Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib.

BACKGROUND: Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. METHODS: We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. RESULTS: Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. CONCLUSION: GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. IMPLICATIONS FOR PRACTICE: This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Comparative safety of BRAF and MEK inhibitors (vemurafenib, dabrafenib and trametinib) in first-line therapy for BRAF-mutated metastatic melanoma.

A retrospective observational study was conducted on patients diagnosed with serine/threonine-protein kinase B-Raf (BRAF)-mutated metastatic melanoma, who underwent first-line therapy with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors (vemurafenib, dabrafenib or a combination of dabrafenib and trametinib) at the Miguel Servet University Hospital (Zaragoza, Spain) between November, 2011 and August, 2015. The aim of this study was to analyse the toxicity produced by BRAF and MEK inhibitors. The most common toxicities were similar to those published in clinical trials, particularly arthralgia, alopecia and photosensitivity in the vemurafenib group; asthenia, hyperkeratosis and dry skin in the dabrafenib group; and diarrhoea and dry skin in the dabrafenib plus trametinib group. Toxicities that had not been described in clinical trials were also identified. Thus, the present study confirmed that the results obtained in clinical trials are similar to those obtained in clinical practice.

Influence of vitamin D status on the effect of statins on bone mineral density and bone turnover markers in postmenopausal women.

OBJECTIVE: This study sought to assess whether the association between statin use and bone mineral density (BMD) and bone turnover markers is modulated by serum 25-hydroxyvitamin D (25OHD) levels in postmenopausal women. Design, Participants, and Settings: Approximately 1422 postmenopausal women were recruited from the Camargo Cohort after excluding those with any known medical disorder or drug that might affect bone metabolism. Participants were categorized into four groups: 25OHD levels of 20 ng/mL or less and not taking statins (group 1; n = 492); 25OHD levels greater than 20 ng/mL and on statins (group 2; n = 143); 25OHD levels of 20 ng/mL or less and using statins (group 3; n = 112); and 2OHD levels greater than 20 ng/mL and non-statin use (group 4; n = 675). Multivariate analyses were performed to compare BMD and bone turnover markers between groups. RESULTS: Women in group 2 had an adjusted femoral neck and total hip BMD higher than women in group 1 (P < .0001 and P = .003, respectively). A trend toward a significant difference was observed regarding lumbar BMD (P = .08). Serum aminoterminal propeptide of type 1 collagen and C-terminal telopeptide of type 1 collagen levels were lower in group 2 than in group 1, in crude and adjusted models, although only serum C-terminal telopeptide of type 1 collagen difference was significant (P = .009). CONCLUSIONS: Women on statins and serum 25OHD levels above 20 ng/mL have greater BMD and less bone resorption than those without either of the factors. Differences, however, are not significant in women with only one of them. Vitamin D and statins seem to interact positively in their effects on bone metabolism.

Bone turnover markers and bone mineral density in hypertensive postmenopausal women on treatment.

OBJECTIVE: To evaluate bone mineral density (BMD) and bone metabolism in hypertensive postmenopausal women, and to differentiate the effect of thiazides from that of other antihypertensive agents. SUBJECTS AND METHODS: A community-based population of 636 postmenopausal women, 293 with hypertension (160 receiving thiazides, and 133 receiving other antihypertensive treatments), and 343 control women, were evaluated. Serum levels of aminoterminal propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (beta-CTX), 25-hydroxivitamin D, and intact parathyroid hormone were measured by electrochemiluminiscence. BMD was determined by DXA, and heel quantitative ultrasound measurements (QUS) with a gel-coupled device. RESULTS: BMD expressed as Z-score was higher in both groups of hypertensive women at all locations. Expressed as g/cm(2), it was also higher in patients on thiazides at femoral neck and lumbar spine. Only in the latter site, differences remained significant after adjusting for potential confounding variables, including BMI. Bone turnover markers were lower in both groups of hypertensive women, although the difference was greater in those on thiazides. After adjusting for potential confounders, differences remained significant only in the thiazide group. CONCLUSIONS: Our results add evidence to the idea that thiazides are beneficial to prevent bone loss.

Dramatic complete response in patient with lung adenocarcinoma.

The poor prognosis of non-small-cell lung cancer (NSCLC) is changing thanks to the constant development of new treatments and the introduction of target therapies, even in stage IV disease. This patient had bone metastases when he was diagnosed. Maintenance treatment, a much discussed topic nowadays, achieved a dramatic complete response.