VOLUME

30

NUMBER

15

MAY

20

2012

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Definition and Impact of Pathologic Complete Response on
Prognosis After Neoadjuvant Chemotherapy in Various
Intrinsic Breast Cancer Subtypes
Gunter von Minckwitz, Michael Untch, Jens-Uwe Blohmer, Serban D. Costa, Holger Eidtmann, Peter A. Fasching,
Bernd Gerber, Wolfgang Eiermann, Jo¨rn Hilfrich, Jens Huober, Christian Jackisch, Manfred Kaufmann,
Gottfried E. Konecny, Carsten Denkert, Valentina Nekljudova, Keyur Mehta, and Sibylle Loibl
Gunter von Minckwitz, Valentina Nekljudova, Keyur Mehta, and Sibylle Loibl,
German Breast Group, Neu-Isenburg;
Michael Untch, Helios-Klinikum; Jens-Uwe
Blohmer, St Gertrauden Krankenhaus;
Carsten Denkert, Institute for Pathology,
Charite´, Berlin; Serban D. Costa,
Universita¨ts-Frauenklinik, Magdeburg;
Holger Eidtmann, Universita¨ts-Frauenklink,
Kiel; Peter A. Fasching, Frauenklinik des
Universita¨tsklinikums Erlangen, Erlangen;
Bernd Gerber, Universita¨ts-Frauenklinik,
Rostock; Wolfgang Eiermann, Klinikum
zum Roten Kreuz, Mu¨nchen; Jo¨rn Hilfrich,
Henrietten-Stiftung, Hannover; Christian
Jackisch, Sta¨dtische Kliniken, Offenbach;
Manfred Kaufmann, Universita¨tsFrauenklinik, Frankfurt; Jens Huober,
Kantonsspital, St Gallen, Switzerland; and
Gottfried E. Konecny, University of California Los Angeles, Los Angeles, CA.
Submitted August 15, 2011; accepted
December 21, 2011; published online
ahead of print at www.jco.org on April 16,
2012.
Written on behalf of the German Breast
Group and Arbeitsgemeinschaft Gyna¨kologische Onkologie—Breast Group.

See accompanying editorial on page 1747
A

B

S

T

R

A

C

T

Purpose
The exact definition of pathologic complete response (pCR) and its prognostic impact on survival
in intrinsic breast cancer subtypes is uncertain.
Methods
Tumor response at surgery and its association with long-term outcome of 6,377 patients with
primary breast cancer receiving neoadjuvant anthracycline-taxane– based chemotherapy in seven
randomized trials were analyzed.
Results
Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ
residuals in breast or nodes (n ⫽ 955) compared with patients with residual ductal carcinoma in
situ only (n ⫽ 309), no invasive residuals in breast but involved nodes (n ⫽ 186), only focal-invasive
disease in the breast (n ⫽ 478), and gross invasive residual disease (n ⫽ 4,449; P ⬍ .001). Hazard
ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive
and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no
invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were
included in the definition. pCR was associated with improved DFS in luminal B/human epidermal
growth factor receptor 2 (HER2) –negative (P ⫽ .005), HER2-positive/nonluminal (P ⬍ .001), and
triple-negative (P ⬍ .001) tumors but not in luminal A (P ⫽ .39) or luminal B/HER2-positive (P ⫽ .45)
breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with
excellent prognosis.

Amgen, Bristol-Myers Squibb, Chugai,
Roche, and sanofi-aventis had no role in
the design, conduct, or interpretation
of this analysis. The decision to publish and
the drafting of the manuscript was undertaken entirely by the authors and staff at
the German Breast Group headquarters.

Conclusion
pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate
between patients with favorable and unfavorable outcomes. Patients with noninvasive or
focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR.
pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive
(nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal
A tumors.

Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article.

J Clin Oncol 30:1796-1804. © 2012 by American Society of Clinical Oncology

Clinical Trials repository link available on
JCO.org.
Corresponding author: Gunter von
Minckwitz, MD, German Breast
Group, c/o GBG Forschungs GmbH,
Martin-Behaim-Straße 12, 63263
Neu-Isenburg, Germany; e-mail:
gunter.vonminckwitz@
germanbreastgroup.de.
© 2012 by American Society of Clinical
Oncology
0732-183X/12/3015-1796/$20.00
DOI: 10.1200/JCO.2011.38.8595

1796

INTRODUCTION

Neoadjuvant chemotherapy represents an option for
patients with early breast cancer when an indication for
chemotherapy is given.1 Pathologic complete response
(pCR) has predicted long-term outcome in several
neoadjuvant studies and is therefore a potential surrogate marker for survival.2,3 However, selected trials comparing different neoadjuvant regimens have
failed to demonstrate an association between pCR
rate and improved outcome.4

Methodologic limitations are likely to be the
reason for this unexpected discrepancy. First, no
standardized definition for pCR exists. Some trials
have applied the pCR definition to the breast tumor
only, whereas others have included the axillary
nodes.5,6 Furthermore, some studies have included
the presence of focal invasive cancer7 or noninvasive
cancer residuals in their pCR definition,6 whereas
others have defined pCR as the complete eradication
of all invasive and noninvasive cancer.8 Second, incidence and prognostic impact of pCR vary among

© 2012 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on January 15, 2015. For personal use only. No other uses without permission.
Copyright © 2012 American Society of Clinical Oncology. All rights reserved.

