Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation

Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma

Drug therapy for hereditary cancers

<p>Abstract</p> <p>Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from <it>BRCA1 </it>or <it>BRCA2 </it>mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of <it>BRCA</it>-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with <it>BRCA1</it>-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies.</p

Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma

Purpose The purpose of this study was to define the contribution of docetaxel to combination chemotherapy in the outcome of patients with advanced gastric or gastroesophageal adenocarcinoma. We compared the overall response rate (ORR) and safety of docetaxel plus cisplatin (DC) with DC plus fluorouracil (DCF) to select either DC or DCF as the experimental treatment in the ensuing phase III part of trial V-325. Patients and Methods In this phase II randomized study, untreated patients with confirmed advanced gastric or gastroesophageal adenocarcinoma received either DCF (docetaxel 75 mg/m(2), cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2)/d as continuous infusion on days 1 to 5) or DC (docetaxel 85 mg/m(2) and cisplatin 75 mg/m(2) on day 1) every 3 weeks. An independent data monitoring committee (IDMC) was to select one of the two regimens based primarily on ORR and safety profile. Results Of 158 randomly assigned patients, 155 (DCF, n = 79; DC, n = 76) received treatment. The confirmed ORR was 43% for DCF (n = 79) and 26% for DC (n = 76). Median time to progression was 5.9 months for DCF and 5.0 months for DC. Median overall survival time was 9.6 months for DCF and 10.5 months for DC. The most frequent grade 3 and 4 events per patient included neutropenia (DCF = 86%; DC = 87%) and GI (DCF = 56%; DC = 30%). Conclusion Both regimens were active, but DCF produced a higher confirmed ORR than DC. Toxicity profiles of DCF were considered manageable. The IDMC chose DCF for the phase III part of V-325, which compares DCF with cisplatin plus fluorouracil

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 study group

Purpose In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part. Patients and Methods Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) (day 1) plus fluorouracil 750 mg/m(2)/ d ( days 1 to 5) every 3 weeks or cisplatin 100 mg/m(2) ( day 1) plus fluorouracil 1,000 mg/m(2)/ d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP). Results In 445 randomly assigned and treated patients ( DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P <.001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P =.02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF (chi(2) P =.01). Grade 3 to 4 treatment-related adverse events occurred in 69% ( DCF) v 59% ( CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy ( 19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%). Conclusion Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in <i>BRCA1</i>-Driven Breast Cancer Patients

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication