Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

Auto-immune neutropenia occurring in association with malignant melanoma

Neutropenia is frequently observed in the practice of oncology, usually resulting from the use of cytotoxic drugs. Less frequently, neutropenia is due to infiltration of the bone marrow by malignant disease. Both of these usually cause some depletion of all haematopoietic linages. True isolated neutropenia is, in contrast, a less frequent phenomenon. We report a case of auto-immune neutropenia occurring in a patient with metastatic melanoma, and discuss the differential diagnosis and implications for patient management

Clinical development of src family kinase inhibitors in malignant melanoma

Currently available systemic therapies for malignant melanoma are unsatisfactory and there is an urgent need for effective and well tolerated drugs for use in both early and advanced disease. The Src family of cytoplasmic tyrosine kinases (SFKs) have been implicated in the regulation of many of the hallmarks of malignancy making them attractive targets in solid tumours including melanoma. The first generation of selective SFK inhibitors to enter the clinic (AZD0530, dasatinib, bosutinib) have demonstrated safety, tolerability and target modulation in phase I trials. Phase II trials in patients with advanced melanoma are now planned in the USA and Europe. Here we discuss the rationale for, and challenges facing, the successful development of SFK inhibitors in melanoma. Furthermore, as dasatinib is also a potent inhibitor of the receptor tyrosine kinase (RTK), c-Kit, we reconsider the utility of targeting this kinase in the light of recent molecular epidemiological data

Niraparib for Advanced Breast Cancer with Germline <i>BRCA1</i> and <i>BRCA2</i> Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study.

Purpose To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (g BRCA m) advanced breast cancer. Patients and methods BRAVO was a randomized, open-label phase III trial. Eligible patients had g BRCA m and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor-positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm ( n = 141) versus 3.1 months in the PC arm [ n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65-1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63-1.42) and 0.65 (95% CI, 0.46-0.93), respectively. ORR was 35% (95% CI, 26-45) with niraparib and 31% (95% CI, 19-46) in the PC arm. Conclusions Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population