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Keratins are the intermediate filament (IF)-forming proteins of epithelial cells. Since their initial characterization almost 30 years ago, the total number of mammalian keratins has increased to 54, including 28 type I and 26 type II keratins. Keratins are obligate heteropolymers and, similarly to other IFs, they contain a dimeric central α-helical rod domain that is flanked by non-helical head and tail domains. The 10-nm keratin filaments participate in the formation of a proteinaceous structural framework within the cellular cytoplasm and, as such, serve an important role in epithelial cell protection from mechanical and non-mechanical stressors, a property extensively substantiated by the discovery of human keratin mutations predisposing to tissue-specific injury and by studies in keratin knockout and transgenic mice. More recently, keratins have also been recognized as regulators of other cellular properties and functions, including apico-basal polarization, motility, cell size, protein synthesis and membrane traffic and signaling. In cancer, keratins are extensively used as diagnostic tumor markers, as epithelial malignancies largely maintain the specific keratin patterns associated with their respective cells of origin, and, in many occasions, full-length or cleaved keratin expression (or lack there of) in tumors and/or peripheral blood carries prognostic significance for cancer patients. Quite intriguingly, several studies have provided evidence for active keratin involvement in cancer cell invasion and metastasis, as well as in treatment responsiveness, and have set the foundation for further exploration of the role of keratins as multifunctional regulators of epithelial tumorigenesis. [ABSTRACT FROM AUTHOR]

Previous studies have shown that increased levels of the adaptor protein Sequestosome 1/p62 are observed in human breast cancers and significantly correlate with HER2 overexpression. However, the role of p62 in the pathophysiology of HER2-induced mammary tumorigenesis has not yet been investigated. In this study, we report that p62 facilitates HER2-mediated cell survival in both two-dimensional and three-dimensional cell culture and that HER2-induced cellular transformation requires p62, as well as NRF2, which is known to become stabilized by its release from Kelch-like ECH-associated protein 1 (KEAP1) via p62-KEAP1 interaction. In agreement with these results, genetic ablation of p62 delays HER2-induced mammary tumorigenesis in tumor cell allografts in nude mice, and in MMTV-Neu transgenic mice. We also report that ablation of p62 impairs AKT and β-catenin activation in association with PTEN (phosphatase and tensin homolog deleted on chromosome ten) accumulation, both in vitro and in vivo. Further in vivo studies suggest that loss of p62 also impairs NF-κB and NRF2 activation. Collectively, our results provide compelling evidence that p62 contributes to HER2-induced mammary tumorigenesis through multiple signaling pathways, including the PTEN/phosphoinositide-3-kinase/AKT axis, WNT/β-catenin signaling, the NF-κB pathway and the NRF2-KEAP1 axis, and offer novel insights into the potential role of p62 in the regulation of the tumor suppressor PTEN. [ABSTRACT FROM AUTHOR]

Background: In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1-staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported.Methods: We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator's choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine-carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed.Results: A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab-chemotherapy group, and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group and 16.1 months in the placebo-chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P = 0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P = 0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab-chemotherapy group and in 66.9% in the placebo-chemotherapy group, including death in 0.4% of the patients in the pembrolizumab-chemotherapy group and in no patients in the placebo-chemotherapy group.Conclusions: Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.). [ABSTRACT FROM AUTHOR]

The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic triple-negative breast cancer (TNBC). Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs). Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels. ClinicalTrials.gov identifier: NCT02622074. • Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC. • Two chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 qw; paclitaxel 80 mg/m2 qw + carboplatin AUC5 q3w. • pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80% to 100% across cohorts. • pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels. [ABSTRACT FROM AUTHOR]

Background: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.Methods: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population.Results: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively.Conclusions: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.). [ABSTRACT FROM AUTHOR]

Background Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. Results All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9–31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9–34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0–2.2), and median overall survival was 18.0 months (95% CI 12.9–23.0). Conclusions Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. Clinical trial registration ClinicalTrials.gov, NCT02447003. [ABSTRACT FROM AUTHOR]

Background Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. Results All enrolled patients (N  =   170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2+–21.5+) and in the PD-L1–positive (range, 6.3–21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. Clinical trial registration ClinicalTrials.gov, NCT02447003 [ABSTRACT FROM AUTHOR]

