapy. The aim of the ESPAC-3 (v2) trial was to compare 5FU/FA vs GEM to
identify if either adjuvant chemotherapy was associated with a significantly better
survival. Methods: Patients with an R0/R1 resection for pancreatic ductal
adenocarcinoma were randomized (stratified for resection margin status and
country) <8 weeks of surgery to receive either 5FU/FA (FA, 20 mg/m2, iv bolus
injection followed by 5-FU, 425 mg/m2, iv bolus injection given 1-5d every 28 days)
or GEM (1,000mg/m2 iv infusion 1d, 8d and 15d every 4 weeks) for 6 months. The
primary outcome measure was overall survival; the secondary measures were
toxicity, progression free survival and quality of life. 1,030 patients were needed to
detect a 10% difference in 2-year survival rates with 90% power. Results: 1,088
patients from 16 countries were randomized from July 2000 to Jan 2007 (5FU/FA =
551, GEM = 537). Median (range) age was 63 (31-85) years; 598 (55%) were men.
Median tumor size was 30 (20-350) mm; 384 (35%) were R1 resections; 777 (72%)
were node positive; and 263 (25%) were poorly differentiated tumors. Final analysis
was carried out on an intention to treat basis with a minimum of 2 years follow-up
after 753 (69%) patients had died. Median (IQR) follow-up of 335 alive patients was
34.2 (27.1-43.4) months, equal across treatment groups. Median survival from
resection of patients treated with 5FU/FA was 23.0 (95% CI: 21.1, 25.0) months and
for patients treated with GEM this was 23.6 (95%CI: 21.4, 26.4) months. Log-rank
analysis revealed no statistically significant difference in survival estimates between
the treatment groups (c2LR=0.7, p=0.39, HRGEM=0.94 (95%CI: 0.81, 1.08)). There
was no significant difference in the effect of treatment across subgroups according
to R status (test of heterogeneity c21=0.3, p=0.56). Conclusions: This is the largest
adjuvant trial ever conducted for pancreatic ductal adenocarcinoma and showed no
significant difference in survival between adjuvant 5FU/FA and adjuvant GEM.
A randomized trial of gemcitabine (G) versus G plus cisplatin in
chemotherapy-naive advanced pancreatic adenocarcinoma: The GIP-
1 (Gruppo Italiano Pancreas— GOIM/GISCAD/GOIRC) study.

Sub-category:
Pancreatic Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4504
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4504)
Author(s):
G. Colucci, R. Labianca, F. Di Costanzo, V. Gebbia, G. Cartenì, B. Massidda, L.
Frontini, M. Falconi, C. Gallo, M. Di Maio; National Cancer Institute, Bari, Italy;
Ospedali Riuniti, Bergamo, Italy; Azienda Ospedaliero-Universitaria Careggi, Firenze,
Italy; Università di Palermo, Casa di Cura La Maddalena, Palermo, Italy; Cardarelli
Hospital, Napoli, Italy; Policlinico Universitario, Cagliari, Italy; San Gerardo Hospital,
Monza, Italy; University of Verona, Policlinico G.B. Rossi, Verona, Italy; Seconda
Università , Napoli, Italy; National Cancer Institute, Napoli, Italy
Abstract:
Background: Single-agent gemcitabine (G) remains standard treatment for
advanced pancreatic adenocarcinoma (APC). The GIP-1 randomized phase III trial
(clinicaltrials.gov ID NCT00813696) was performed to compare the combination of
cisplatin (P) and G vs. G alone as 1st-line treatment. Methods:Patients (pts) with
locally advanced and/or metastatic pancreatic adenocarcinoma, age 18-75,
Karnofsky Performance Status (KPS) ≥50, were randomized to receive G (arm A) or
G+P (arm B). In arm A, G was administered at 1000 mg/m2 weekly for 7
consecutive wks, and, after a 2-week rest, on day 1, 8, 15 every 4 wks. In Arm B, P
25 mg/m2 weekly (with the exception of day 22) was added to G, same dose used
in Arm A (Colucci et al, Cancer 2002; 94:902-10). No maximum number of cycles
was planned. Primary endpoint was overall survival (OS). Clinical benefit (CB),
objective response rate (ORR), progression-free survival (PFS), toxicity and quality
of life were secondary endpoints. To have 80% power of detecting a 0.74 Hazard
Ratio (HR) of death (corresponding to increase in median OS from 4.8 to 6.5
months, with bilateral alpha=0.05, 400 pts were planned and 355 deaths were
required for final analysis. Results: From April 2002 to April 2007, 400 pts were
enrolled (A:199, B; 201) in 46 Italian Institutions. Median age was 63 yrs (range 35-
75), 59% were males, 84% stage IV, 83% KPS≥80. After a median follow-up of 38.2
months and 357 deaths, median OS was 8.3 vs 7.2 months in arm A and B,
respectively (HR 1.10, 95% CI 0.89-1.35, p=0.38). Median PFS was 3.9 vs 3.8
months in arm A and B, respectively (HR 0.97, 95% CI 0.80-1.19, p=0.80). ORR was
10.1% in arm A and 12.9% in B (p=0.37). CB response was experienced by 23.0%
and 15.1% (Arm A vs B, p=0.057). Patients assigned to combination arm
experienced more anaemia (all grades: 50% vs 39%, G3: 5% vs 1%), more
neutropenia (all grades: 44% vs 36%, G3&4: 25% vs 14%) and more
thrombocytopenia (all grades: 57% vs 29%, G3&4: 16% vs 5%). No relevant
differences were seen in non-haematological toxicity. Conclusions: Weekly
combination of P and G, compared to single-agent G as 1st-line treatment of APC,
failed to demonstrate any improvement in OS, PFS, ORR and clinical benefit.
A prospective, randomized trial of chemotherapy with or without the
low molecular weight heparin (LMWH) enoxaparin in patients (pts)
with advanced pancreatic cancer (APC): Results of the CONKO 004
trial.

