ABSTRACT
BACKGROUND: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. MATERIALS AND METHODS: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. RESULTS: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). CONCLUSIONS: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.
Subject(s)
Breast Neoplasms , Breast Neoplasms/pathology , Female , Germ Cells/pathology , Germ-Line Mutation , Humans , Mutation , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers. METHODS: We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50-69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis. RESULTS: Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor-negative or HER2-positive status (odds ratio=1.7; 95% confidence interval [CI]: 1.1-2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%-94.5%) versus 93.8% (95% CI: 86.5%-100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6-16.7). CONCLUSIONS: IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.
Subject(s)
Breast Neoplasms/diagnosis , Early Detection of Cancer , Population Surveillance/methods , Receptor, ErbB-2/metabolism , Registries/statistics & numerical data , Aged , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , Disease-Free Survival , Female , Humans , Italy , Middle Aged , Neoplasm Staging , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , PrognosisABSTRACT
Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Breast Neoplasms/drug therapy , Neoadjuvant Therapy , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/therapeutic use , Quinazolines/therapeutic use , Receptor, ErbB-2/analysis , Receptors, IgG/genetics , Trastuzumab/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/immunology , Chemotherapy, Adjuvant , Clinical Trials, Phase II as Topic , Disease-Free Survival , Female , Gene Frequency , Genotype , Humans , Lapatinib , Mastectomy , Middle Aged , Pharmacogenetics , Pharmacogenomic Testing , Phenotype , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects , Randomized Controlled Trials as Topic , Retrospective Studies , Time Factors , Trastuzumab/adverse effects , Treatment OutcomeABSTRACT
This article analyses the mortality data used for the calculation of relative survival, within the survival study of the cases incident in 1990-1994. The mortality data used in the 14 cancer registries come from ISTAT or other official sources. Results show higher death risk for all causes of death in men and lower in women. Risk increases with age, values are generally higher in the North and lower in the Centre and the South of the country. Consistently with mortality trends, the difference between observed and relative survival is higher in older age groups, and in men rather than women, with an increasing difference the further from the date of diagnosis.