The Pak4 serine/threonine kinase is highly expressed in many cancer cell lines and human tumors. Although several studies have addressed the role for Pak4 in transformation of fibroblasts, most human cancers are epithelial in origin. Epithelial cancers are associated not only with changes in cell growth but also with changes in the cellular organization within the three-dimensional (3D) architecture of the affected tissues. In this study we used immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the role for Pak4 in mammary tumorigenesis. iMMECs are an excellent model system for studying breast cancer, as they can grow in 3D-epithelial cell culture, in which they form acinar structures that recapitulate in vivo mammary morphogenesis. Although Pak4 is expressed at low levels in wild-type iMMECs, it is overexpressed in response to oncogenes, such as oncogenic Ras and Her2/neu. In this study we found that overexpression of Pak4 in iMMECs leads to changes in 3D acinar architecture that are consistent with oncogenic transformation. These include decreased central acinar cell death, abrogation of lumen formation, cell polarity alterations and deregulation of acinar size and cell number. Furthermore, iMMECs overexpressing Pak4 form tumors when implanted into the fat pads of athymic mice. Our results suggest that overexpression of Pak4 triggers events that are important for the transformation of mammary epithelial cells. This is likely to be owing to the ability of Pak4 to inhibit apoptosis and promote cell survival and thus subsequent uncontrolled proliferation, and to its ability to deregulate cell shape and polarity. [ABSTRACT FROM AUTHOR]

Background A high-risk subpopulation of ER+/HER2− breast cancer (BC) is characterized by high-grade tumors, decreased sensitivity to endocrine therapy (ET), higher responsiveness to chemotherapy (CT), and worse prognosis. Prior studies suggest that increased pathological complete response (pCR) rates after neoadjuvant CT may have a substantial impact for patients with high-risk, early-stage, HR+/HER2− BC. KEYNOTE-756 (NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (vs placebo) + CT as neoadjuvant treatment followed by pembrolizumab (vs placebo) + ET as adjuvant treatment for patients with high-risk, early-stage, ER+/HER2− BC. Trial design Patients with T1c-2 cN1-2 (tumor size ≥2 cm) or T3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive [CPS ≥1] vs negative [CPS <1]), ER positivity (ER + ≥10% vs ER + <10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo combined with paclitaxel (80 mg/m2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m2) or epirubicin (100 mg/m2), each with cyclophosphamide (600 mg/m2) Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembrolizumab (200 mg Q3W) or placebo for 9 more administrations combined with ET, which can be given for up to 10 years. No crossover between treatment cohorts when moving from neoadjuvant to adjuvant treatment is allowed. Dual primary endpoints are pCR rate (ypT0/Tis ypN0) and event-free survival (EFS). Secondary endpoints include ypT0/Tis and ypT0 ypN0 pCR rates in all patients and all 3 pCR definitions in those with PD-L1+ tumors, EFS in patients with PD-L1+ tumors, overall survival, safety, and health-related quality of life. Enrollment is currently ongoing in 22 countries around the world, including Korea, Taiwan, China, and Japan. Clinical trial identification NCT03725059. Legal entity responsible for the study Merck & Co. Inc. Funding Funding for this study was provided by Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Disclosure F. Cardoso: Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas/Medivation; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Daiichi-Sankyo; Advisory / Consultancy: Eisai; Advisory / Consultancy: GE Oncology; Advisory / Consultancy: Genentech; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Medscape; Advisory / Consultancy: Merck-Sharp; Advisory / Consultancy: Merus BV; Advisory / Consultancy: Mylan; Advisory / Consultancy: Mundipharma GmbH; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pierre-Fabre; Advisory / Consultancy: prIME Oncology; Advisory / Consultancy: Roche. A. Bardia: Advisory / Consultancy, Research grant / Funding (self): bioTheranostics; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Innocrin Pharmaceuticals; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Radius Health; Advisory / Consultancy: Radius Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Spectrum Pharmaceuticals. F. André: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Roche. D.W. Cescon: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche/Genentech. H. McArthur: Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: OBI Pharma; Advisory / Consultancy: Roche; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Syndax Pharmaceuticals; Advisory / Consultancy: Peregrine; Advisory / Consultancy: Calithera; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): MedImmunne; Research grant / Funding (self): LLC/AstraZeneca. M. Telli: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Aduro; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Immunomedics; Advisory / Consultancy: Celldex; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): OncoSec; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Vertex; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): PharmaMar. S. Loi: Advisory / Consultancy: AstraZeneca/MedImmune; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Puma Biotechnology. J. Cortes: Shareholder / Stockholder / Stock options: MedSIR; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self): Samsung; Advisory / Consultancy: Cellestia Biotech; Advisory / Consultancy, Research grant / Funding (institution): AstaZeneca; Advisory / Consultancy: Biothera; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi-Sankyo; Advisory / Consultancy: ERYTECH Pharma; Advisory / Consultancy: Polyphor; Research grant / Funding (institution): ARIAD; Research grant / Funding (institution): Baxalta GmbH; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Merck. P. Schmid: Full / Part-time employment: Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Celgene; Honoraria (self): Eisai; Honoraria (self), Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Pfizer; Honoraria (self): Puma Biotechnology; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Oncogenex. N. Harbeck: Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. C. Denkert: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Teva; Honoraria (self): Roche; Shareholder / Stockholder / Stock options: Sividon Diagnostics; Advisory / Consultancy: Daiichi-Sankyo; Advisory / Consultancy: MSD Oncology; Licensing / Royalties, patent application—therapy response: EP20150702464; Licensing / Royalties, patent application— cancer immunotherapy: EP18209672; Licensing / Royalties, digital pathology software: VMScope. C. Jackisch: Honoraria (self), Advisory / Consultancy: Merck. L. Jia: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. K. Hirshfield: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. V. Karantza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck. [ABSTRACT FROM AUTHOR]