noninvasive breast residuals and infiltrated lymph nodes allowed. which only accepted patients with a tumor size of ⱖ 3 cm.13 ypTⱕ1mic ypN0/⫹. Used by MD Anderson Cancer Center. No gross invasive residuals in the breast. All seven trials had comparable main eligibility criteria. cT4.21 AGO 1. Patients Between 1998 and 2006. No invasive residual in breast or nodes.20 GeparQuattro (NCT00288002).9 Including all intrinsic subtypes might therefore attenuate the prognostic information of pCR. Used by French groups using the Sataloff index. ypTis ypN0. Human epidermal growth factor receptor 2 (HER2) status was assessed by immunohistochemistry (HER2 positivity if the score was 3) or fluorescent in situ hybridization. Patients with ER. For example. ypT0/is ypN⫹.19. and the most recent GeparQuattro trial. The following definitions were used: Luminal A–like tumors. death. Chicago. RS 1 indicating minimal signs of tumor regression. NCT00795899)25 have been reported in detail in a review. the GBG and AGO-B study groups conducted seven prospective clinical trials that explored neoadjuvant systemic chemotherapy in patients with operable or nonoperable primary breast cancer. other prior malignancies.jco.8. Luminal B/HER2-negative–like tumors. All patients provided written informed consent for study participation and data collection.23. Tumor size had to be at least 2 cm in the majority of trials.377 patients with breast cancer received neoadjuvant anthracycline-taxane– based chemotherapy in © 2012 by American Society of Clinical Oncology Downloaded from jco.17 GeparTrio pilot18 and main study (NCT00544765). The study designs of GeparDuo (NCT00793377). ypT1mic ypN0/⫹. grade 3. whereas patients with triple-negative (TN) breast cancer show a high pCR rate but have an unfavorable outcome. Patients with primary metastatic disease. 1797 .10 ypT0/is ypN0. ER positive and/or PgR positive. ER positive and/or PgR positive. and Neo–Breast International Group. HER2 positive. or cN3 disease according to national guidelines. PgR.26 All trials were approved by the relevant ethics committees. the largest tumor was evaluated for response. No invasive residual in the breast. 6. tumor grade. Cox regression models were conducted as full models including all factors in the final model regardless of their statistical significance. patients with HER2-positive tumors (n ⫽ 622) received trastuzumab simultaneously with neoadjuvant chemotherapy as well as postoperatively to complete 1 full year of treatment. Histologic type. All seven trials used chemotherapy with anthracyclines and taxanes. In the GeparQuattro and Techno studies.22 PREPARE (Preoperative Epirubicin Paclitaxel Aranesp Study. Adjuvant radiotherapy was recommended for patients who underwent breast-conserving surgery as well for patients underwent mastectomy but had initial stage cT3. Estrogen (ER) and progesterone receptor (PgR) status were considered positive if ⱖ 10% of cells stained positive or the Remmele score was ⱖ 3.Prognosis After pCR by Intrinsic Breast Cancer Subtype breast cancer–intrinsic subtypes.ascopubs. Hazard ratios (HRs). 2015. ER positive and/or PgR positive. HER2-positive (nonluminal) –like tumors. For the Techno study. Used by the German study groups (German Breast Group [GBG] and Arbeitsgemeinschaft Gyna¨kologische Onkologie—Breast Group [AGO-B]) as part of the Sinn score. grade 1 or 2. missing data for ER and PgR status from pretreatment biopsies were substituted with information available at surgery. This test was also used with pCR as categorized covariate to determine the prognostic impact of pCR in various subgroups. and RS 0 indicating no signs of regression.5.12 ypT0/is ypN0/⫹.377 patients participating in these trials. Statistics Individual patient data regarding baseline characteristics. METHODS Objectives and End Points The first aim of this pooled analysis was to compare currently used definitions of pCR and investigate their role in predicting risk of recurrence or death. their overall prognosis is favorable. ER negative. the following distinct subgroups according to their residual tumor extent after neoadjuvant chemotherapy were used: ypT0 ypN0.16 Because information on Ki-67 was not available. and follow-up were extracted for this pooled analysis from the original databases from all 6. No invasive or noninvasive residual in breast or nodes. In patients with bilateral disease. Diagnosis of invasive breast cancer was histologically confirmed in all patients by core biopsy. Intrinsic breast cancer subtypes were determined according to clinicopathologic criteria recently recommended by the St Gallen panelists. Baseline parameters were correlated with pCR using two-sided ␹2 or Fisher’s exact test. or prior treatment for invasive breast cancer were excluded in all trials.6. we used grade to capture cell proliferation. Locally advanced (cT4a-d) and inflammatory breast cancers were eligible for all trials except GeparDuo. ultrasound. All rights reserved.org patients. and corresponding P values between categorized score values were calculated using Cox regression analysis. HER2 positive. We further investigated three residual disease scoring systems to determine whether they could differentiate prognostic subgroups of patients with residual invasive breast cancer: ypT staging system according to TNM14. For personal use only. Female patients needed to have measurable disease of the breast tumor either by palpation.org on January 15. Copyright © 2012 American Society of Clinical Oncology. only patients with HER2-positive disease were eligible. HER2 negative. As defined in the protocols. PgR negative. and histologic breast regression score (RS) as proposed by Sinn. or mammography. NCT00544232). dummy variables were used for categorized covariates. RS 3 indicating only noninvasive residuals in the breast. although patients with luminal A–like breast cancer show a low pCR rate. or last follow-up and plotted as Kaplan-Meier curves.10 with RS 4 indicating no viable tumor cell residuals in the breast. Used by National Surgical Adjuvant Breast and Bowel Project. HER2 negative. histopathologic results at surgery. noninvasive breast residuals allowed.7 Therefore. ER negative and PgR negative. all grades. Only patients who received at least one cycle of systemic treatment were included in the analysis. Austrian Breast and Colorectal Cancer Study Group. Individual patient data from case report forms based on local histopathologic assessments allowed evaluation of the following pCR definitions reported in the literature: ypT0 ypN0.11. Prognostic information of the residual disease scores was compared in a Cox regression model. patients with missing data for histologic response were counted as having no response.15 taking into account the frequency and intensity of the staining. TN tumors. and HER2 status were assessed in the primary tumor core biopsy sample by the local pathologist. ypN staging system according to TNM14. except for the AGO1 trial. Luminal B/HER2-positive–like tumors. and ypT⬎1mic ypN0/⫹ (no pCR according to any definition). and patients with missing values for any factor were excluded from these analyses. cN2. all grades. SPSS 14. Log-rank P values were calculated for different pCR definitions and residual disease scores.24 and TECHNO (Taxol Epirubicin Cyclophosphamide Herceptin Neoadjuvant.0 (SPSS. No other uses without permission. RESULTS Patient Baseline Characteristics In the current pooled analysis. IL) was used to perform all analyses. and ER. The second aim of this analysis was to assess the prognostic relevance of pCR (according to the best definition as identified in the first part of this analysis) in various intrinsic subtypes. Disease-free (DFS) and overall survival (OS) were calculated from date of registration to local or distant invasive relapse. to compare the impact of the components of the definition on prognosis. HER2 negative. all grades. focal invasive and noninvasive residuals in breast and infiltrated lymph nodes allowed. In 510 www. RS 2 indicating only focal (⬍ 5 mm) invasive residuals in the breast.and/or PgR-positive tumors should receive adjuvant endocrine treatment for at least 5 years. which accepted patients with a tumor size ⱖ 1 cm according to ultrasound measurements. 95% CIs.

