Genetic testing for epithelial ovarian cancer.

As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.

Pathological complete response to neoadjuvant systemic therapy in 789 early and locally advanced breast cancer patients: The Royal Marsden experience.

PURPOSE: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer predicts the risk of recurrence and increasingly may indicate the need for additional therapy postoperatively. METHODS: We identified non-metastatic breast cancer patients receiving NACT during 2013-2017. Patients' and disease characteristics, rates of pCR (ypT0-is ypN0), toxicities, dose delays and reductions, and survival outcomes were recorded. RESULTS: 789 patients had median age of 50 years. 67.8% had stage II disease, 71.1% had grade 3 , and 91.8% had ductal histopathology. 32.8% had estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 25.5% had triple-negative (TN), and 38.0% HER2-positive disease. 6.8% received platinum. 48.2% of the HER2-positive patients received trastuzumab and pertuzumab and 51.8% received trastuzumab. Overall pCR rate was 33.5% and differed according to disease subtype, receptor status, grade, histology, and early discontinuation, but not according to age, dose reductions/delays, or year of treatment. The addition of pertuzumab to trastuzumab marginally improved the pCR rates. Survival outcomes were better following pCR. CONCLUSIONS: In our analysis, pCR rates are consistent with the published data. Even with contemporary therapies, many patients have residual disease following NACT, suggesting a significant risk of recurrence, and may benefit from additional postoperative systemic therapy.

Treatment and prognosis of leptomeningeal disease secondary to metastatic breast cancer: A single-centre experience.

PURPOSE: Leptomeningeal disease (LMD) is an uncommon complication of advanced breast cancer. The prognosis is poor, and although radiotherapy (RT), systemic and intra-thecal (IT) chemotherapy are accepted treatment modalities, efficacy data are limited. This study was designed to evaluate potential predictors of survival in this patient group. METHODS: Breast cancer patients with LMD diagnosed by MRI in a 10-year period (2004-2014) were identified from electronic patient records. PFS and OS estimates were calculated using Kaplan-Meier method, with planned sub-group analysis by treatment modality. Cox regression was employed to identify significant prognostic variables. RESULTS: We identified 182 eligible patients; all female, median age at LMD diagnosis 52.5 years (range 23-80). Ninety patients (49.5%) were ER positive/HER2 negative; 48 (26.4%) were HER2 positive, and 27 (14.8%) were triple negative. HER2 status was unknown in 17 (9.3%). Initial management of LMD was most commonly whole or partial brain RT in 62 (34.1%), systemic therapy in 45 (24.7%) or supportive care alone in 37 (20.3%). Fourteen patients (7.7%) underwent IT chemotherapy, of whom two also received IT trastuzumab. From diagnosis of LMD, the median PFS was 3.9 months (95%CI 3.2-5.0) and median OS was 5.4 months (95%CI 4.2-6.6). Patients treated with systemic therapy had the longest OS (median 8.8 months, 95%CI 5.5-11.1), compared to RT; 6.1 months (95%CI 4.2-7.9 months), IT therapy; 2.9 months (95%CI 1.2-5.8) and supportive care; 1.7 months (95%CI 0.9-3.0). On multivariable analysis, triple negative histology, concomitant brain metastases, and LMD involving both the brain and spinal cord were associated with poor OS. CONCLUSIONS: Breast cancer patients with triple negative LMD, concomitant brain metastases or LMD affecting both the spine and brain have the poorest prognosis. Clinical trials to identify more effective treatments for these patients are urgently needed.

PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression.

BACKGROUND: Lobular carcinoma in situ (LCIS) is a non-invasive breast lesion that is typically found incidentally on biopsy and is often associated with invasive lobular carcinoma (ILC). LCIS is considered by some to be a risk factor for future breast cancer rather than a true precursor lesion. The aim of this study was to identify genetic changes that could be used as biomarkers of progression of LCIS to invasive disease using cases of pure LCIS and comparing their genetic profiles to LCIS which presented contemporaneously with associated ILC, on the hypothesis that the latter represents LCIS that has already progressed. METHODS: Somatic copy number aberrations (SCNAs) were assessed by SNP array in three subgroups: pure LCIS, LCIS associated with ILC and the paired ILC. In addition exome sequencing was performed on seven fresh frozen samples of LCIS associated with ILC, to identify recurrent somatic mutations. RESULTS: The copy number profiles of pure LCIS and LCIS associated with ILC were almost identical. However, four SCNAs were more frequent in ILC than LCIS associated with ILC, including gain/amplification of CCND1. CCND1 protein over-expression assessed by immunohistochemical analysis in a second set of samples from 32 patients with pure LCIS and long-term follow up, was associated with invasive recurrence (P = 0.02, Fisher's exact test). Exome sequencing revealed that PIK3CA mutations were as frequent as CDH1 mutations in LCIS, but were not a useful biomarker of LCIS progression as they were as frequent in pure LCIS as in LCIS associated with ILC. We also observed heterogeneity of PIK3CA mutations and evidence of sub-clonal populations in LCIS irrespective of whether they were associated with ILC. CONCLUSIONS: Our data shows that pure LCIS and LCIS co-existing with ILC have very similar SCNA profiles, supporting the hypothesis that LCIS is a true precursor lesion. We have provided evidence that over-expression of CCND1 may identify a subgroup of patients with pure LCIS who are more likely to develop invasive disease, in contrast to PIK3CA mutations, which occur too early in lobular tumorigenesis to be informative.