Sub-category:
Pancreatic Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4506
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Author(s):
H. Riess, U. Pelzer, G. Deutschinoff, B. Opitz, M. Stauch, P. Reitzig, S. Hahnfeld, A.
Hilbig, J. Stieler, H. Oettle; Universitätsmedizin Berlin - Charité, Berlin, Germany;
Hospital, Hagen, Germany; Hospital-St. Elisabeth & St. Barbara, Halle, Germany;
Outpatient Department, Kronach, Germany; Sana Hospital , Berlin-Lichtenberg,
Germany; Outpatient Department, Jena, Germany
Abstract:
Background: The course of pts with APC is often complicated by venous
thromboembolic events (VTE). Anticoagulation therapy with LMWH may prevent VTE
and is under discussion to improve overall survival (OS) in cancer. Based on our
previous pilot study (Hilbig et al, Onkologie 2005;28(suppl 3)) indicating the safety
and feasibility to the addition of the LMWH enoxaparin to chemotherapy in pts with
APC we started the open, prospective, randomized, multicenter study to investigate
the role of enoxaparin in these pts.Methods: Primary endpoint was the reduction of
symptomatic VTE (sVTE) from an expected 10% to 3% within the first 12 weeks of
treatment. The occurrence of sVTE (secured by an independent, blinded event
review board) in 24 pts was calculated to be necessary in order to define the role of
enoxaparin in decreasing the risk of VTE. Toxicity, time to progression (TTP), and OS
were among the secondary endpoints of the study approved by the ethics
committees of the participating centers. VTE-naive and chemotherapy-naive pts
with histologically or cytologically confirmed APC were randomized to receive or not
to receive additional LMWH (enoxaparin 1mg/kg once daily) starting in parallel to
palliative systemic chemotherapy. Results: In January 2009 after recruitment of
312 pts the study was closed. There were 22 sVTE in 152 pts of the observation
group (O) and 8 in 160 pts of the enoxaparin group (E). ITT and PP analyses
demonstrated significant risk reductions from 14.5% to 5.0% (65% RRR) and 14.5%
to 3.8% (74% RRR) for E, respectively. Major bleeding events were 9.9% for O and
6.3% for E (ITT; n.s.). In each group there was one tumor-related fatal hemorrhage.
Preliminary data show no difference in TTP (O:19 vs. E:22 w) and OS (O:29 vs. E:31
w). Conclusions: Enoxaparin is effective and safe in the primary prevention of
sVTE applied in parallel with cytotoxic chemotherapy in pts with APC. Final results
on TTP and OS are pending.
Cáncer biliar avanzado
Gemcitabine with or without cisplatin in patients (pts) with advanced
or metastatic biliary tract cancer (ABC): Results of a multicenter,
randomized phase III trial (the UK ABC-02 trial).