1 20.1 19.6 936 878 80 19 34.5 10.1 1.0 8.2 20.3 54 937 151 63 46 25.1 16.001 ypT0/is ypN0/⫹ P No.1 23.2 23. During a median follow-up of 46.001 35.001 ⬍ .8 12.6 40.9 1.8 10.4 26.6 2.1 years (range.0 34.7 24.5 17.6 32.7 7.4 725 644 59 15 27.6 62.3 months (range.258 ⬍ .8 17.771 (60.7 24.2 32.1 12.2 11.2 454 119 181 14.1 38.8 754 413 33.7 34.0 0. No other uses without permission.001 ⬍ .9 23.377 254 108 93 P ⬍ .1 14.001 ⬍ . pCR pathologic complete response. median tumor size was 4.681 2.8 ⬍ .2 10.6 184 63 83 123 93 168 362 11.org on January 15.184 39.380 448 3.9 7. % 1.8 19 522 771 8.3 40. 5.5 5.4 67.128 ⬍ .001 Abbreviations: ER.001 ⬍ .3 590 287 26.1 48.001 ⬍ . 1798 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.3 9.0 834 334 29. years ⬍ 35 35-39 40-49 50-59 ⱖ 60 Tumor stage cT1 cT2 cT3 cT4a-c cT4d Missing Nodal status cN0 cN1 cN2 cN3 Missing Histologic type Ductal invasive Other type Lobular invasive Missing Tumor grade 1 2 3 Missing ER status Negative Positive Missing PgR status Negative Positive Missing HER2 status Negative Positive without trastuzumab Positive with trastuzumab Missing Subtype Luminal A Luminal B/HER2 negative Luminal B/HER2 positive without trastuzumab Luminal B/HER2 positive with trastuzumab HER2 positive (nonluminal) without trastuzumab HER2 positive (nonluminal) with trastuzumab Triple negative Missing 6.9 56.323 6.001 ⬍ .2 .9 60 1.3 10. online only).2 13.5 1.1 21.1 10.377) and Corresponding pCR Rates Patients by Subtype All Patients ypT0 ypN0 Characteristic No.4 843 501 37.001 ⬍ .8 44.0 64.001 ⬍ .2 32.7 19.7 800 79 51 16.9 17 434 685 7.001 ⬍ .0 231 3.4 513 391 35 7 19.ascopubs.869 patient years.001 ⬍ .001 44.0 ypT0/is ypN0 P No.7 1.7 99 111 340 244 161 24.0 21.5 9. .9 146 55 68 115 79 152 326 8.235 348 46.001 ⬍ .1 644 185 295 21.2 13.456 22.6 14.4 ⬍ .0 955 15. All rights reserved.1 16.2 105 40 47 79 66 98 282 6.2 27.001 P ⬍ .9 48. estrogen receptor.001 179 224 676 526 323 ⬍ .7 32.4 3.2 24.8 39.8 16.8 24.8 15.377 100.001 ⬍ .0 35.001 .3 13. Median age of patients at time of study entry was 50.2 11.2 to 33. PgR.1 12. % All patients Age.8 125 152 442 326 216 30.3 2. 2015.3 1.0 7.5 15.0 cm). 0 to 127 months) and observation of 22.233 106 91 24.3 6.001 ⬍ .0 24.001 ⬍ .3 33.9 27.4 1.8 10.001 ⬍ .6 22. human epidermal growth factor receptor 2.3 16.8 20.4 17.001 % 30.8 147 171 511 390 237 36.109 1.4 889 255 370 29.0 404 640 2.060 465 294 65 3.2 15.990 69.771 338 37.466 relapses (23%) and 775 deaths (12. Baseline Patient Characteristics (N ⫽ 6.1 51.9 33.4 39.1 31.261 19.623 125 141 32.2 8. For personal use only.1 27.4 4.0 cm (range.060 185 73 63 27.001 ⬍ .2 15. % 1.8 7.4 26.8 12. HER2.2 4.4%) and for Table 1. progesterone receptor.3 53.9 18.972 389 844 172 80.2 216 4.9 312 96 122 173 122 191 440 19.1 29.0 32.001 ypT0/is/mic ypN0/⫹ ⬍ .179 626 42.1 26.060 94 75 21.4 13.0 40.0 33.4 8.9 2.2 31.1 20.2 19.8 21.7 21.001 76 1.022 785 45.901 1.1 7.928 ⬍ .8 27.001 ⬍ .1 6.9 30.von Minckwitz et al the setting of seven randomized clinical trials (Appendix Table A1.7 28 790 939 12.6 21.9 22.794 3.6 32. 1.001 ⬍ .7 5.4 5.3 35.060 665 662 1.4 11.636 225 47 788 48.6 673 525 42 9 25.268 3.001 ⬍ .277 1.1 28.001 ⬍ . % No.6 2.3 24.001 No.3 55.7 ⬍ . Copyright © 2012 American Society of Clinical Oncology. Tumors stained positive for ER in 3.001 ⬍ .8 1.0 47.8 17.5 15. 1.0 27.3 ⬍ .001 .2 31.001 ⬍ .637 357 395 356 239 298 911 2.3 952 392 34.2%) were observed.6 51.0 39 719 107 49 32 18.0 23.3 35.6 38.8 15.2 17.0 10 319 530 4.9 56.3 557 155 271 18.1 16.318 2.9 15. 1.9 4.9 14.5 640 238 22. 21 to 81 years).618 patients had operable and 759 had locally advanced breast cancer.9 31.0 17.5 17.

