ABSTRACT
PURPOSE: Routine use of the oncotype DX recurrence score (RS) in patients with early-stage, estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer is limited internationally by cost and availability. We created a supervised machine learning model using clinicopathologic variables to predict RS risk category in patients aged over 50 years. METHODS: From January 2012 to December 2018, we identified patients aged over 50 years with T1-2, ER+/HER2-, node-negative tumors. Clinicopathologic data and RS results were randomly split into training and validation cohorts. A random forest model with 500 trees was developed on the training cohort, using age, pathologic tumor size, histology, progesterone receptor (PR) expression, lymphovascular invasion (LVI), and grade as predictors. We predicted risk category (low: RS ≤ 25, high: RS > 25) using the validation cohort. RESULTS: Of the 3880 tumors identified, 1293 tumors comprised the validation cohort in patients of median (IQR) age 62 years (56-68) with median (IQR) tumor size 1.2 cm (0.8-1.7). Most tumors were invasive ductal (80.3%) of low-intermediate grade (80.5%) without LVI (80.9%). PR expression was ≤ 20% in 27.3% of tumors. Specificity for identifying RS ≤ 25 was 96.3% (95% CI 95.0-97.4) and the negative predictive value was 92.9% (95% CI 91.2-94.4). Sensitivity and positive predictive value for predicting RS > 25 was lower (48.3 and 65.1%, respectively). CONCLUSION: Our model was highly specific for identifying eligible patients aged over 50 years for whom chemotherapy can be omitted. Following external validation, it may be used to triage patients for RS testing, if predicted to be high risk, in resource-limited settings.
Subject(s)
Breast Neoplasms , Aged , Biomarkers, Tumor/genetics , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Female , Gene Expression Profiling , Humans , Middle Aged , Neoplasm Recurrence, Local/genetics , Predictive Value of Tests , Prognosis , Receptor, ErbB-2/genetics , Supervised Machine LearningABSTRACT
BACKGROUND: Patients often fear axillary lymph node dissection (ALND) because of its associated complications; however, its effect on quality of life (QOL) is not well described. We aimed to evaluate the effect of ALND on QOL over time and to identify predictors of worse QOL. PATIENTS AND METHODS: Breast cancer patients undergoing ALND were enrolled in a prospective lymphedema screening study. Arm volumes were measured and QOL questionnaires completed at baseline, postoperatively, and at 6-month intervals. The upper limb lymphedema-27 questionnaire was used to assess the effect of upper extremity symptoms on QOL in three domains (physical, psychological, and social). Predictors of QOL were identified by univariate and multivariable regression analyses. RESULTS: From November 2016 through March 2020, 304 ALND patients were enrolled; 242 patients with at least two measurements and 6 months of follow-up were included. Median age was 48 years, and median follow-up was 1.2 years. The 18-month lymphedema rate was 18%. Overall, QOL scores in all three domains decreased postoperatively and improved over time. On multivariable analysis, after adjusting for baseline scores, symptoms necessitating lymphedema therapy referral (p = 0.006) were associated with worse physical QOL. Younger age (p = 0.005) and lymphedema therapy referral (p = 0.006) were associated with worse psychological QOL. Arm volume was not correlated with QOL. CONCLUSIONS: QOL scores initially decreased after ALND but improved by 6 months post-surgery. Decreases in QOL were independent of arm volume. Patients with worse QOL more often sought lymphedema therapy, although the effect of therapy on QOL remains unknown.