Sub-category:
Hepatobiliary Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4503
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4503)
Author(s):
J. W. Valle, H. S. Wasan, D. D. Palmer, D. Cunningham, D. A. Anthoney, A.
Maraveyas, S. K. Hughes, M. Roughton, J. A. Bridgewater; Christie Hospital NHS
Trust, Manchester, United Kingdom; Imperial College Healthcare Trust, London,
United Kingdom; University of Birmingham , Birmingham, United Kingdom; Royal
Marsden Hospital, London, United Kingdom; St. James' University Hospital, Leeds,
United Kingdom; Castle Hill Hospital, Hull, United Kingdom; University College
London, London, United Kingdom
Abstract:
Background: There is no established standard chemotherapy for pts with
inoperable ABC. We previously reported an improvement in progression-free
survival (PFS) in a randomised phase II trial of 86 pts (ABC-01) using
gemcitabine/cisplatin (GemCis) vs. gemcitabine (Gem) (Valle ASCO-GI 2006, abstr.
98). This study was extended into ABC-02, a phase III trial, to recruit a further 314
pts with overall survival (OS) as the primary end-point. Methods: Consenting pts
with histologically/cytologically-confirmed ABC, aged ≥18 years, ECOG performance
status 0 - 2, and adequate haematological, hepatic and renal function were
randomised to receive either Cis (25 mg/m2) followed by Gem (1000 mg/m2 D1, 8
q21d) for 8 cycles, or Gem alone (1000 mg/m2 on D1, 8, 15 q28d) for 6 cycles,
stratified by extent of disease, site of primary tumour, ECOG score and centre. The
trial had an 80% power to detect an OS hazard ratio of 0.73.Results: From May
2005 to October 2008, 324 pts were randomised to ABC- 02 from 34 UK centres. We
report the pre-planned combined analysis of ABC-01 and ABC-02 based on 410 pts
(GemCis=206/Gem=204). Patient characteristics: median age 64 yrs (range 23-85);
male (47%); metastatic disease (75%), locally advanced (25%); gallbladder (36%),
bile duct (59%), ampulla (5%); and ECOG 0-1 (87%), 2 (12%). With a median follow-
up of 6.1 months and 263 deaths, the median OS was greater with GemCis than
Gem, 11.7 vs. 8.2 months (log rank p=0.002), with hazard ratio 0.68 (95%-CI 0.53,
0.86). The median PFS was greater with GemCis than Gem, 8.5 vs. 6.5 months (log
rank p=0.003), with hazard ratio 0.70 (95%-CI 0.56, 0.88).Toxicity was similar
between the arms (by week 12, 57% had a grade 3/4 toxicity in each arm), though
there was a slight excess of neutropenia using GemCis.Conclusions: This is the
largest ever study in ABC and demonstrates a clear survival advantage for GemCis
without added clinically significant toxicity, setting a new international standard of
care.
Cáncer de Estómago
Efficacy results from the ToGA trial: A phase III study of trastuzumab
added to standard chemotherapy (CT) in first-line human epidermal
growth factor receptor 2 (HER2)-positive advanced gastric cancer
(GC).