4 0. 2.4 0.(n = 478) ypT > 1mic ypN+/. OS: P ⬍ .41.2 0 25 50 75 100 125 0.0 Proportion Surviving Proportion Disease Free A 1.(n = 4.001 1. (G) DFS and (H) OS in 5.8%). Prognostic impact of various definitions of pathologic complete response on survival.078) RS 3 only noninvasive residuals (n = 378) RS 2 focal invasive residuals (n = 487) RS 1 minimal regression (n = 2.74.001 1. 1799 .001 1.449) 0.ascopubs. 2.8%).001.34.org differed between components of pCR definition (DFS: P ⬍ .29.354) ypT2 (n = 1.001 1.6 0. regression score. 95% CI.4 0.Prognosis After pCR by Intrinsic Breast Cancer Subtype 0. All baseline characteristics. 0.38. 1.28 to 2.078) RS 3 only noninvasive residuals (n = 378) RS 2 focal invasive residuals (n = 487) RS 1 minimal regression (n = 2.001. All rights reserved.465) ypN2 (n = 602) ypN3 (n = 254) 25 50 75 100 125 Overall Survival (months) Fig 1.166).2 0 RS 4 no tumor residuals (n = 1. 95% CI.6 0. except nodal status at baseline.001.8 0. PgR in 3. Their prognosis was also better than that of patients with ypT0/is ypN⫹ (DFS: HR.0 Proportion Disease Free 0. P ⬍ . Prognosis www.0 0.001. ypTis ypN0 in 309 (4.63 to 6.001 0. ypT1mic ypN0/⫹ in 478 (7.5%).6 0.589) ypN1 (n = 1. Table 2). Figs 1A and 1B). P ⬍ .001. 1.0 Log-rank P < . Copyright © 2012 American Society of Clinical Oncology. correlated significantly with pCR rates according to the four definitions.33.2 0 ypT0 (n = 1.4 0 Log-rank P < .(n = 478) ypT > 1mic ypN+/.589) ypN1 (n = 1.81 to 3.0%). noninvasive residuals only (ypTis ypN0).001 1. No other uses without permission. (E) DFS and (F) OS in 5.8 0.191) 25 50 75 100 E 125 0.8 0.001) and showed a trend toward better OS (HR.4 0.078) ypTis (n = 378) ypT1 (n= 2. 95% CI.2 0 ypN0 (n = 3.8 0.990 patients (31. P ⬍ .191) 25 50 75 100 125 Disease-Free Survival (months) F Proportion Surviving Log-rank P < .001) or ypT1mic ypN0/⫹ tumors (DFS: HR.449 patients (69.41.6 0. 1.235 patients (51. P ⫽ .354) ypT2 (n = 1. RS.139) RS 0 no regression (n = 1. Correlation Between pCR Rate and Outcome Stage ypT0 ypN0 was diagnosed in 955 (15. For personal use only.2 0 Overall Survival (months) Proportion Disease Free Proportion Surviving 1.org on January 15.24.0 0.6 0. 3.9%).273 patients according to histologic breast regression score.4 0.8 B RS 4 no tumor residuals (n = 1.jco. P ⬍ .0 50 1. 95% CI.377 patients according to no residual tumor (ypT0 ypN0).910 patients according to postoperative nodal (ypN) stage. 95% CI.894 patients according to postoperative tumor size (ypT stage). OS: HR. P ⬍ .2%) because measurement of HER2 was only implemented in the study procedures after 2001. 1. and invasive residual in breast or nodes (ypTⱖ1 or ypN⫹).0 Overall Survival (months) G 25 C Log-rank P < .001 0. No data on HER2 status were available in 1.493) 25 50 ypT3 (n = 408) ypT4a-c (n = 154) ypT4d (n = 29) 75 100 125 Overall Survival (months) Log-rank P < . ypT0/is ypN⫹ in 186 (2.(n = 4.2 Disease-Free Survival (months) D Log-rank P < .18.8 0. 2.36. (A) Disease-free (DFS) and (B) overall survival (OS) in 6.2 0 ypT0 (n = 1.61 to 3. and ypT⬎1mic ypN0/⫹ in 4. HR for DFS comparing © 2012 by American Society of Clinical Oncology Downloaded from jco. patients with the worst prognostic factors seemed to have the best pCR rates (Table 1).8 0. In general.87 to 2.449) 0.6 0.4 ypT0 ypN0 (n = 955) ypTis ypN0 (n = 309) ypT0/is ypN+ (n = 186) ypT1mic ypN+/. 4. Patients with stage ypT0/is ypN⫹ tumors experienced the worst DFS and OS (Figs 1A and 1B).6 0.4 0.001 0. (C) DFS and (D) OS in 5. 1.05.01. 95% CI.078) ypTis (n = 378) ypT1 (n= 2. 2.139) RS 0 no regression (n = 1.6 0.0 ypT0 ypN0 (n = 955) ypTis ypN0 (n = 309) ypT0/is ypN+ (n = 186) ypT1mic ypN+/.8 0. 2015.8%).31 to 4.465) ypN2 (n = 602) ypN3 (n = 254) 25 50 75 100 125 Disease-Free Survival (months) 75 100 125 Log-rank P < . Patients with ypT0 ypN0 tumors experienced better DFS compared with patients with ypTis ypN0 tumors (HR.2 0 ypN0 (n = 3. OS: HR.493) 25 50 ypT3 (n = 408) ypT4a-c (n = 154) ypT4d (n = 29) 75 100 125 Disease-Free Survival (months) H Proportion Surviving Proportion Disease Free Log-rank P < .

