Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in ...patients with
or
germline mutation-associated early breast cancer.
We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with
or
germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.
A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval CI, 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.
Among patients with high-risk, HER2-negative early breast cancer and germline
or
pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).
The DNA-damage response (DDR) pathways consist of interconnected components that respond to DNA damage to allow repair and promote cell survival. The DNA repair pathways and downstream cellular ...responses have diverged in cancer cells compared with normal cells because of genetic alterations that underlie drug resistance, disabled repair and resistance to apoptosis. Consequently, abrogating DDR pathways represents an important mechanism for enhancing the therapeutic index of DNA-damaging anticancer agents. In this review, we discuss the DDR pathways that determine antitumor effects of DNA-damaging agents with a specific focus on treatment outcomes in tumors carrying a defective p53 pathway. Finely tuned survival and death pathways govern the cellular responses downstream of the cytotoxic insults inherent in anticancer treatment. The significance and relative contributions of cellular responses including apoptosis, mitotic catastrophe and senescence are discussed in relation to the web of molecular interactions that affect such outcomes. We propose that promising combinations of DNA-damaging anticancer treatments with DDR-pathway inhibition would be further enhanced by activating downstream apoptotic pathways. The proposed rationale ensures that actual cell death is the preferred outcome of cancer treatment instead of other responses, including reversible cell cycle arrest, autophagy or senescence. Finally, to better measure the contribution of different cellular responses to anticancer treatments, multiplex in vivo assessments of therapy-induced response pathways such as cell death, senescence and mitotic catastrophe is desirable rather than the current reliance on the measurement of a single response pathway such as apoptosis.
The aim of this study was to ascertain if oestrogen receptor (ER) status predicts for pathological complete response (pCR) to neoadjuvant chemotherapy in operable breast cancer, and the effects of ...pCR on survival. Using a single-institution database, 435 patients were identified, who received neoadjuvant chemotherapy for operable breast cancer and were eligible for the analysis. Patients whose tumours were ER negative were more likely to achieve a pCR than patients who were ER positive (21.6 vs 8.1%, P<0.001). Owing to a strong correlation between ER status and grade, these variables were not shown to be independent predictors of pCR. Overall survival (OS) was better in those patients who achieved a pCR compared to those who did not (5-year OS 91 vs 73%; P=0.02). This was still the case when only patients with ER-negative tumours were examined (5-year OS 90 vs 52%, P=0.005), but not in the subset of patients with ER-positive tumours (5-year OS 93 vs 79%; P=0.3). Therefore, patients with ER-negative tumours were found to be more likely to achieve a pCR to neoadjuvant chemotherapy than those with ER-positive tumours, and pathological response did not have prognostic significance in patients with ER-positive tumours.
Aims : Cytokeratin (CK) 14, a myoepithelial marker, is also expressed in a proportion of breast carcinomas. There is evidence that these tumours show a differing metastatic pattern and clinical ...outcome from other invasive ductal carcinomas (IDCs) and may need different management. Currently, they are not identified in routine practice and no morphological guidelines exist to aid their identification. The aim of this study was to analyse the histological features of CK14+ IDC.
Methods and results : A detailed histological review of 453 grade 3 IDCs revealed 88 (19.4%) that expressed CK14. Assessment was made independently by two pathologists using a standardized ‘tick‐box’ proforma covering grade, architectural and cytological features. The results were analysed using logistic regression to identify features that predicted for basal phenotype. Concordance between the two pathologists was fair to good for most parameters (κ 0.4–0.6). On multiple logistic regression, the basal phenotype was highly significantly associated with the presence of a central scar (P = 0.005), tumour necrosis (P < 0.0001), presence of spindle cells (P = 0.006) or squamous metaplasia (P < 0.0001), high total mitotic count (> 40 per 10 high‐power field) (P = 0.0002) and high nuclear–cytoplasmic ratio (P = 0.0002).
Conclusions : Specific morphological features are strongly associated with basal‐like breast carcinoma. These could be used in routine diagnostic practice to identify this important subset of tumours.
Background: Grade-III invasive ductal carcinomas of no special type (IDCs-NST) constitute a heterogeneous group of tumours with different clinical behaviour and response to chemotherapy. As many as ...25% of all grade-III IDCs-NST are known to harbour a basal-like phenotype, as defined by gene expression profiling or immunohistochemistry for basal cytokeratins. Patients with basal-like breast carcinomas (BLBC) are reported to have a shorter disease-free and overall survival. Material and methods: A retrospective analysis of 49 patients with BLBC (as defined by basal cytokeratin expression) and 49 controls matched for age, nodal status and grade was carried out. Histological features, immunohistochemical findings for oestrogen receptor (ER), progesterone receptor (PgR) and HER2, and clinical outcome and survival after adjuvant chemotherapy were compared between the two groups. Results: It was more likely for patients with BLBCs to be found negative for ER (p<0.0001), PgR (p<0.0001) and HER2 (p<0.01) than controls. Patients with BLBCs were found to have a significantly higher recurrence rate (p<0.05) and were associated with significantly shorter disease-free and overall survival (both p<0.05). In the group of patients who received anthracycline-based adjuvant chemotherapy (BLBC group, n = 47; controls, n = 49), both disease-free and overall survival were found to be significantly shorter in the BLBC group (p<0.05). Conclusions: BLBCs are a distinct clinical and pathological entity, characterised by high nuclear grade, lack of hormone receptors and HER2 expression and a more aggressive clinical course. Standard adjuvant chemotherapy seems to be less effective in these tumours and new therapeutic approaches are indicated.
Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and ...BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes – TP53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz–Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low‐penetrance breast cancer susceptibility alleles, is also a well‐recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype–phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.
Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched ...germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer.
We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n=26) or BRCA2 (n=22) or from non-carriers (non-BRCA1/2; n=30).
Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2.
Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.
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