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Pembrolizumab Traducido PDF
Pembrolizumab Traducido PDF
doi:10.1093/annonc/mdw216
Published online 23 May 2016
Background: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell
carcin-oma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic
options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential
original articles
2019
introduction with high possibility of cure [2]. In contrast, locally advanced
penile SqCC, particularly those with spread to regional lymph
Squamous cell carcinoma (SqCC) is the most common primary nodes, may require a multimodal approach, including primary
neoplasm of the penis [1]. The vast majority of penile SqCC lymphadenectomy, adjuvant radiation, and/or chemotherapy;
present as clinically localized disease, for which organ-preserving despite these aggressive treatment strategies, however, high-
surgical excision and/or radiation are usually sufficient for primary stage tumors have a poor prognosis with significant morbidity
treatment and management of subsequent local recur-rences, and and mortality [2]. Thus, there is a clear need for additional
overall, low-stage tumors have a good prognosis therapeutic options for patients with locally advanced and/or
metastatic penile SqCC.
*Correspondence to: Dr Rohit Mehra, Department of Pathology, University of Michigan
Recent advances in immunotherapy offer promising new
Health System, Room 2G332 UH, 1500 E. Medical Center Drive, Ann Arbor, MI, USA. Tel: treatments for some solid tumors [3]. The PD-1/PD-L1
+1-734-647-9125; Fax: +1-734-763-4095; E-mail: mrohit@med.umich.edu immune checkpoint pathway, for example, is one of the major
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
Annals of Oncology original articles
targets of a new generation of immunotherapeutics. PD-1, a co- mortality was measured from the time of diagnosis to death or date of last
inhibitory receptor present on a subset of CD8-positive follow-up (at which point the patient was censored). All statistical analyses
cytotoxic T cells, interacts with its ligand PD-L1 on tumor cell were carried out using SAS, version 9.4 (Cary, NC), and statistical signifi-
membranes, resulting in suppression of T-cell activation and cance was defined as P < 0.05.
proliferation, and thereby, dampening of the host anti-tumor
immune response [4]; inhibiting the PD-1/PD-L1 interaction,
therefore, should augment tumor cell killing by cytotoxic T
results
cells. Indeed, immunotherapeutic approaches targeting PD-1 or Of the 37 primary penile SqCC tumors examined, 23 (62.2%)
PD-L1 have been shown to enhance anti-tumor activity in were positive for PD-L1 expression (see Materials and
preclinical models [5, 6], and anti-PD-1 and anti-PD-L1 immu- methods); essentially, all positive samples showed moderate to
notherapeutics have yielded promising results in early and late strong membranous staining (Figure 1), and the percentage of
phase clinical trials [7–13], with recent Food and Drug tumor cells staining ranged from 5% to 70% (median = 20%).
PD-L1 expression and other examined clinicopathologic para- and EGFR. In the current study, we sought to integrate our
meters, including age, circumcision status, HPV status, and primary penile SqCC tumor PD-L1 expression results with
p16 expression. these prior molecular data. As shown in supplementary Table
Thirty-six of the primary penile SqCC tumors examined in this S1, available at Annals of Oncology online, there were no
study were previously interrogated by our group for recur-rent significant associations between primary tumor PD-L1 expres-
molecular alterations (somatic mutations and copy number sion and specific molecular alterations, although by logistic re-
alterations) using a targeted next-generating sequencing ap-proach gression, there was a non-statistically significant trend toward
[21]. In that prior study, the five most common priori-tized somatic association between increased total number of molecular
mutations involved TP53, CDK2NA, PIK3CA, HRAS, and altera-tions and PD-L1 expression (P = 0.16), with an odds
NFE2L2, and the five most frequent prioritized copy number ratio of 1.36 compared with a sample with one fewer alteration
alterations involved CDK2NA, MYC, CCND1, SOX2, (95% confidence interval = 0.88–2.11).
2019
Of the patients with primary penile SqCC tumors examined in this versus N0/NX), primary tumor PD-L1 expression ( positive
study, two experienced local recurrence, five had distant pro-gression, versus negative) was significantly associated with decreased
and seven died of disease. Importantly, although primary tumor PD-L1 cancer-specific survival [log-rank test statistic = 6.54, P =
expression was not significantly associated with local recurrence 0.011; supplementary Table S2, available at Annals of
(10.0% versus 0.0% of PD-L1-positive and -negative tumors, Oncology online]. (Hazard ratios from proportional hazards
respectively, P = 0.501), patients with PD-L1-positive primary tumors models were not estimable because there were no observed
were more likely to have distant progression (25.0% versus 0.0% of lethal events for patients with T1 pathologic stage, non-usual
PD-L1-positive and -negative tumors, respectively, P = 0.063) and die histologic subtype, or negative PD-L1 expression.)
of disease (31.8% versus 0.0% of PD-L1-positive and -negative Finally, no significant associations were detected between
tumors, respectively, P = 0.029). In addition to pathologic stage (T2–4 the intensity of host inflammatory response or presence of PD-
versus T1), histologic subtype (usual versus other), and lymph node L1 staining on tumor-infiltrating mononuclear cells and
status (N1–3 primary penile or metastatic SqCC tumor PD-L1 expression,
Table 1. Association of primary tumor PD-L1 expression (both relatively poor prognostic factors), and furthermore, PD-
with clinicopathologic parameters L1-positive primary tumors are significantly associated with
Parameter PD-L1-positive PD-L1-negative P value decreased cancer-specific survival. These results suggest that
(n = 23) (n = 14) PD-L1-positive tumors may define a subset of clinically
aggres-sive penile SqCC and provide a rational basis for
Age subsequent in-vestigation of anti-PD-1 and anti-PD-L1
≤65 years 11 (47.8%) 9 (64.3%) 0.498 immunotherapeutics in the treatment of patients with locally
>65 years 12 (52.2%) 5 (35.7%) advanced and/or meta-static penile SqCC. Indeed, based on the
Circumcision status
results of monotherapy clinical trials in other malignancies [7–
Yes 4 (22.2%) 2 (18.2%) 1.000
11], which suggest that patients with PD-L1 expression by
No 14 (77.8%) 9 (81.8%)
tumor cells have a greater response to PD-1 and/or PD-L1
Histologic subtype
inhibition, our findings suggest that a subset of penile SqCC
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Background: ARCHER 1042, a randomized phase II trial, explored the impact of prophylactic treatment on select derma-tologic
adverse events of interest (SDAEI), diarrhea, and mucositis associated with dacomitinib, an oral irreversible pan-human
epidermal growth factor receptor (HER) inhibitor, in development for advanced non-small-cell lung cancer (NSCLC).
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.