Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Triple negative tumours: a critical review.

Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types.

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature.

A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer.

Individuals harboring germ-line mutations in the BRCA1 or BRCA2 genes are at highly elevated risk of a variety of cancers. Ten years of research has revealed roles for BRCA1 and BRCA2 in a wide variety of cellular processes. However, it seems likely that the function of these proteins in DNA repair is critically important in maintaining genome stability. Despite this increasing knowledge of the defects present in BRCA-deficient cells, BRCA mutation carriers developing cancer are still treated similarly to sporadic cases. Here we describe our efforts, based on understanding the DNA repair defects in BRCAdeficient cells, to define the optimal existing treatment for cancers arising in BRCA mutation carriers and, additionally, the development of novel therapeutic approaches. Finally, we discuss how therapies developed to treat BRCA mutant tumors might be applied to some sporadic cancers sharing similar specific defects in DNA repair.

The role of positron emission tomography in the management of colorectal cancer.

Positron emission tomography (PET) is a functional imaging modality that has made the transition from the research environment to the clinical environment over the last 10 years. Its major role is in the field of oncology where it is being used increasingly in the management of several tumour types including colorectal cancer. This review aims to outline the current and future role of PET scanning in the field of colorectal cancer.