Neoadjuvant studies in breast cancer (BC) patients have well-demonstrated that attaining pathological complete response (pCR) is associated with improved event-free survival (EFS) and overall survival (OS); and the association is strong in triple negative BC (TNBC) subtype. This study aimed to comprehensively evaluate the association of pCR and survival outcomes in TNBC by incorporating most recent studies; and to explore the impact of different study settings, thresholds of hormone receptor positivity defining TNBC and adjuvant chemotherapy usage on this association. A literature search of neoadjuvant studies in TNBC was conducted up to October 2018. Clinical trials (CTs), real-world evidence (RWE) studies and meta-analyses (MA) with EFS/OS reported by pCR outcome were included. Main analyses were restricted to pCR definition of absence of tumor in the breast and axillary nodes, which is aligned with FDA guidance. Hazard ratios (HRs) evaluating the association between pCR and EFS/OS were derived from meta-analyses using fixed-effect and random-effects models. To further quantify the association, meta-analyses were conducted to synthesize the published survival curves by pCR outcome. A random-effects frailty model was utilized to account for between-study variation. Four randomized CTs, 2 single-arm CTs, 18 RWE studies and 1 MA for a total of 4,330 patients with TNBC were included in this study. Achieving pCR was strongly associated with improved survival outcomes (HR of EFS: 0.26, 95% CI: 0.22-0.30; and HR of OS: 0.20, 95% CI: 0.16-0.25). HR results were similar across study settings of CTs, RWE and MA. TNBC definition and adjuvant chemotherapy use did not have significant impact on HR results. The meta-analyses showed numerically longer survival in studies that reported adjuvant chemotherapy usage compared with those which did not, irrespective of attainment of pCR. This study confirms the strong association between pCR and survival outcomes in TNBC based on evidence synthesis from both clinical and real-world settings. In addition, this study suggests potential survival benefit of subsequent adjuvant therapy for TNBC patients who received neoadjuvant therapy. Merck & Co., Inc. Merck & Co., Inc. P.A. Fasching: Advisory / Consultancy: Merck & Co., Inc. M. Huang: Full / Part-time employment: Merck & Co., Inc. J. Cortés: Advisory / Consultancy: Merck & Co., Inc. J. Zhao: Full / Part-time employment: Merck & Co., Inc. J. O'Shaughnessy: Advisory / Consultancy: Merck & Co., Inc. P. Hu: Full / Part-time employment: Merck & Co., Inc. A. Haiderali: Full / Part-time employment: Merck & CO., Inc. V. Karantza: Full / Part-time employment: Merck & Co., Inc. G. Aktan: Full / Part-time employment: Merck & Co., Inc. A. Briggs: Advisory / Consultancy: Merck & Co., Inc. S. Ramsey: Advisory / Consultancy: Merck & Co., Inc. C.Z. Qi: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. J. Xie: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. C. Gu: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. K. Qian: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. M. Yuan: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. E.Q. Wu: Advisory / Consultancy, Employee of Analysis Group, Inc., which has received consulting fees from Merck & Co., Inc.: Merck & Co., Inc. [ABSTRACT FROM AUTHOR]