Natural History of Germline BRCA1 Mutated and BRCA Wild-type Triple-negative Breast Cancer.

We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone. SIGNIFICANCE: In germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

Development and characterization of a patient­derived orthotopic xenograft of therapy­resistant breast cancer.

Numerous years of cell line­based studies have enhanced the current understanding of cancer and its treatment. However, limited success has been achieved in treating hormone receptor­positive, HER2­negative metastatic breast cancers that are refractory to treatment. The majority of cancer cell lines are unsuitable for use as pre­clinical models that mimic this critical and often fatal clinical type, since they are derived from treatment­naive or non­metastatic breast cancer cases. The aim of the present study was to develop and characterize patient­derived orthotopic xenografts (PDOXs) from patients with endocrine hormone receptor­positive, HER2­negative metastatic breast cancer who had relapsed on therapy. A patient who progressed on endocrine hormone therapy provided her tumor via a biobank. This tumor was implanted in mice. It was then serially passaged by implanting PDOX tumor fragments into another set of mice to develop further generations of PDOXs. These tissues were characterized using various histological and biochemical techniques. Histological, immunofluorescence and western blot analyses indicated that the PDOX tumors retained a similar morphology, histology and subtype­specific molecular features to that of the patient's tumor. The present study successfully established PDOXs of hormone­resistant breast cancer and characterized them in comparison with those derived from the original breast cancer tissue of the patient. The data highlight the reliability and usefulness of PDOX models for studies of biomarker discovery and preclinical drug screening. The present study was registered with the clinical trial registry of India (CTRI; registration no. CTRI/2017/11/010553; registered on 17/11/2017).

Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice.

BACKGROUND: There is scant data from India on efficacy and safety of palbociclib and ribociclib in routine clinical practice. METHODS: This retrospective, observational, single institution study included patients with estrogen and/or progesterone receptor positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancers, who received palbociclib or ribociclib with any partner endocrine therapy in any line of treatment between January 2016 and June 2019. Data were analyzed for progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: The study included 101 female patients with median age of 57 (IQR 48-62) years, of whom 80 (79.2%) were postmenopausal, 79 (78.2%) received palbociclib or ribociclib in second- or later-line treatment, 59 (58.4%) received fulvestrant and 41 (40.6%) received an aromatase inhibitor. In first-line treatment, at a median follow-up of 21.7 (0.5-41.9) months, median PFS and OS were 21.1 (95%CI 16.36-not estimable) months and not reached, respectively. In second- or later-line setting, at a median follow-up of 17.2 (0.5-43.7) months, median PFS and OS were 5.98 (95%CI 4.96-7.89) months and 20.2 (95%CI 14.1-not estimable) months, respectively. Grade 3-4 neutropenia and febrile neutropenia were seen in 45 (45.0%) and 9 (9.0%) patients, respectively while dose reduction was required in 32 (31.7%) patients. In multivariable Cox regression analysis, first-line setting (HR 0.49, 95%CI 0.25-0.97, p = 0.043) and ECOG performance status 1 (HR 0.43, 95%CI 0.20-0.91, p = 0.028) were significantly associated with PFS while only ECOG PS 1 was significantly associated (HR 0.04, 95%CI 0.008-0.206, p = 0.000) with OS. CONCLUSION: Palbociclib and ribociclib, when used in routine clinical practice in first or subsequent lines of treatment, resulted in efficacy and toxicity outcomes in concordance with those expected from pivotal trials.

A Multicentre Observational Study on Risk Factors for Breast Cancer.

BACKGROUND: Breast cancer is the most common malignancy in Indian women. There is scant data from Indian hospital-based populations on the prevalence of risk factors of this disease. We performed this study to quantify and analyze various epidemiological risk factors in Indian breast cancer patients. METHODS: This was a multicenter collaborative study wherein breast cancer patients older than 18 years were served a structured questionnaire after informed consent. Patients or their relatives were required to fill out the questionnaire and those who were unable to read and write were excluded. Data were abstracted from case record forms and variables were descriptively analyzed. RESULTS: Between January 2015 and February 2016, 800 patients were screened, of whom 736 patients with a mean age of 50.13 years were enrolled in the study. The mean number of pregnancies was 2.75 (0-11), the number (percentage) of women who had breastfed for more than 6 months was 628 (85.3) and 406 (55.1%) patients were post-menopausal at the time of breast cancer diagnosis. Of the enrolled patients, 91 (12.8%) had history of exposure to passive smoke, 13 (1.8%) had partners who were heavy smokers, 27 (3.7%) had history of oral contraceptive use, 4 (0.5%) had history of hormone replacement therapy, and 103 (14%) had undergone hysterectomy with oophorectomy. CONCLUSION: Our study contributes to the descriptive prevalence of some known risk factors in Indian breast cancer patients.

Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or IIB Squamous Cervical Cancer: A Randomized Controlled Trial.

Purpose We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical cancer. Patients and Methods This was a single-center, phase III, randomized controlled trial ( ClinicalTrials.gov identifier: NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every 3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free survival (DFS), defined as survival without relapse or death related to cancer, and secondary end points included overall survival and toxicity. Results Between September 2003 and February 2015, 635 patients were randomly assigned, of whom 633 (316 patients in the neoadjuvant chemotherapy plus surgery group and 317 patients in the concomitant chemoradiation group) were included in the final analysis, with a median follow-up time of 58.5 months. The 5-year DFS in the neoadjuvant chemotherapy plus surgery group was 69.3% compared with 76.7% in the concomitant chemoradiation group (hazard ratio, 1.38; 95% CI, 1.02 to 1.87; P = .038), whereas the corresponding 5-year OS rates were 75.4% and 74.7%, respectively (hazard ratio, 1.025; 95% CI, 0.752 to 1.398; P = .87). The delayed toxicities at 24 months or later after treatment completion in the neoadjuvant chemotherapy plus surgery group versus the concomitant chemoradiation group were rectal (2.2% v 3.5%, respectively), bladder (1.6% v 3.5%, respectively), and vaginal (12.0% v 25.6%, respectively). Conclusion Cisplatin-based concomitant chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer.