Search

Background: Hot flashes are a common side effect of endocrine therapy (ET) that contribute to poor quality of life and decreased treatment adherence. Methods: Patients with breast cancer wo were receiving ET and experiencing hot flashes were enrolled through three parallel, randomized trials conducted in the United States, China, and South Korea. Participants were randomized to either immediate acupuncture (IA) or delayed acupuncture control (DAC). IA participants received 20 acupuncture sessions over 10 weeks, whereas DAC participants received usual care, then crossed over to acupuncture with a reduced intensity. The primary end point was a change in score on the endocrine symptom subscale of the Functional Assessment of Cancer Therapy (FACT)‐Endocrine Symptoms between baseline and week 10. Secondary end points included the hot flash score and the FACT‐Breast score. A planned pooled analysis of individual patient data was performed using longitudinal mixed models. Results: In total, 158 women with stage 0–III breast cancer were randomized (United States, n = 78; China, n = 40; South Korea, n = 40). At week 10, IA participants reported statistically significant improvements in the endocrine symptom subscale score (mean change ± standard error: 5.1 ± 0.9 vs. 0.2 ± 1.0; p =.0003), the hot flash score (−5.3 ± 0.9 vs. −1.4 ± 0.9; p <.003), and the FACT‐Breast total score (8.0 ± 1.6 vs. −0.01 ± 1.6; p =.0005) compared with DAC participants. The effect of the acupuncture intervention differed by site (p =.005). Conclusions: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer‐specific quality of life in women undergoing ET for breast cancer in the United States, China, and South Korea. In a pooled analysis of three parallel trials, acupuncture significantly reduced hot flashes and other endocrine symptoms in women with stage 0–III breast cancer undergoing endocrine therapy in the United States, China, and South Korea. In the women studied, acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer‐specific quality of life. [ABSTRACT FROM AUTHOR]

Background: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAFV600E‐mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor–sensitive and BRAF inhibitor–resistant mutant cell lines. Methods: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small‐molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAFV600E/K–mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. Results: Twenty‐two patients with metastatic, BRAFV600E–mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose‐limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%–27%), a disease control rate of 47.6% (90% CI, 29%–67%), and a median overall survival of 5.1 months (90% CI, 3.4–7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. Conclusions: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach. Heat shock protein 90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of disease control in a heavily pretreated population of patients with BRAFV600E–mutant solid tumors. Translational work is needed to identify the tumor types and mechanisms of resistance most sensitive to this targeted approach. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal immune‐related adverse events are frequently caused by immune checkpoint inhibitors (ICIs) and often require interruption of cancer treatment. Compared with ICI colitis and enteritis, limited information exists about ICI gastritis. This study characterized clinical features and treatment outcomes of ICI gastritis. Methods: Consecutive cancer patients who received ICIs and underwent endoscopy with gastric biopsies while on ICIs from 2011 to 2021 were retrospectively assessed. Specific histopathologic features identified ICI gastritis. Results: Of 6450 ICI‐treated patients, 162 (2.5%) underwent endoscopy with gastric biopsies. ICI gastritis was identified in 54 (33%) biopsied patients; 38 (70%) had concurrent ICI enteritis/colitis and 16 (30%) had isolated ICI gastritis. Dyspepsia (38%) and bloating (25%) were the most frequent symptoms of isolated ICI gastritis. Compared with patients with concomitant enteritis/colitis, patients with isolated gastritis were less likely to have diarrhea (13% vs 68%; p <.001) or abdominal pain (19% vs 47%; p =.07). Patients with isolated ICI gastritis less frequently required glucocorticoids (69% vs 92%; p =.04) and had lower incidence of ICI hold/withdrawal (13% vs 42%; p =.06). There was no association between severity or extent of luminal inflammation and antitumor response (p =.85 and p =.44, respectively). Endoscopically, gastric mucosa appeared normal in 11 (20%) patients with biopsy‐proven ICI gastritis. Conclusion: ICI gastritis may present alone or more commonly with concurrent enteritis/colitis, which may differentiate its clinical course. Gastric biopsies are required to diagnose a substantial minority of endoscopically normal, clinically significant cases. Most patients with isolated gastritis can continue ICI therapy uninterrupted, but a notable proportion require glucocorticoids. Plain language summary: Immune checkpoint inhibitors are effective anticancer treatments, but can cause inflammatory toxicities, including of the stomach (gastritis), intestine, and colon. Limited information is available on gastritis triggered by these agents.Adult patients with cancer who were treated with immune checkpoint inhibitors and had an upper gastrointestinal endoscopy with biopsies of the stomach were examined. More than two‐thirds (70%) of people with checkpoint inhibitor gastritis also had inflammatory changes of the small intestine and/or colon.Compared with patients with isolated checkpoint gastritis, the subgroup with concomitant enteritis/colitis more frequently had abdominal pain, diarrhea, needed steroids, and/or needed to pause or stop antitumor therapy. Immune checkpoint inhibitor (ICI) gastritis frequently presents with concomitant enteritis/colitis, which differentiates its clinical presentation and management from patients with isolated gastric involvement. A substantial minority of ICI gastritis cases are diagnosed histologically despite normal endoscopic appearance, highlighting the importance of gastric biopsies in patients with suspicious symptoms of or risk factors for checkpoint inhibitor gastritis. [ABSTRACT FROM AUTHOR]