pCR.67 to 5.8 112 65 57 125 1.0 2.2 40.001 ⬍ .3 ⬍ .89 2.89 1.0 2.910 3.99 1. ypT4a-c.81 1.13 1.13 to 11.6 145 90 126 437 372 OS No.449 5.04 3.001 1.9 7. Tumor stage after neoadjuvant chemotherapy (ypT) was significantly associated with prognosis (P ⬍ . of Patients With Event HR 95% CI P 15.0 4.86 2.44 to 2.87 to 2.61 1.41 4.56 1.74 3.001 1.97 5.001 ⬍ .001 ⬍ .64 5.07 to 5.894 1.001).001 ⬍ .28 to 2.4 83.84 to 2. A multivariate Cox regression model showed that all three residual disease scores provided independent prognostic information (Appendix Table A2. Prognostic Information of pCR in Various Subpopulations For the following analysis.30 to 2.001 ⬍ .07 to 6.31 21.7 24.21 1.139 1.002 ⬍ .001 1.51). NSABP.54 0.3 599 418 199 140 20.11).0 1.56 to 2.13 2.001 ⬍ . ypT0/is ypN0/⫹ (2.27 to 3.001 ⬍ .78 1. GBG ypT0 ypN0 No pCR MD Anderson ypT0/is ypN0 No pCR NSABP ypT0/is ypN0/⫹ No pCR French ypT0/is/mic ypN0/⫹ No pCR 3.493 408 154 29 5.017 .38 1. Patients with noninvasive residuals only did not experience a significantly different outcome compared with those with focal-invasive residuals or minimal or no signs of regression (Table 2.11 3.62 to 2.589 1.0 7.54 to 2.084 3.94 3.org on January 15.41 1.67 1.0 5. Comparable results were observed for nodal stage ypN.001 . patients with or without pCR according to the various pCR definitions was highest for ypT0 ypN0 (4.77 to 5.16 .82 to 2.001 69 40 60 221 197 1.74 60.48 2.938 979 2. Figs 1800 © 2012 by American Society of Clinical Oncology 1E and 1F).35 to 3.598 DFS % No.001 ⬍ .001 1.3 6.9 75.078 378 2.09 to 2.78 to 2.001 ⬍ .38 ⬍ . overall survival.39 4.ascopubs.0 1. hazard ratio.68 1.0 1.09 to 2.001 ⬍ .72 18.001 ⬍ .63 to 6. Copyright © 2012 American Society of Clinical Oncology.33 ⬍ .293 3.49 to 14. Patients with ypN2 and ypN3 disease had a median DFS of 70 and 30 months.001 2.001 % No. HR.001 50 24 35 59 607 1. of Patients Who Died HR 95% CI Pⴱ ⬍ .45 to 6.29 2.001 254 227 130 81 1. .72 ⬍ .0 66.001 ⬍ .001 ⬍ .70 1.001 ⬍ .4 39.8 2.001 ⬍ .24 1.95 1.3 6.001 303 84 1.001 ⬍ .166 ⬍ .31 1.4 7.7 78.24 1.0 1.62 6.50 4.938 854 3.001 ⬍ .2 4.51 1.34 to 2.0 3.18 4. RS.96 4.959 3.66 to 2.0 2. online only).39 .0 2.377 955 309 186 478 4.017 DFS ⴱ OS No.0 2.66 2. All rights reserved.1 131 662 34. Figs 1G and 1H).5 69.37 to 2.9 25.01 1.88 2.8 10.273 1.08 ⬍ .23 1. Correlation Between Residual Disease Score and Outcome Overall.00 ⬍ .001 ⬍ .001 26 361 1.50 4. OS.90 to 3.40 ⬍ .37 to 2.354 1.4 to 4. histologic breast RS significantly correlated with DFS and OS (P ⬍ .29 3.72 3.77).38 ⬍ .14 to 4.51 24.4 4.37 1.33 2.001.001 1.465 602 254 5.0 2. GBG.46 ⬍ . †Adjusted by multivariate Cox regression analyses including all factors.54 1.18 2.von Minckwitz et al Table 2.01 7.01 ⬍ .05 2.98 1.23 1.191 All Patients Adjusted analyses of pCR definitions† No.6 0. No other uses without permission.99 3. disease-free survival.04) and decreased monotonously for ypT0/is ypN0 (3.80 2. of Patients Who Died HR 95% CI Pⴱ ⬍ .36 2.001 ⬍ .001 ⬍ .11 1. especially for patients with ypT3.2 9.938 1.108 1.0 3.0 4.77 2.340 2. JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.9 2. Prognostic Impact of Residual Disease Scoring Systems on DFS and OS All Patients Score No. who had the worst outcome (Table 2).34 to 1. of Patients With Event HR 95% CI P 16.0 1. regression score. as categorized in Table 1. 2015. pCR definition ypT0 ypN0 ypTis ypN0 ypT0/is ypN⫹ ypT1mic ypN0/⫹ ypT⬎1mic ypN0/⫹ ypT staging system ypT0 ypTis ypT1 ypT2 ypT3 ypT4a-c ypT4d ypN staging system ypN0 ypN1 ypN2 ypN3 Histologic breast RS RS 4 (no viable tumor residuals) RS 3 (only noninvasive residuals) RS 2 (only focal invasive residuals) RS 1 (minimal signs of regression) RS 0 (no signs of regression) 6.3 92 701 1.001 69 40 255 197 76 40 14 1.79 1.61 1.29 to 1.49 ⬍ .6 58 735 1. respectively (Table 2.938 645 3.61 1.078 378 487 2.79 to 4. pathologic complete response.97 1.5 145 90 514 377 144 66 18 1.92 to 2. and ypT0/ is/mic ypN0/⫹ (2.001 16 371 1. pCR was defined as ypT0 ypN0 showing the lowest HR comparing patients with or without pCR.87 1.53 1.001 ⬍ .17 to 1.26 2. German Breast Group.13 to 2.0 221 572 ⴱ Abbreviations: DFS.34 2.74 2. For personal use only. and ypT4 disease.17 to 3. ⴱ P values refer to pairwise comparison of each group with reference group.61 to 3.45 to 12. pCR seemed to predict a more favorable outcome independent of age.60 ⬍ . National Surgical Breast and Bowel Project.31 to 4.001 ⬍ .81 to 3.39 to 7.001 48 339 1.99 to 9.6 22. Figs 1C and 1D).

