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.

Risk factors for the development of triple-negative breast cancer versus non-triple-negative breast cancer: a case-control study.

The risk factors for breast cancer have been defined in several studies but there is deficient data for specific subtypes. We report here the pathological characteristics of a breast cancer cohort and risk factors for patients with triple-negative disease. In this case-control study, a prospective breast cancer cohort was evaluated for demographic, reproductive, obesity-related and other risk factors using a validated questionnaire. Tumors were characterized for routine pathological characteristics and immunohistochemical markers of basal-like breast cancer. Patients with triple-negative breast cancer (TNBC) constituted cases and those with non-TNBC were controls. Odds ratios (OR) were calculated for each risk factor and independent associations were tested in an unconditional logistic regression analysis. Between 2011 and 2014, 1146 patients were recruited, of whom 912 [TNBC 266 (29.1%), non-TNBC 646 (70.9%)] with sufficient pathology material were analysed. Reproductive factors of parity, breastfeeding, age-at-menarche, age at first full-term pregnancy and oral contraceptive use were not significantly associated with TNBC. Higher body mass index (BMI > 24.9 vs ≤ 24.9, OR 0.89, 95%CI 0.63-1.24, p = 0.49) was not significantly associated while lesser waist circumference (> 80 cm vs ≤ 80 cm, OR 0.64, 95%CI 0.45-0.9, p = 0.012) and lower waist-to-hip ratio were significantly associated (> 0.85 vs ≤ 0.85, OR 0.72, 95%CI 0.51-1.0, p = 0.056), with TNBC. History of tobacco use was not significantly associated while lower socio-economic status was borderline associated with TNBC (socio-economic category > 5 versus ≤ 5, OR 0.73, 95%CI 0.50-1.06, p = 0.106). No factor was significant after adjustment for covariates. Central obesity seems to be preferentially associated with non-TNBC, and lower socio-economic status with TNBC in India, while most other conventional risk factors of breast cancer show no significant association with TNBC versus non-TNBC.

Survival outcomes with 12 weeks of adjuvant or neoadjuvant trastuzumab in breast cancer.

Background: There is limited access to 1 year of adjuvant trastuzumab in resource-constrained settings. Most randomized studies have failed to prove non-inferiority of shorter durations of adjuvant trastuzumab compared to 1 year However, shorter durations are often used when 1 year is not financially viable. We report the outcomes with 12 weeks of trastuzumab administered as part of curative-intent treatment. Methods: This is a retrospective analysis of patients treated at Tata Memorial Centre, Mumbai, a tertiary care cancer center in India. Patients with human epidermal growth factor receptor (HER2)-positive early or locally advanced breast cancer who received 12 weeks of adjuvant or neoadjuvant trastuzumab with paclitaxel and four cycles of an anthracycline-based regimen in either sequence, through a patient assistance program between January 2011 and December 2012, were analyzed for disease-free survival (DFS), overall survival (OS), and toxicity. Results: A total of 102 patients were analyzed with a data cutoff in September 2019. The median follow-up was 72 months (range 6-90 months), the median age was 46 (24-65) years, 51 (50%) were postmenopausal, 37 (36%) were hormone receptor-positive, and 61 (60%) had stage-III disease. There were 37 DFS events and 26 had OS events. The 5-year DFS was 66% (95% Confidence Interval [CI] 56-75%) and the OS was 76% (95% CI 67-85%), respectively. Cardiac dysfunction developed in 11 (10.7%) patients. Conclusion: The use of neoadjuvant or adjuvant 12-week trastuzumab-paclitaxel in sequence with four anthracycline-based regimens resulted in acceptable long-term outcomes in a group of patients, most of whom had advanced-stage nonmetastatic breast cancer.

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.

Effect of body mass index on pharmacokinetics of paclitaxel in patients with early breast cancer.

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.

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.

Translation and validation of European Organization for Research and Treatment for Cancer quality of life questionnaire-OV-28 module into Indian languages (Hindi and Marathi) to study quality of life of ovarian cancer patients from a tertiary care cancer center.

AIM: The aim is to translate and validate the European Organization for Research and Treatment for Cancer (EORTC) ovarian cancer (OC) module (OV-28) into Hindi and Marathi to use for patients and scientific community. METHODS AND RESULTS: The EORTC OV-28 was translated into Hindi and Marathi languages using prescribed guidelines by the EORTC. The process included forward translation by four translators (2 each for Hindi and Marathi). The questionnaires obtained were then given to independent backward-translators who then translated them back into English. These 2 questionnaires were then compared with the original EORTC questionnaire and the second intermediate questionnaires were formed. The second intermediate questionnaire was subsequently administered in twenty patients (10 each for Hindi and Marathi) diagnosed with OC who had never seen the questionnaire before, for pilot testing. Each of these ten patients after filling up the questionnaire themselves was then interviewed for any difficulty encountered during the filling up of the questionnaires. These were in the form of specific modules including difficulty in answering, confusion while answering, and difficulty to understand, whether the questions were upsetting and if patients would have asked the question in any different way. The suggestions were incorporated into the second intermediate questionnaires to form the final Hindi and Marathi ON-28 questionnaires. These questionnaires were then sent to the EORTC for the final approval to be used in clinical studies. CONCLUSION: We have successfully translated EORTC OV-28 module into Hindi and Marathi languages, and EORTC approved them to be used in clinical practice and studies for OC 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.