Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.
TPS619 Background: Triple negative breast cancers (TNBCs) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination-deficient tumors, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Methods: This is a 3-stage open-label randomized phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. The aim is to establish whether the addition of olaparib to neoadjuvant platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. In stages 1 and 2, all patients receive 4 cycles of 3-weekly carboplatin AUC5/weekly paclitaxel 80mg/m2. They are randomly assigned 1:1:1 to a control arm, or to one of two research arms. These research arms include different treatment schedules of olaparib 150 mg BD for 12 days. In stage 3, patients are randomly assigned 1:1 to either the control or research arm chosen following stage 2. The primary endpoints are: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. Key eligibility criteria are age 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by combining olaparib with platinum-based chemotherapy. This trial includes an optional pathway called PARTNERING for patients with residual disease after six chemotherapy cycles. This aims to establish if adding new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Each cohort will consist of 15 patients. Since May 2016, 756 patients from 30 sites have been enrolled. An IDSMC review following stages 1 and 2 identified no safety concerns and Research Arm 2 was selected (olaparib administration on days 3-14). Stage 3 phase I (recruitment of non-gBRCA and gBRCA patients) completed December 2021. Stage 3 phase II (recruitment of gBRCA patients) remains open to patients in the U.K. and internationally. 5 patients have enrolled in PARTNERING. Follow-up duration is 10 years. Clinical trial information: NCT03150576.
BRAF gene driver mutations are found in 40%-50% of patients with metastatic melanoma, and oral kinase inhibitors targeting the MAP kinase pathway have been routinely available in clinical practice for almost a decade (Carlino et al., 2015;Kong et al., 2016). Patients with advanced BRAF-mutant melanoma generally have access to two different treatment modalities: immunotherapy (with immune checkpoint inhibitors) and BRAF-targeted therapies. Understanding how best to sequence these different treatment modalities is a key research priority (Giunta et al., 2020;Pavlick et al., 2019).The apparent advantages of MAP kinase pathway inhibition over immunotherapy include a very high initial response rate which can be achieved within a few weeks of starting treatment,
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