36 2.41 1. estrogen receptor.81 . In contrast. †HRs and P values refer to comparison of survival in patients with or without pathologic complete response.40 to 14.09 2.235 779 607 3.56 to 5.002 1.92 1. No other uses without permission.28 1.10 2.37 1.004 ⬍ .54 2.52 2.242 3. ER.46 0 to ⬎ 1.12 3.86 ⬍ .17 to 24. 1801 . Comparable results were obtained when only patients receiving trastuzumab were analyzed (data not shown). Prognosis according to intrinsic subtype was analyzed separately for patients with or without pCR.180 1.28 3.950 1.277 1.02 1.001 .75 .43 . Whereas pCR seems to be prognostic in luminal B/HER2-negative tumors.020 0.90 0.75 to 13.323 98 168 460 424 317 2.001 .001 .82 to 5.14 1. Copyright © 2012 American Society of Clinical Oncology.16 .25 0.80 1.54 .001 .16 5.79 1.001 .39 .13 1.13 to 4.64 .72 4.000 .145 97 188 2.47 to 6.03 ⬍ .47 3.15 ⬍ .64 to 5. HR.305 5.009 .92 to 1. OS.80 to 8.74 to 4. Prognosis in patients without pCR was comparable to that in patients receiving systemic treatment after surgery (luminal tumor showing better prognosis than © 2012 by American Society of Clinical Oncology Downloaded from jco.24 1.15 1. different outcomes in subgroups were observed for histologic type.88 ⬍ .61 0.27 to 3.60 1.ascopubs.76 0. However.05 2.001 ⬍ .953 8.05 1. tumor grade.79 1.67 to 2.98 2.19 4.37 to 3.32 1. of Patients Who Died HR† OS 95% CI P† 404 640 2.85 1.03 to 4.22 1. ⴱ Group size listed in Table 2.89 to 8. and positive ER or PgR status.20 to 6.41 1.66 4.559 . Low proliferating luminal A–like tumors showed no prognostic impact of pCR.810 285 92 527 760 103 52 1.318 2.59 to 2.57 0.24 0.org on January 15.76 2.048 ⬍ .04 2.69 to 4.01 ⬍ .59 29.org HER2-positive (nonluminal) and TN tumors showed a significant prognostic impact of pCR.30 1. progesterone receptor.001 216 4.68 to 12.001 49 83 228 217 198 1. patients age ⬍ 35 years [n ⫽ 404].82 to 3.90 to 2.60 to 10.98 1.91 13.001 ⬍ .83 ⬍ .15 2.72 0. and ER and PgR status.10 14.56 to 3.71 to 2.96 to 1.227 3.007 ⬍ .14 to 2.13 0.001 .63 to ⬎ 1.014 ⬍ .01 2.04 .11 0.98 2.001 1.70 589 55 102 231 3.04 to 4. pCR was predictive for neither DFS nor OS in subgroups associated with lower proliferation.11 3.46 to 24.48 0. of Patients Patients With Event DFS HR† 95% CI P† No.013 .46 1.32 ⬍ . tumor size.65 to 4.001 1.001 .53 0.001 .738 6.001 21.26 3.380 34 693 652 0.23 to 3. human epidermal growth factor receptor 2.056 2.20 1.794 3.972 389 844 1. Prognostic Impact of Pathologic Complete Response on Survival in Various Subgroupsⴱ Baseline Characteristic Age. All rights reserved.08 to 1.14 398 326 5.69 2.15 3.109 1.92 to 9.71 to 8.038 25 412 160 88 80 2.003 . hazard ratio.37 to 2.76 1.03 3.63 1.59 2.95 1.001 0.001 14 345 364 2.50 to 2.002 39.49 2.637 357 395 356 239 298 911 240 79 80 62 68 60 253 1.38 1.99 1.36 3. For personal use only.75 0.38 2.001 ⬍ .70 to 2.05 to 2.94 29.124 .87 to 102 . whereas highly aggressive www.63 to 2. it did not correlate with prognosis in luminal B/HER2-positive tumors (Table 3.22 0.93 to 103.43 to 7.207 ⬍ .49 ⬍ .17 2.35 1. nodal status.99 ⬍ .86 to 2. of No. pCR was predictive for DFS and OS in ductal or other histologic types.037 .jco. patients with cT4a-c [n ⫽ 465] or cN3 disease [n ⫽ 92]).77 .666 21.001 100 38 38 11 43 25 161 1. A heterogeneous pattern was observed for luminal B–like tumors.73 ⬍ .85 2.012 .80 12.78 to 2.05 to 4. Nonsignificant trends for DFS or OS were found only in small subpopulations (eg.268 3.001 324 84 36 4.901 1. namely lobular type.25 .31 2. grade 1.99 .12 to ⬎ 1.54 to 3.000 .22 to 5.19 to 3.68 1.70 to 37.54 ⬍ .39 1.76 ⬍ .25 .42 to 2.43 to 3.12 to ⬎ 1.001 .82 to 26.88 1.84 0.000 .060 465 294 51 840 296 143 123 1.60 to 2.48 1.52 3.31 0.001 .91 1. and negative ER or PgR status.04 2. PgR.32 to 6.771 653 734 4.84 to 4.17 1 to 748 .6 1.51 1.08 441 282 4.001 ⬍ .001 0.001 .016 . Figs 2A to 2E). disease-free survival.009 1.93 2.00 to 2. Importantly.01 5.76 . 2015.Prognosis After pCR by Intrinsic Breast Cancer Subtype Table 3.69 to 4.001 Abbreviations: DFS.97 ⬍ .78 1.37 2.85 .97 0. years ⬍ 35 35-39 40-49 50-59 ⱖ 60 Tumor stage cT1 cT2 cT3 cT4a-c cT4d Nodal status cN0 cN1 cN2 cN3 Histologic type Ductal invasive Other type Lobular invasive Tumor grade 1 2 3 ER status Negative Positive PgR status Negative Positive HER2 status Negative Positive without trastuzumab Positive with trastuzumab Subtype Luminal A Luminal B/HER2 negative Luminal B/HER2 positive without trastuzumab Luminal B/HER2 positive with trastuzumab HER2 positive (nonluminal) without trastuzumab HER2 positive (nonluminal) with trastuzumab Triple negative No.001 .99 2.0 1.04 1.00 1.002 .70 . overall survival.68 to 3.000 .60 to 2.24 .25 0. HER2.60 to 4.35 1.65 1.41 ⬍ .27 0.15 2.11 1.71 ⬍ .47 to 2.41 .060 665 662 605 153 124 2.051 246 412 62 38 4. grade 2 or 3 tumors.88 2. or HER2 status (Table 3).18 1.67 to 3.90 to 3.36 0.

