Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.

BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure. PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973.

Rapidly fatal neuropathies and an ALS clinical presentation.

OBJECTIVES - The objective of this report is to describe patients with an unusually severe, rapidly fatal acquired polyneuropathy. METHODS - The clinical, electrodiagnostic (EDX), laboratory, and pathological findings in three patients with a distinctive form of neuropathic illness are discussed. RESULTS - Three patients, ages 67, 54, and 50, had clinical findings that met accepted clinical criteria for amyotrophic lateral sclerosis (ALS) - definite in two and probable in one. The EDX studies in these patients had abnormalities that would be highly atypical for ALS. There were features consistent with an asymmetrical, non-length-dependent process as well findings consistent with demyelination - features consistent with a chronic acquired polyneuropathy. All patients had a rapidly progressive course with death because of respiratory failure in 4-30 months. The patients did not respond to immunomodulating therapies. Extensive evaluations in these patients did not reveal a cause for the patients' neuropathies. Postmortem examination in two of the patients did not reveal evidence for ALS. In one of these patients, there were pathological findings thought possibly consistent with an immunologically mediated process. CONCLUSION - This report emphasizes the importance of considering other diagnoses in patients who clinically appear to have ALS and raise the specter of an as of yet poorly understood, severe neuropathic illness.