Debora de Melo Gagliato

Clinical Impact of Delaying Initiation of Adjuvant Chemotherapy in Patients With Breast Cancer

PURPOSE For patients with breast cancer (BC), the optimal time to initiation of adjuvant chemotherapy (TTC) after definitive surgery is unknown. We evaluated the association between TTC and survival according to breast cancer subtype and stage at diagnosis. PATIENTS AND METHODS Women diagnosed with BC stages I to III between 1997 and 2011 who received adjuvant chemotherapy at our institution were included. Patients were categorized into three groups according to TTC: ≤ 30, 31 to 60, and ≥ 61 days. Survival outcomes were estimated and compared according to TTC and by BC subtype. RESULTS Among the 6,827 patients included, the 5-year overall survival (OS), relapse-free survival (RFS), and distant RFS (DRFS) estimates were similar for the different TTC categories. Initiation of chemotherapy ≥ 61 days after surgery was associated with adverse outcomes among patients with stage II (DRFS: hazard ratio [HR], 1.20; 95% CI, 1.02 to 1.43) and stage III (OS: HR, 1.76; 95% CI, 1.26 to 2.46; RFS: HR, 1.34; 95% CI, 1.01 to 1.76; and DRFS: HR, 1.36; 95% CI, 1.02 to 1.80) BC. Patients with triple-negative BC (TNBC) tumors and those with human epidermal growth factor receptor 2 (HER2) -positive tumors treated with trastuzumab who started chemotherapy ≥ 61 days after surgery had worse survival (HR, 1.54; 95% CI, 1.09 to 2.18 and HR, 3.09; 95% CI, 1.49 to 6.39, respectively) compared with those who initiated treatment in the first 30 days after surgery. CONCLUSION TTC influenced survival outcomes in the overall study cohort. This finding was particularly meaningful for patients with stage III BC, TNBC, and trastuzumab-treated HER2-positive tumors who experienced worse outcomes when chemotherapy was delayed. Our findings suggest that early initiation of chemotherapy should be granted for patients in these high-risk groups.

Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer.

Breast Cancer (BC) is a highly prevalent disease. A woman living in the United States has a 12.3% lifetime risk of being diagnosed with breast cancer [1]. It is the most common female cancer and the second most common cause of cancer death in women [2]. Of note, amplification or overexpression of Human Epidermal Receptor 2 (HER2) oncogene is present in approximately 18 to 20% of primary invasive breast cancers, and until personalized therapy became available for this specific BC subtype, the worst rates of Overall Survival (OS) and Recurrence-Free Survival (RFS) were observed in the HER2+ BC cohort, compared to all other types, including triple negative BC (TNBC) [3]. HER2 is a member of the epidermal growth factor receptor (EGFR) family. Other family members include EGFR or HER1, HER3 and HER4. HER2 can form heterodimers with any of the other three receptors, and is considered to be the preferred dimerization partner of the other HER or ErbB receptors [4]. Phosphorylation of tyrosine residues within the cytoplasmic domain is the result of receptor dimerization and culminates into initiation of a variety of signalling pathways involved in cellular proliferation, transcription, motility and apoptosis inhibition [5]. In addition to being an important prognostic factor in women diagnosed with BC, HER2 overexpression also identifies those patients who benefit from treatment with agents that target HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and small molecules tyrosine kinase inhibitors of HER2 [6, 11, 127]. In fact, trastuzumab altered the natural history of patients diagnosed with HER2+ BC, both in early and metastatic disease setting, in a major way [8–10]. Nevertheless, there are many women that will eventually develop metastatic disease, despite being treated with anti-HER2 therapy in the early disease setting. Moreover, advanced tumors may reach a point where no anti-HER2 treatment will achieve disease control, including recently approved drugs, such as T-DM1. This review paper will concentrate on major biological pathways that ultimately lead to resistance to anti-HER2 therapies in BC, summarizing their mechanisms. Strategies to overcome this resistance, and the rationale involved in each tactics to revert this scenario will be presented to the reader.

Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications. Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status. Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response. Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.

Multigene Clinical Mutational Profiling of Breast Carcinoma Using Next-Generation Sequencing

OBJECTIVES The advent of next-generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics provides multigene mutational profiling through massively parallel sequencing. METHODS We analyzed 415 breast carcinoma samples from 354 patients using NGS in known hotspots of 46 commonly known cancer-causing genes. RESULTS A total of 281 somatic nonsynonymous mutations were detected in 62.1% of patients. TP53 was most frequently mutated (38.8%), followed by PIK3CA (31.7%), AKT1 (6%), and ATM (3.9%), with other mutations detected at a lower frequency. When stratified into clinically relevant therapeutic groups (estrogen receptor [ER]/progesterone receptor [PR]+ human epidermal growth factor receptor 2 [HER2]-, ER/PR+HER2+, ER/PR-HER2+, ER/PR/HER2-), each group showed distinct mutational profiles. The ER/PR+HER2- tumors (n = 132) showed the highest frequency of PIK3CA mutations (38%), while the triple-negative tumors (n = 64) had a significantly higher number of TP53 mutations (62%). Of the 61 patients tested for both primary and metastatic tumors, concordant results were seen in 47 (77%) patients, while 13 patients showed additional mutations in the metastasis. CONCLUSIONS Our results indicate that breast cancers may harbor potentially actionable mutations for targeted therapeutics. Therefore, NGS-based mutational profiling can provide useful information that can guide targeted cancer therapy.