Fig 2F).388 25 50 75 100 125 0. We further demonstrate that in subgroups considered to have slowly proliferating tumors.70). pCR was not prognostic in the luminal B/HER2positive subgroup irrespective of trastuzumab treatment.0 0. Copyright © 2012 American Society of Clinical Oncology.29 but similar outcomes were observed in the adjuvant trastuzumab studies.30 Inclusion of noninvasive residuals in the pCR definition has been mainly supported by the hitherto largest analysis of the MD Anderson group of 2.8 0. (F) comparison of DFS in 717 patients achieving pCR according to breast cancer intrinsic subtype. whereas in subgroups with highly proliferating tumors. Figs 2A to 2E [gold curves]). HER2-positive or TN tumors27. (B) luminal B/human epidermal growth factor receptor 2 (HER2) –negative–like tumors. resulting in a much lower statistical power to show prognostic differences. n = 164) Triple negative (n = 282) Log-rank P = . prognostic impact of pCR is highest in HER2-positive (nonluminal) and TN tumors.6 0.0 0.02. .Inthecase of low pCR rates.4 0.2 0 Disease-Free Survival (months) E 1. (A) Patients with luminal A–like tumors. However.055.8 0.4 0. However. the number of patients with ypT0 ypN0 (n ⫽ 199) and ypTis ypN0 (n ⫽ 78) tumors was much lower than in our analysis.2 0 Luminal A (n = 105) Luminal B HER2 negative (n = 40) Luminal B HER2 positive (n = 126) HER2 positive (nonluminal.4 0. pCR restricted to this stage showed the lowest adjusted HR for DFS and OS compared with the other definitions (Table 2). (D) HER2-positive (nonluminal) –like tumors.4 0. However. The recently proposed clinicopathologic definition of the St Gallen panel nicely recognizes these subgroups.4 0.von Minckwitz et al 0. DISCUSSION This is. these studies become severely underpowered.001 25 50 75 100 125 Disease-Free Survival (months) pCR (n = 126) no pCR (n = 625) Log-rank P = . noninvasive residuals only.6 0.0 0. the first individual patient– based pooled analysis analyzing different pCR definitions for their prognostic impact on survival of patients with breast cancer treated with neoadjuvant anthracycline-taxane– based chemotherapy.ascopubs. and (E) triple-negative tumors.193 patients according to breast cancer intrinsic subtype. For personal use only. In fact.005 F 1. Only 42% of patients received a combination of anthracyclines and taxanes.0 Proportion Disease Free B 1.001 25 50 75 100 125 Disease-Free Survival (months) 25 50 75 100 125 1.6 0. we show that these subpopulations have an increased risk of relapse and sometimes of death as well compared with the group of patients with stage ypT0 ypN0 breast cancer. The large patient collective included sufficient subpopulations with small residual disease volume (eg.6 0. In fact.org on January 15. No other uses without permission. or no invasive tumor in the breast but involved lymph nodes).2 0 pCR (n = 105) no pCR (n = 1. Surprisingly.possiblybecauseofsmall sample sizes.8 0. (C) luminal B/HER2-positive–like tumors. JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco. to the best of our knowledge.0 Proportion Disease Free Proportion Disease Free A 1.4 0. All rights reserved.2 0 pCR (n = 282) no pCR (n = 629) Log-rank P < . Over the last decades. pCR rates were low. resulting in lower pCR rates.31 However. prognosis was not significantly different for the intrinsic subtypes (DFS: P ⫽ . in patients achieving pCR.8 0. focal-invasive disease ⬍ 5 mm.32.11. pCR can dis1802 © 2012 by American Society of Clinical Oncology criminate between patients with good and poor prognosis accurately.33 Another argument for inclusion of low-volume residual diseaseinthepCRdefinitionhascomefrombiomarkerstudies. Prognostic impact of pathologic complete response (pCR) on disease-free survival (DFS) in 4.6 0.6 0. In this subgroup. pCR is not associated with prognosis. 2015.302 patients.28.31 Other analyses have failed to show correlation betweendifferentpCRdefinitionsandoutcome. OS: P ⫽ . these subpopulations have frequently been considered to have achieved pCR. where patients achieving pCR show a prognosis comparable to that of patients with luminal A tumors. This may be attributed to less intense neoadjuvant treatment. showing no difference in DFS or OS between patients with ypT0 ypN0 and ypTis ypN0 tumors.2 0 Disease-Free Survival (months) Proportion Disease Free Proportion Disease Free D pCR (n = 40) no pCR (n = 317) Log-rank P = .445 25 50 75 100 125 Disease-Free Survival (months) Proportion Disease Free 0. DFS of patients with HER2-positive and TN tumors was better than that of those with luminal B/HER2-positive tumors (P ⬍ .532) Log-rank P = . despite concomitant anti-HER2 therapies.0 0.055 25 50 75 100 125 Disease-Free Survival (months) Fig 2.8 0.8 C 1.2 0 pCR (n = 164) no pCR (n = 373) Log-rank P < .