Sub-category:
Esophageal, Gastric, or Small Bowel Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA4509
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4509)
Author(s):
E. Van Cutsem, Y. Kang, H. Chung, L. Shen, A. Sawaki, F. Lordick, J. Hill, M. Lehle, A.
Feyereislova, Y. Bang; University Hospital Gasthuisberg, Leuven, Belgium; Asan
Medical Center, Seoul, Republic of Korea; Yonsei University College of Medicine ,
Seoul, Republic of Korea; Peking University School of Oncology, Beijing, China; Aichi
Cancer Center, Nagoya, Japan; National Centre for Tumour Diseases, Heidelberg,
Germany; Roche Products Pty Ltd, Dee Why, New South Wales, Australia; F.
Hoffmann-La Roche Ltd, Basel, Switzerland; Seoul National University Hospital,
Seoul, Republic of Korea
Abstract:
Background: Advanced GC is an incurable disease; new and less toxic treatments
are needed. HER2 overexpression has been reported in 6-35% of stomach and
gastroesophageal tumors. Trastuzumab (H; Herceptin), a monoclonal antibody
against HER2, has shown survival benefits when given with CT in patients (pts) with
HER2-positive early and metastatic breast cancer. The ToGA study is the first
randomized, prospective, multicenter, phase III trial to study the efficacy and safety
of H in HER2- positive GC. Methods: Pts with HER2-positive gastroesophageal and
gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were
randomized to receive H+CT (5-fluorouracil or capecitabine and cisplatin) q3w for 6
cycles or CT alone. H was given until disease progression. The primary end point
was overall survival (OS); secondary end points included overall response rate
(ORR), progression-free survival, time to progression, duration of response, and
safety. An interim analysis was planned at 75% of deaths and the Independent Data
Monitoring Committee recommended releasing the data as the pre-specified
boundary was exceeded and median follow-up of pts was 17.1
months. Results: Tumors from 3,807 pts were centrally tested for HER2 status:
22.1% were HER2 positive (abstract #4556). 594 pts were randomized 1:1 at sites
in Europe, Latin America, and Asia. Baseline characteristics were well balanced
across arms. Median OS was significantly improved with H+CT compared to CT
alone: 13.5 vs. 11.1 months, respectively (p=0.0048; HR 0.74; 95% CI 0.60, 0.91).
ORR was 47.3% in the H+CT arm and 34.5% in the CT arm (p=0.0017). Safety
profiles were similar with no unexpected adverse events in the H+CT arm. There
was no difference in symptomatic congestive heart failure between arms.
Asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of
pts in the H+CT arm and 1.1% in the CT arm. Conclusions: This first randomized
trial investigating anti-HER2 therapy in advanced GC showed that H+CT is superior
to CT alone. The OS benefit indicates that H is a new, effective, and well-tolerated
treatment for HER2-positive GC.
Tumores Neuroendocrinos
Placebo-controlled, double-blind, prospective, randomized study of
the effect of octreotide LAR in the control of tumor growth in
patients with metastatic neuroendocrine midgut tumors: A report
from the PROMID study group.

Sub-category:
Other: Gastrointestinal (noncolorectal) Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2009 ASCO Annual Meeting
Abstract No:
4508
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 4508)
Author(s):
R. Arnold, H. Müller, C. Schade-Brittinger, A. Rinke, K. Klose, P. Barth, M. Wied, C.
Mayer, B. Aminossadati, PROMID Study Group; Philipps University, Marburg,
Germany
Abstract:
Background: Octreotide is currently used for the control of symptoms in patients
with gastroenteropancreatic neuroendocrine tumors (NETs). However, the ability of
long-acting somatostatin analogues to control the growth of well-differentiated
metastatic NETs is a matter of debate. The analysis of the first randomized, double-
blind, placebo-controlled, multicenter, phase IIIb study of octreotide LAR in patients
with metastatic NETs of the midgut is presented. Methods: Treatment-naïve
patients with histologically confirmed locally inoperable or metastasized well-
differentiated NETs and a Karnofsky index >60 were randomized to receive either
octreotide LAR 30 mg/month (mo) or placebo for 18 mos, or until tumor progression
or death. The primary endpoint was median time to tumor progression. Secondary
endpoints included objective tumor response rate (WHO criteria), measured every 3
mos, as well as symptom control and overall survival. This was a planned interim
analysis using the Lan-DeMets error spending approach. Results: Eighty-five
patients (n=43 octreotide LAR; n=42 placebo) have been enrolled to date and data
from 67 patients with tumor progressions and 16 deaths (n=7 octreotide LAR; n=9
placebo) are included here. Median time to tumor progression in the octreotide LAR
and placebo groups were 14.3 mos and 6 mos, respectively (HR: 0.34; 95% CI: 0.20-
0.59; P=0.000072). After 6 mos of treatment, stable disease was seen in 67% and
37.2% of patients treated with octreotide LAR and placebo, respectively. Due to the
low number of observed deaths, median survival time could not be
estimated. Conclusions: Octreotide LAR significantly lengthens median time to
tumor progression compared with placebo in patients with metastatic NETs of the
midgut. Patients treated with octreotide LAR had a 66% risk reduction of tumor
progression compared with patients receiving placebo. Octreotide LAR
demonstrates substantial tumor control and shows a more favorable
antiproliferative response than placebo as two-thirds of patients treated with
octreotide LAR achieved stable disease at 6 mos.
Melanoma
Ulceration of primary melanoma and responsiveness to adjuvant
interferon therapy: Analysis of the adjuvant trials EORTC18952 and
EORTC18991 in 2,644 patients.

Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2009 ASCO Annual Meeting
Abstract No:
9007
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 9007)
Author(s):
A. M. Eggermont, S. Suciu, A. Testori, P. Patel, A. Spatz, EORTC Melanoma Group; Erasmus University
Medical Center - Daniel den Hoed Cancer Center, Rotterdam, Netherlands; EORTC, Brussels, Belgium;
Istituto Europeo de Oncologia, Milano, Italy; University of Nottingham, Nottingham, United Kingdom;
McGill University, Montreal, QC, Canada
Abstract:
Background: Ulcerated (Ulc) melanomas have a worse prognosis than non-
ulcerated (N-Ulc) melanomas. Ulc and N-Ulc primaries have different stromal
characteristics and gene profiles reflecting differences in biology. We analyzed
outcome after adjuvant interferon (IFN) therapy in the 2 largest phase III trials
(EORTC18952 and 18991) ever conducted in stage IIB-III melanoma patients
(pts). Methods:EORTC18952 compared IFNα-2b (10 MIU, sc, qd, 5 days/wk, for 4
wks) followed by either 10MIU,sc, tiw for 12 mts, or 5MIU for 24 mts) with
observation in 1,388 stage IIB-III pts (Lancet 2005;366). EORTC18991 evaluated
pegylated IFNα-2b (6 µg/Kg, 1x/wk, for 8 wks followed by 3µg/Kg, 1x/wk for up to 5
yrs) versus observation in 1,256 stage III pts (Lancet 2008;372). Using meta-
analytical methods, predictive value for Ulc on the value of IFN on relapse-free
survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS)
was assessed, overall, and according to stage (IIB, III-N1 or N2=microscopic or
macroscopic-nodal disease). Results: Overall, the comparison (PEG-)IFNα-2b
versus observation regarding RFS, DMFS, and OS led to a reduction in the hazard
ratio (HR) of -16% (SE=5%), -13%(5%), and -8%(5%). Among 2,644 pts randomized,
849 had Ulc primaries, 1,336 N-Ulc primaries, and 459 Ulc unknown. In Ulc group
the impact was much greater than in N-Ulc group for RFS (Test For Interaction:
p=0.02), DMFS (p<0.001), and OS (p<0.001). The greatest reductions occurred in
pts with Ulc and stages IIB/III-N1 In N-Ulc pts reduction was absent. Consistency in
the treatment impact was seen in both trials.Conclusions: The post hoc analyses
of EORTC1892 and EORTC18991 indicate strongly that pts with an Ulc primary are
far more sensitive to IFN than pts with N-Ulc primaries. This hypothesis will now be
tested in the EORTC18081 trial, which compares PEG-IFNα-2b versus observation in
pts with Ulc primaries > 1mm.