ABSTRACT
BACKGROUND: Among patients with multifocal or multicentric (MF/MC) breast cancer (BC) of similar morphology, concordance in Oncotype DX recurrence scores (RS) between tumors has been reported to be 87%. The effect of age and variation in histologic subtypes on RS concordance according to TAILORx criteria is unknown. METHODS: We identified patients with MF/MC, estrogen receptor-positive, HER2-negative, node-negative BC with two or more RS results treated at our institution from 2009 to 2018. Patients were analyzed by age group (≤ 50 and > 50 years). Low- and high-risk cut-offs were RS ≤ 25 and > 25 for age > 50 years, and RS ≤ 20 and > 20 for age ≤ 50 years. RS concordance was defined as no change in management based on RS variation between lesions. RESULTS: Overall, 120 patients with MF/MC BC were identified-82 (68.3%) aged > 50 years and 38 (31.7%) aged ≤ 50 years. Patients aged ≤ 50 years had higher mean RS for both multifocal (20 vs. 14; p = 0.006) and multicentric (17 vs. 13; p = 0.003) tumors and more frequently had high-risk tumors (p < 0.0001). Among patients aged > 50 years, 95.1% had RS concordance between tumors (same subtype, 98.2%; variable subtype, 88.9%; p = 0.1). Among patients aged ≤ 50 years, RS concordance was 81.6%. CONCLUSIONS: Among patients with MF/MC BC, RS concordance was high, particularly in those aged > 50 years with tumors of the same histologic subtype. RS testing of one focus may be sufficiently prognostic and predictive in patients aged > 50 years, regardless of subtype concordance. Testing of individual foci should be considered in patients aged ≤ 50 years due to a higher likelihood of RS discordance.
Subject(s)
Breast Neoplasms , Neoplasm Recurrence, Local , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Receptor, ErbB-2/geneticsABSTRACT
BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.
Subject(s)
Imidazoles/administration & dosage , Melanoma/drug therapy , Oximes/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins B-raf/genetics , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Australia , Female , Humans , Imidazoles/adverse effects , Male , Melanoma/metabolism , Middle Aged , Oximes/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyridones/adverse effects , Pyrimidinones/adverse effects , Skin Neoplasms/metabolism , Survival Analysis , Tertiary Care Centers , Treatment Outcome , United StatesABSTRACT
Importance: Risk factors for breast cancer-related lymphedema (BCRL) after axillary lymph node dissection (ALND) are poorly understood. Objective: To evaluate rates of and risk factors associated with BCRL in a prospective cohort of women treated with ALND. Design, Setting, and Participants: This prospective BCRL screening study performed at a tertiary cancer center enrolled women with breast cancer 18 years and older undergoing breast surgery and unilateral ALND in the primary setting or after sentinel lymph node biopsy. Exposures: Risk of BCRL during the first 2 years after ALND and radiotherapy. Main Outcomes and Measures: Patients were prospectively evaluated with arm volume (perometer) measurements, and BCRL was defined as a relative volume change of 10% or greater from baseline. Cumulative incidence of BCRL was assessed using competing risk analysis. Risk factors for BCRL were assessed on univariate and multivariable analyses. Results: From November 2016 to March 2020, 304 patients were enrolled; 276 had at least 1 longitudinal measurement. Median (IQR) age was 48 (40-57) years; median (IQR) body mass index, calculated as weight in kilograms divided by height in meters squared, was 26.4 (22.5-31.2). Of the 276 patients included in the analysis, 29 (11%) self-identified as Asian, 55 (20%) as Black, 16 (6%) as Hispanic, 166 (60%) as White, and 10 (3%) as unknown race and ethnicity; 70% received neoadjuvant chemotherapy (NAC); 93% received nodal irradiation. The 24-month BCRL rate was 23.8% (95% CI, 17.9%-29.8%), with significant variation by race and ethnicity (24-month rate: 37.2% [Black], 27.7% [Hispanic], 22.5% [Asian], and 19.8% [White]; P = .004). The BCRL rates were also higher among patients receiving NAC vs up-front surgery (24-month rate: 29.3% vs 11.1%; P = .01). On multivariable analysis, Black race and Hispanic ethnicity (compared with White race) (odds ratio [OR], 3.88; 95% CI, 2.14-7.08 and OR, 3.01; 95% CI, 1.10-7.62, respectively; P < .001 for each), receipt of NAC (compared with up-front surgery) (OR, 2.10; 95% CI, 1.16-3.95; P = .01), older age (OR, 1.04; 95% CI, 1.02-1.07 per 1-year increase; P = .001), and a longer follow-up interval (OR, 1.57; 95% CI, 1.30-1.90 per 6-month increase; P < .001) were independently associated with an increased risk of BCRL, while ERBB2-positive subtype was associated with a decreased risk of BCRL (compared with hormone receptor positive/ERBB2 negative): OR, 0.50; 95% CI, 0.23-0.99; P = .04). Conclusion and Relevance: In this cohort study, Black race, Hispanic ethnicity, NAC receipt, older age, and longer follow-up were independently associated with risk of BCRL. Studies are warranted to evaluate the biologic mechanisms behind racial and ethnic disparities in BCRL development and alternatives to NAC to avoid ALND in tumor subtypes unlikely to achieve nodal pathologic complete response.