Roche. Buzdar AU. Novartis (U) Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Gunter von Minckwitz. Rezai M. GlaxoSmithKline. Loibl S. Geburtshilfe Frauenheilkd 54:552-558. and the lack of central assessment of surgical specimens. Novartis (U) Stock Ownership: None Honoraria: Gunter von Minckwitz. Sibylle Loibl Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors 5. Liedtke C. rendering this argument moot. 1994 11. Amgen. sanofi-aventis. J Clin Oncol 24:1940-1949. sanofi-aventis (C). Although some parameters were incomplete. 2010 9. Weaknesses of this analysis are the unavailability of Ki-67 to measure proliferation. Novartis (C). Christian Jackisch. Cancer Res 70. Prestipino AJ. Jens Huober. Kaufmann M. Extent of residual disease and evidence of regression provide helpful additional prognostic information. sanofi-aventis (C). and luminal B/HER2-negative tumors but not for luminal B/HER2-positive and luminal A tumors. Schmid H. 2007 2. sanofi-aventis (C). 2008 www. et al: Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: An update. Green MC. comparable to that of patients with tumor residuals in breast and nodes. Jakesz R.org matter under consideration in this article. J Clin Oncol 26:778-785. Manfred Kaufmann. All rights reserved. Eur J Cancer 7. J Clin Oncol 26:12751281. abstr 3) 13. GlaxoSmithKline. residual cancer burden. Carsten Denkert. Manfred Kaufmann. et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. et al: A randomized phase III study comparing epirubicin. Roche. Michael Untch. sanofi-aventis. Peter A. Sataloff DM. Roche. the following author(s) indicated a financial or other interest that is relevant to the subject REFERENCES 1. Roche (C). Roche (C). Sibylle Loibl Provision of study materials or patients: Gunter von Minckwitz. et al: Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy [in German]. Novartis. However. The prognostic importance of involved lymph nodes after neoadjuvant chemotherapy has already been stressed by others. For a detailed description of the disclosure categories. Valentina Nekljudova. Bernd Gerber. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration. please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. 2005 7. J Clin Oncol 16:26722685. 1995 8. sanofi-aventis (C). Konecny. Roche. Sinn HP. Mazouni C. 2006 3. Genentech (C). 2015. 2010 (suppl. sanofi-aventis. and ypN⫹ residuals only are associated with increased relapse risk and should therefore no longer be considered as pCR. and their combination plus paclitaxel in women with HER2-positive primary breast cancer. pCR is a suitable surrogate end point for patients with HER2-positive (nonluminal). Konecny. GlaxoSmithKline. or for more information about ASCO’s conflict of interest policy. Christian Jackisch. Michael Untch. Bear HD. Bernd Gerber. Holger Eidtmann. Bear HD. et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. Jens-Uwe Blohmer. docetaxel and capecitabine (EDC) to epirubicin and docetaxel (ED) as neoadjuvant treatment for early breast cancer: First results of ABCSG-24. Employment or Leadership Position: None Consultant or Advisory Role: Gunter von Minckwitz.ascopubs. et al: Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. Bear HD.wecannowdemonstratethatthesmallgroupof patientswithypT0/isypN⫹tumorshasaconsiderablyinferiorprognosis. Anderson SJ. 2009 (suppl. von Minckwitz G. randomized. Peter A. Roche (C). Amgen (C). et al: First results of the NeoALTTO trial (BIG 01-06/EGF 106903): A phase III. Amgen. sanofi-aventis. Holger Eidtmann. Jens Huober. ypTis. No other uses without permission. Certain relationships marked with a “U” are those for which no compensation was received. Holger Eidtmann.34 grading by Miller-Payne35). Jens Huober. Amgen. GlaxoSmithKline (C). Amgen (U). Wolfgang Eiermann. Goldhirsch A. 2008 10. Copyright © 2012 American Society of Clinical Oncology. receiving comparable anthracycline-taxane–containing neoadjuvant regimens under homogenous national treatment conditions. Serban D. All patients participated in prospective trials. Pfizer Research Funding: None Expert Testimony: Gottfried E. The strengths of this pooled analysis are the large sample size and considerable number of patient years available.37 However. Smith T. J Clin Oncol 23:59835992. Fasching. Pfizer. Costa. Jens-Uwe Blohmer. Newman LA. Amgen. Valentina Nekljudova. 2003 6. We could not assess other pCR scores (eg. Kaufmann M. open label. the imprecise categorization of breast cancer subtypes because of the lack of gene profiles. 1998 © 2012 by American Society of Clinical Oncology Downloaded from jco. 1999 4. Roche. Holger Eidtmann. Amgen (C). this data set is currently unique because of the availability of HER2 status. GlaxoSmithKline. Fasching. Smith TM. Wolfgang Eiermann. Hortobagyi GN.36. AstraZeneca.jco. Junkermann H. Bryant J. Serban D. For personal use only. Bradbury I. Novartis. J Clin Oncol 21:4165-4174. Ann Oncol 18:1927-1934. et al: Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: A determinant of outcome. von Minckwitz G. Jo¨rn Hilfrich. We conclude that pCR defined as ypT0 ypN0 is associated with highly favorable outcome. Brown A. Novartis. Roche (C). Steger GG. sanofi-aventis. Christian Jackisch. Costa. 1803 . Costa. Serban D. Amgen (U). Rastogi P. Mason BA. sanofi-aventis. et al: Effect of preoperative chemotherapy on outcome of women with operable breast cancer. J Am Coll Surg 180:297-306. et al: Capecitabine in addition to anthracycline/taxanebased neoadjuvant treatment in patients with primary breast cancer: The phase III GeparQuattro study. Anderson S. et al: Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: New perspectives 2006. AstraZeneca (C). those relationships marked with a “C” were compensated. TN. Keyur Mehta. J Clin Oncol 17:460-469. Because of this. ypT1mic. Sibylle Loibl Collection and assembly of data: Gunter von Minckwitz. Jens Huober. Roche. Wolfgang Eiermann. Greil R. withthelargesamplesize. Pfizer (U). et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. Hess KR. it is possible that the poorer outcome of patients with residual ductal carcinoma in situ could have been the result of invasive parts not being detected because of insufficient histopathologic examination. Wolmark N. we suggest that a more thorough comparison of all these scores is necessary to decide whether more extensive pathologic assessments are necessary. Gottfried E. Bernd Gerber. Fisher B. J Clin Oncol 28:2015-2023. Kuerer HM.Prognosis After pCR by Intrinsic Breast Cancer Subtype the more active treatments used today result in pCR rates of 20% to 40%. Jörn Hilfrich. Novartis (C). abstr S3-3) 12. Keyur Mehta. Jens-Uwe Blohmer. Roche. Baselga J. Amgen. trastuzumab. neoadjuvant study of lapatinib. Eidtmann H. et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer.org on January 15. Roche. Bernd Gerber.

TX. Symmans WF.ascopubs. Breast Cancer Res Treat 125:145-156. et al: Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Peintinger F. Loibl S. et al: Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. December 8-12. 2011 25. J Clin Oncol 24:2019-2027. 2011 24. San Antonio. No other uses without permission. Klijanienko J. Miller ID. Anderson S. 2007 35. 2015. Presented at the 33rd Annual San Antonio Breast Cancer Symposium. Gianni L. December 8-12. J Clin Oncol 29:3351-3357. San Antonio. et al: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: Results from the GeparQuatro study. 2003 36. Computer-assisted image analysis (QIC score) vs. Jones RL. 2008 31. Ann Oncol 22:1999-2006. Untch M. Mo¨bus V. Konecny GE. et al: PREPARE trial: A randomized phase III trial comparing preoperative. 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Ogston KN. et al: Intensive dose-dense compared with conventionally sched- uled preoperative chemotherapy for high-risk primary breast cancer. et al: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Untch M. Raab G. Bear HD. Coates AS. Mailliez A. Sørlie T. J Natl Cancer Inst 100:542551. Extra JM. Smith RE. TX. Untch M. Vogel P. von Minckwitz G. 2006 ■ ■ ■ 1804 © 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco. New York. Fasching PA. dose-intensified chemotherapy with epirubicin.von Minckwitz et al 14. Baranzelli MC. Vogel P. 2000 28. Springer. et al: Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: The GEPARDUO study of the German Breast Group. 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