Estimated reduction or increase in hazard ratio (SE%) of (PEG-) IFNα-2b vs


observation)
Non-ulcerated primary (N=1336) Ulcerated primary (N=849)
RFS DMFS OS RFS DMFS OS
All pts -4% (7%) +7% (8%) +11% (8%) -27% (7%) -33% (7%) -31% (7%)
IIB/III-N1 -14% (11%) +1% (13%) +10% -31% (7%) -42% (9%) -44% (10%)
Background: Ulcerated (Ulc) melanomas have a worse prognosis than non-
ulcerated (N-Ulc) melanomas. Ulc and N-Ulc primaries have different stromal
characteristics and gene profiles reflecting differences in biology. We analyzed
outcome after adjuvant interferon (IFN) therapy in the 2 largest phase III trials
(EORTC18952 and 18991) ever conducted in stage IIB-III melanoma patients
(pts). Methods:EORTC18952 compared IFNα-2b (10 MIU, sc, qd, 5 days/wk, for 4
wks) followed by either 10MIU,sc, tiw for 12 mts, or 5MIU for 24 mts) with
observation in 1,388 stage IIB-III pts (Lancet 2005;366). EORTC18991 evaluated
pegylated IFNα-2b (6 µg/Kg, 1x/wk, for 8 wks followed by 3µg/Kg, 1x/wk for up to 5
yrs) versus observation in 1,256 stage III pts (Lancet 2008;372). Using meta-
analytical methods, predictive value for Ulc on the value of IFN on relapse-free
survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS)
was assessed, overall, and according to stage (IIB, III-N1 or N2=microscopic or
macroscopic-nodal disease). Results: Overall, the comparison (PEG-)IFNα-2b
versus observation regarding RFS, DMFS, and OS led to a reduction in the hazard
ratio (HR) of -16% (SE=5%), -13%(5%), and -8%(5%). Among 2,644 pts randomized,
849 had Ulc primaries, 1,336 N-Ulc primaries, and 459 Ulc unknown. In Ulc group
the impact was much greater than in N-Ulc group for RFS (Test For Interaction:
p=0.02), DMFS (p<0.001), and OS (p<0.001). The greatest reductions occurred in
pts with Ulc and stages IIB/III-N1 In N-Ulc pts reduction was absent. Consistency in
the treatment impact was seen in both trials.Conclusions: The post hoc analyses
of EORTC1892 and EORTC18991 indicate strongly that pts with an Ulc primary are
far more sensitive to IFN than pts with N-Ulc primaries. This hypothesis will now be
tested in the EORTC18081 trial, which compares PEG-IFNα-2b versus observation in
pts with Ulc primaries > 1mm.

Estimated reduction or increase in hazard ratio (SE%) of (PEG-) IFNα-2b vs


observation)
Non-ulcerated primary (N=1336) Ulcerated primary (N=849)
RFS DMFS OS RFS DMFS OS
(15%)
III-N2 +2% (9%) +11% +12% -19% (11%) -20% (9%) -13% (12%)
(10%) (11%)

A phase III multi-institutional randomized study of immunization with


the gp100:209-217(210M) peptide followed by high-dose IL-2
compared with high-dose IL-2 alone in patients with metastatic
melanoma.

Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2009 ASCO Annual Meeting
Abstract No:
CRA9011
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr CRA9011)
Author(s):
D. J. Schwartzentruber, D. Lawson, J. Richards, R. M. Conry, D. Miller, J. Triesman, F.
Gailani, L. B. Riley, D. Vena, P. Hwu; Center for Cancer Care, Goshen, IN; Winship
Cancer Institute, Emory University, Atlanta, GA; Lutheran General Hospital Cancer
Care Center, Park Ridge, IL; UAHSF Comprehensive Cancer Center, Birmingham, AL;
James Graham Brown Cancer Center, Louisville, KY; Medical Consultants, Milwaukee,
WI; Riverside Creek Medical Center, Riverside, CA; St. Luke's Hospital, Bethlehem,
PA; The EMMES Corporation, Rockville, MD; M. D. Anderson Cancer Center, Houston,
TX
Abstract:
Background: In a phase II study, 13 (42%) of 31 patients with metastatic
melanoma receiving high-dose (HD) IL-2 plus gp100:209-217(210M) peptide
experienced objective responses (S.A. Rosenberg, et al, Nature Medicine 4: 321-
327, 1998). Other studies showed a lower response rate (RR) but no randomized
studies have been done. Methods: A prospective randomized phase III trial was
conducted at 21 centers with 185 patients. Eligibility: stage IV or locally advanced
stage III cutaneous melanoma, HLA A0201, no brain metastases, eligible for HD IL-2,
and no previous HD IL-2 or gp100:209-217(210M). Arm 1 received HD IL-2 alone
(720,000 IU/kg/dose) and Arm 2 gp100:209-217(210M) peptide + Montanide ISA
followed by HD IL-2. The primary objective was clinical response. Secondary
objectives were toxicity, disease free/progression free survival, immunologic
response and quality of life. Central HLA typing, pathology review, and blinded
response assessment were done at the NIH. Central data monitoring was done by
The EMMES Corp. and a Data Safety Monitoring Board. Results: Numbers of
patients enrolled, treated, and evaluable for response in Arm 1 were 94, 93, and 93
respectively; in Arm 2 91, 86, and 86. Toxicities were consistent with HD IL-2 ±
vaccine. Investigator assessed RR showed significant improvement in overall RR for
Arm 2=22.1% vs 9.7% (P=0.0223, Chi-Square) and progression free survival (PFS)
in favor of Arm 2=2.9 months (1.7-4.5) vs 1.6 (1.5-1.8) (P=0.0101). Median overall
survival favors Arm 2=17.6 months (11.8-26.6) vs 12.8 (8.7-16.3) (P=0.0964).
Blinded response review is ongoing. Conclusions: RR and PFS were superior with
peptide vaccine and HD IL-2 compared to HD IL-2 alone. This represents the first
evidence of clinical benefit of vaccination in patients with melanoma.
Adjuvant radiotherapy and regional lymph node field control in
melanoma patients after lymphadenectomy: Results of an intergroup
randomized trial (ANZMTG 01.02/TROG 02.01).

Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2009 ASCO Annual Meeting
Abstract No:
LBA9084
Citation:
J Clin Oncol 27:18s, 2009 (suppl; abstr LBA9084)
Author(s):
M. A. Henderson, B. Burmeister, J. F. Thompson, J. Di Iulio, R. Fisher, A. Hong, R.
Scolyer, K. Shannon, H. Hoesktra, J. Ainslie; Peter MacCallum Cancer Centre,
Melbourne, Australia; Princess Alexandra Hospital, Brisbane, Australia; Sydney
Melanoma Unit, Sydney, Australia; Royal Princess Alfred Hospital, Sydney, Australia;
Groningen University Medical Center, Groningen, Netherlands
Abstract:
Background: Adjuvant radiotherapy (RT) is an option for patients with isolated
regional recurrence of melanoma considered to be at high risk of further regional
recurrence after lymphadenectomy. This is the first completed study to assess the
effects of RT on regional recurrence, survival, morbidity and quality of life (QOL) in
these patients. Methods: Multicenter randomized study of patients with isolated
regional recurrence at increased risk (>25%) of regional recurrence. Eligibile
patients included ≥1 parotid, ≥ 2 cervical or axillary or ≥ 3 groin nodes or extra
nodal spread of tumor or maximum metastatic node diameter ≥3cm in neck or
axilla or ≥4cm in the groin. Patients were randomized to observation or regional
nodal basin RT (48Gy in 20 fractions) after lymphadenectomy. Regional recurrence
was the primary end point and morbidity, QOL, patterns of relapse, disease free and
overall survival were secondary end points. The target sample size was 220
patients, which would enable a difference in 3 year regional relapse (cumulative
incidence) rates of 30% versus 15% to be detected with a power of 80% (using a
two sided logrank test at the 5% level of significance). Results: 250 pts were
randomized from 16 centers from March 2002 to September 2007. There were 123
in the RT group and 127 in OBS group. 2 pts withdrew consent and 31 were
excluded from analysis of the main objective following an independent blinded
review of eligibility compliance by two reviewers. 227 pts were available for analysis
of the main objective (109 RT, 108 OBS). Median follow-up was 27 mo. There was a
statistically significant improvement in lymph node field control with radiotherapy,
20 RT pts and 34 OBS pts relapsed (HR 1.77 1.02-3.08 p=0.041). Median survival
times were 2.6 years (RT) and 3.9 years (OBS) p=0.14. Conclusions: Adjuvant RT
improved regional control in melanoma patients at high risk of regional relapse after
lymphadenectomy. An effect on survival was not demonstrated.
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation
as a therapeutic target in human cancer.

Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2009 ASCO Annual Meeting
Abstract No:
9000
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 9000)
Author(s):
K. Flaherty, I. Puzanov, J. Sosman, K. Kim, A. Ribas, G. McArthur, R. J. Lee, J. F.
Grippo, K. Nolop, P. Chapman; University of Pennsylvania, Hematology/Oncology,
Philadelphia, PA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Vanderbilt
University Medical Center, Nashville, TN; M. D. Anderson Cancer Center, Houston,
TX; UCLA, Los Angeles, CA; Peter MacCallum Cancer Centre, East Melbourne,
Australia; Hoffmann-La Roche, Nutley, NJ; Plexxikon Inc., Berkeley, CA; Memorial
Sloan-Kettering Cancer Center, New York, NY
Abstract:
Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant
BRAF kinase with preclinical activity. V600E BRAF is the most common kinase
mutation in melanoma (60%), also found in colorectal carcinomas (10%), most
anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian
carcinomas. Methods: Phase I, dose-escalation study designed to determine
maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic
(PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts
of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and
15. Results: 54 pts have been enrolled: metastatic melanoma (n=49), thyroid
(n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline
formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with
associated exposures below target plasma levels. 28 pts received an optimized
formulation with increased bioavailability, predicted to have 10-fold greater
bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-
proportional and above target levels at 240 mg BID and higher. There was 1 DLT at
720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without
myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt
had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at
doses of 240 mg BID or higher of the increased bioavailability formulation have a
minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at > 240 mg
BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1
unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor
regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive
disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to
14 months. 3 thyroid cancer pts with V600E mutations have tumor regression
(range 9-16%) and are progression-free (4-7 months). Conclusions:Dose escalation
of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960
mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF
mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic
target in human cancer.
A phase II study of imatinib mesylate (IM) for patients with advanced
melanoma harboring somatic alterations of KIT.

Sub-category:
Melanoma
Category:
Melanoma
Meeting:
2009 ASCO Annual Meeting
Abstract No:
9001
Citation:
J Clin Oncol 27:15s, 2009 (suppl; abstr 9001)
Author(s):
R. D. Carvajal, P. B. Chapman, J. D. Wolchok, L. Cane, J. B. Teitcher, J. Lutzky, A. C.
Pavlick, B. C. Bastian, C. R. Antonescu, G. K. Schwartz; Memorial Sloan-Kettering
Cancer Center, New York, NY; Mount Sinai Comprehensive Cancer Center, Miami
Beach, FL; New York University Cancer Center, New York, NY; UCSF, San Francisco,
CA
Abstract:
Background: Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with
advanced melanoma reported only 1 response in a pt with acral melanoma. A
proportion of melanomas arising from acral, mucosal, and chronic sun damaged
(CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) and we
hypothesized that this subset of tumors would be sensitive to IM. We thus designed
this phase II study of IM restricted to pts with melanoma harboring such alterations
in KIT.Methods: Pts with unresectable melanoma arising from acral, mucosal, and
CSD sites whose tumor harbored a 4q12 amp by FISH or mut in KIT and who had
measureable disease by RECIST were eligible. Pts received IM 400 mg BID
continually. Response was assessed every cycle (6 wks). A Simon 2-stage design
was employed where initially 16 pts would be treated; if ≥ 2 responses were
observed, a total of 25 pts would be enrolled. If ≥5 responses were seen in 25 pts,
the study was to be considered positive.Results: Of 81 pt tumors screened, 17
(21%) had a KIT mut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%)
CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an
amplification only; 1 (2%) had both. Thus far, 7 have been treated, with 5 currently
evaluable for response. Median age: 64 yrs (range, 61-86); 2 male/5 female; median
KPS: 90 (range, 80- 90); median # of prior therapies: 1 (range, 0-4). 3 pts (43%)
achieved a PR (18 wks - exon 13 mut; 21 wks, ongoing - exon 11 mut; 18 wks,
ongoing - exon 11 mut & amp); 2 pts (28%) achieved SD (12 wks - exon 11 mut; 11
wks - amp). 3 pts required a dose reduction to 400 mg QD for rash, GI toxicity and
fatigue. 1 pt required a second dose reduction to 300 mg QD for visual
changes. Conclusions: In this pt population, 21% of tumors are characterized by
mut or amp of KIT. The 3 responses observed have allowed expansion to the second
stage of enrollment which is currently on-going. While IM has limited activity in a
non-selected melanoma pt population, a substantial proportion of melanomas
harboring KIT mut or amp appear to respond. It may be possible to identify
appropriate pts prospectively for treatment with IM. (Supported by R01FD003445-
01, ASCO YIA, N01CM62206, and the Live4Life Foundation.)