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor–positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1‐98 trial. Methods: BIG 1‐98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow‐up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post‐DR survival. Results: The median follow‐up time after DR was 59 months (interquartile range, 29‐88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post‐DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P =.21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15‐1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00‐1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05‐1.64), progesterone receptor (PR)–negative tumors (HR, 1.25; 95% CI, 1.02‐1.52), or shorter disease‐free survival (DFS) had significantly worse post‐DR survival. Conclusions: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high‐risk features remain prognostic in the metastatic setting. In the Breast International Group 1‐98 study, no difference was observed in post–distant recurrence survival by adjuvant endocrine treatment arm. Older patients and patients with tumors larger than 2 cm, 4 or more positive nodes, progesterone receptor–negative tumors, or shorter disease‐free survival had significantly worse post–distant recurrence survival. [ABSTRACT FROM AUTHOR]

Background: There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis.Methods: We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital.Results: The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort.Conclusions: This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies. [ABSTRACT FROM AUTHOR]

Background: Exercise interventions improve fitness, functional capacity, and quality of life in patients with early-stage breast cancer, but to the authors' knowledge there are few data regarding the feasibility or potential benefits of exercise in women with metastatic breast cancer.Methods: Individuals with metastatic breast cancer were randomized 1:1 to a 16-week moderate-intensity exercise intervention or wait-list control group. Intervention goals included 150 minutes of moderate-intensity aerobic exercise per week. The baseline and 16-week evaluations included a modified Bruce Ramp treadmill test, 7-day Physical Activity Recall interview, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C-30) questionnaire.Results: A total of 101 participants were randomized (48 to the intervention group and 53 to the control group). The median age of the participants was 49 years, the median time since the diagnosis of metastatic breast cancer was 1.1 years, and approximately 42% of participants were undergoing chemotherapy at the time of enrollment. Study attrition was higher in the intervention arm (14 participants vs 8 participants; P = .15). Women randomized to the exercise intervention experienced a nonsignificant increase with regard to minutes of weekly exercise (62.4 minutes vs 46.0 minutes; P = .17) and physical functioning (EORTC QLQ C30: 4.79 vs 0.93 [P = .23] and Bruce Ramp Treadmill test: 0.61 minutes vs 0.37 minutes [P = .35]) compared with control participants.Conclusions: Participation in an exercise intervention did not appear to result in significant improvements in physical functioning in a heterogeneous group of women living with advanced breast cancer. Given the significant benefits of exercise in women with early-stage breast cancer, more work is needed to explore alternative interventions to determine whether exercise could help women with metastatic disease live more fully with fewer symptoms from disease and treatment. [ABSTRACT FROM AUTHOR]

Background: Patients with mucosal and acral melanomas have limited treatment options and a poor prognosis. Mutations of the KIT oncogene in these melanoma subtypes provide a potential therapeutic target.Methods: A multicenter phase 2 trial of sunitinib was conducted in patients with unresectable stage III or IV melanoma of a mucosal or acral primary origin. Patients were treated in 2 cohorts: cohort A received sunitinib at a dose of 50 mg daily for 4 weeks of a 6-week cycle, and cohort B received sunitinib at a dose of 37.5 mg daily on a continuous basis. Dose reductions were permitted for treatment-related toxicities, and tumor assessments were performed every 2 months.Results: Fifty-two patients were enrolled: 21 in cohort A and 31 in cohort B. Four patients had confirmed partial responses, which lasted 5 to 10 months (1 with a KIT mutation). In both cohorts, the proportion of patients alive and progression-free at 2 months was 52% (95% confidence interval, 38%-66%); this was significantly larger than the hypothesized null of 5%. There was no significant difference in response or overall survival between the 25% of patients with a KIT mutation and those without one (response rate, 7.7% vs 9.7%; overall survival, 6.4 vs 8.6 months). The overall disease control rate was 44%, and a high rate of toxicity was associated with the treatment.Conclusions: Sunitinib showed activity in the treatment of mucosal and acral melanoma that was not dependent on the presence of a KIT mutation. However, the medication was poorly tolerated, and there were no prolonged responses. Cancer 2015;121:4007-4015. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined.Methods: To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated.Results: Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥ 1000 cells/μL at week 7 were associated significantly with survival.Conclusions: In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed. [ABSTRACT FROM AUTHOR]