Subject(s)
Breast Neoplasms , Lymphedema , Adult , Axilla/pathology , Breast Neoplasms/pathology , Cohort Studies , Ethnicity , Female , Humans , Lymph Node Excision/adverse effects , Lymphedema/epidemiology , Lymphedema/etiology , Prospective Studies , Risk Factors , Sentinel Lymph Node BiopsyABSTRACT
Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100-400 mg BID) and alpelisib (200-350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4-5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.
ABSTRACT
BACKGROUND: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined. METHODS: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology. RESULTS: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%). CONCLUSIONS: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Immune Checkpoint Inhibitors/administration & dosage , Ipilimumab/administration & dosage , Melanoma/drug therapy , Nivolumab/administration & dosage , Uveal Neoplasms/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Diarrhea/chemically induced , Diarrhea/epidemiology , Diarrhea/immunology , Fatigue/chemically induced , Fatigue/epidemiology , Fatigue/immunology , Female , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/adverse effects , Ipilimumab/adverse effects , Kaplan-Meier Estimate , Male , Melanoma/blood , Melanoma/mortality , Melanoma/pathology , Middle Aged , Nivolumab/adverse effects , Progression-Free Survival , Pruritus/chemically induced , Pruritus/epidemiology , Pruritus/immunology , Retrospective Studies , Transaminases/blood , Uveal Neoplasms/blood , Uveal Neoplasms/mortality , Uveal Neoplasms/pathology , Young AdultABSTRACT
The aim of this study was to test the hypothesis that inhibiting mammalian target of rapamycin and insulin-like growth factor-1 receptor would be efficacious in metastatic uveal melanoma. This was a phase 2 trial of everolimus 10 mg daily plus pasireotide long-acting release 60 mg every 28 days enrolling patients with progressive, metastatic uveal melanoma to treatment until progression by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) or unacceptable toxicity. The primary endpoint was clinical benefit rate, defined as any objective response or RECIST 1.1 stable disease at 16 weeks. A subset of patients underwent baseline indium-111-octreotide scans. A total of 14 patients were enrolled, of which 13 were evaluable for the primary endpoint, before the study was terminated due to poor accrual. Three of 13 (26%) patients obtained clinical benefit. Seven of 13 (54%) had stable disease lasting for a median of 8 weeks (range: 8-16 weeks). Grade 3 adverse events deemed at least possibly related to study drugs were hyperglycemia (n=7), oral mucositis (n=2), diarrhea (n=1), hypophosphatemia (n=1), and anemia (n=1). Seven of 14 (50%) patients required at least one dose reduction due to toxicity. Seven of eight (88%) patients with baseline indium-111-octreotide scans had at least one avid lesion, with significant intrapatient heterogeneity. There was a trend toward an association between octreotide avidity and cytostatic response to therapy (P=0.078). The combination of everolimus and pasireotide has limited clinical benefit in this small metastatic uveal melanoma cohort. Dose reductions for side effects were common. Further investigation into the relationship between somatostatin receptor expression and cytostatic activity of somatostatin analogues is warranted.