BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients.

PURPOSE: BRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy. METHODS: We included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3-4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort). RESULTS: Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups. CONCLUSIONS: BRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

Analysis of the benefit of salvage chemotherapy after progression on nivolumab in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Checkpoint inhibitor (CI) therapies have shown benefit in the treatment of locally recurrent or metastatic head and neck squamous cell carcinoma (R L/M HNSCC). Previous studies have suggested a superior benefit of salvage chemotherapy (SCT) in R/M HNSCC after progression on CI. We aimed to describe the benefit of SCT after progression on nivolumab. PATIENTS AND METHODS: Patients were eligible if they received at least one injection of SCT in the treatment of R/M HNSCC after progression on nivolumab between 2017 and 2022. The present work was a retrospective and monocenter study. Primary endpoint was the objective response rate (ORR) on first regimen of salvage chemotherapy (SCT1). Secondary endpoints were disease-control rate (DCR), ORR on second course of SCT (ORR2), progression-free survival (PFS) on SCT1 and SCT2 (PFS2) and overall survival (OS). RESULTS: Eighty-three patients received an SCT. The ORR on STC1 was 32%. Median progression-free survival (PFS) was 2.20 months (CI 95% 2.06-3.71). Median OS was 5.55 months (CI 95% 4.82-10.20). The ORR to the first line of treatment in the relapse setting was an independent prognostic factor for SCT1 PFS and OS. CONCLUSION: In R/M HNSCC, SCT following nivolumab is associated with ORRs of 32%. These results are consistent with other publications that suggest a superior benefit of SCT after CI treatment, independent of the tumor outcome on previous immunotherapy.

Using Breast Cancer Gene Expression Signatures in Clinical Practice: Unsolved Issues, Ongoing Trials and Future Perspectives.

The development of gene expression signatures since the early 2000's has offered standardized assays to evaluate the prognosis of early breast cancer. Five signatures are currently commercially available and recommended by several international guidelines to individualize adjuvant chemotherapy decisions in hormone receptors-positive/HER2-negative early breast cancer. However, many questions remain unanswered about their predictive ability, reproducibility and external validity in specific populations. They also represent a new hope to tailor (neo)adjuvant systemic treatment, adjuvant radiation therapy, hormone therapy duration and to identify a subset of patients who might benefit from CDK4/6 inhibitor adjuvant treatment. This review will highlight these particular issues, address the remaining questions and discuss the ongoing and future trials.

Publisher Correction: Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.

BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44-0.90 for BRCA1; HR = 0.72; 95%CI, 0.47-1.1 for BRCA2; p = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40-1.1 for BRCA1; HR = 0.78; 95%CI, 0.44-1.38 for BRCA2; p = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28-0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11-1.25, for BRCA2; p = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21-0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11-1.9 for BRCA2; p = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.

An onco-geriatric approach to select older patients for optimal treatments of pancreatic adenocarcinoma.

INTRODUCTION: Pancreatic adenocarcinoma affects mainly older patients. Surgery is indicated for localized tumors while chemotherapy alone is proposed in advanced or metastatic tumors. OBJECTIVE: To evaluate the feasibility of standard of care oncologic treatments in this population, the accuracy of the geriatric evaluation to predict the ability of patients to tolerate the recommended treatments and to identify specific geriatric prognosis factors. METHODS: We included, between 2007 and 2014, all consecutive patients over 70 years of age with a pathologically diagnosed pancreatic cancer. The patients underwent a comprehensive geriatric assessment before therapeutic decision in a multidisciplinary team meeting. We analyzed factors independently associated with all-cause mortality with Cox survival analysis. RESULTS: Seventy-three patients (median age = 77.9 years) were prospectively included. Among them, 42 patients underwent surgery whereas the 31 other patients not eligible for surgical treatment received chemotherapy (n = 22) or best supportive care alone (n = 9). Almost 62% of operated patients received adjuvant chemotherapy. In the non-surgical group, a mean of 9 cycles of palliative chemotherapy per patients were administrated. Median overall survival was 21.3 months in the surgical group and 6.1 months in the palliative group (p = 0.0001). Most of oncologic parameters were found to be independent survival predictors. Age was not associated with the survival, but a significant impact of Lawton's Instrumental Activities of Daily Living (IADL) impairment (IADL<4) (HR = 5.0, p = 0.047), Cumulative Index Rating Scale-Geriatric (CIRS-G) ≥2 (HR = 19, p = 0.035) and weight loss >10% (HR = 4.6, p = 0.03) on survival was detected. Surgery was the only factor independently predictive of survival in multivariate analysis (p < 0.001). CONCLUSION: Almost 90% of selected older pancreatic patients with cancer (64 out of 73 patients) may benefit from the same standard treatments as younger patients. IADL impairment of patients, CIRS-G ≥2, and weight loss >10% constitute survival prognostic factors which should be added to the oncological criteria in the therapeutic decision-making process.