MET Abnormalities in Patients With Genitourinary Malignancies and Outcomes With c-MET Inhibitors

BACKGROUND The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors. PATIENTS AND METHODS Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors. RESULTS MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment. CONCLUSION MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.

Clinical outcomes based on multigene profiling in metastatic breast cancer patients

BACKGROUND Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Synergy Between VEGF/VEGFR Inhibitors and Chemotherapy Agents in the Phase I Clinic

Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5–2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1–2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3–0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5–4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1–0.3), Pinteraction = 0.004]. Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. Clin Cancer Res; 20(23); 5956–63. ©2014 AACR.

Analysis of Drug Development Paradigms for Immune Checkpoint inhibitors

Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.

The Association between EGFR and cMET Expression and Phosphorylation and Its Prognostic Implication in Patients with Breast Cancer

EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall survival (OS). Cox-proportional hazards models were utilized to determine associations between EGFR and cMET with outcomes. Mean age was 58 years with 457 (55%) hormone receptor (HR) positive, 211 (26%) triple-negative (TN) and 148 (18%) HER2 positive tumors (HER2+). HER2+ was associated with higher EGFR expression and phosphorylation, compared to HR and TN (p<0.05). High EGFR expression was associated with higher phosphorylated-cMET (p-cMET) but not cMET (ANOVA p-cMET p < 0.001; cMET p = 0.34). The same association was found with high phosphorylated-EGFR (p-EGFR) group at Tyr992 and Tyr1068 (both p < 0.001). High expressions in either of two p-EGFRs were linked with higher cMET as well (all p<0.001). For the TN subtype, high expression in EGFR and p-EGFR at Tyr992 but not at Tyr1068 was associated with higher p-cMET (p<0.00, p = 0.012, p = 0.4 respectively). Only high expression in p-EGFR at Tyr992 was linked with higher expression of cMET (p = 0.02). In contrast, among HER2 subtype, high expression in p-EGFR at Tyr1068 but not at Tyr992 was associated with higher cMET and p-cMET (cMET p = 0.023;p-cMET p<0.001). Four subgroups of patients defined by dichotomized EGFR/p-EGFR and cMET/p-cMET level demonstrated no significant differences in survival. In multivariate analyses, neither cMET nor EGFR expression/activation was found to be an independent prognostic factor in survival outcome.

Association of hypothyroidism with improved outcomes in first-line treatment of renal cell carcinoma with sunitinib.

466 Background: Sunitinib, a multitarget tyrosine-kinase inhibitor, has become a standard of care for first-line low and intermediate risk metastatic renal cell carcinoma (mRCC). Sunitinib-induced hypothyroidism and hypertension have been correlated with better outcomes in those patients. METHODS Fifty patients with mRCC, treated in the first-line with sunitinib, were retrospective analyzed at one brazilian institution, for overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicity. We evaluated clinical and laboratory parameters, such as hypothyroidism (TSH level > 5,5 mIU/L) and hypertension, to identify prognostic factors. RESULTS The median age of patients was 58 years (range: 37-73 years), 82% were male, 54% were ECOG 0 or 1, and 76% were classified in low or intermediate risk. Nefrectomy was performed in 96% of cases. Lung and bone were the most common sites of metastases. The incidence of hypothyroidism and hypertension during treatment were 40% and 34%, respectively. ORR for the entire population was 40% and it was statistically superior in patients that developed hypothyroidism during treatment (90% vs. 20%; p<0,0001). Median survival and PFS were 21.7 months (10.65-17.70 months, 95% CI) and 14.2 months (15.77-27.58 months, 95% CI), respectively. In univariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001), hypothyroidism (p<00001) and hypertension (p=0,001) were associated with OS. In multivariate analysis, ECOG (p<0,0001), MSKCC criteria (p<0,0001) and hypothyroidism (p<00001) were independent prognostic factors for OS. The most common severe adverse events (G3-4) were asthenia (14%), diarrhoea (6%), neutropenia (14%), thrombocytopenia (10%), hand-foot syndrome (6%) and hypertension (8%). CONCLUSIONS Efficacy in survival and toxicity profile of sunitinib in first-line treatment of mRCC in patients out of clinical trials were comparable to prior studies. Hypothyroidism, MSKCC criteria and ECOG were independent prognostic factors for survival.