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BackgroundThe NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted.Patients and methodsPatients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF.ResultsFEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P

Antimullerian hormone (AMH) is a promising biomarker for ovarian reserve. In this study, we assessed AMH before and 1 year after initiation of adjuvant chemotherapy on National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology B-47 in female participants aged 42 years and younger (median age = 39 years). At baseline, median AMH was 1.2 ng/mL; 13 (4.7%) values were less than 0.1 ng/mL (the threshold for detectable levels, in the perimenopause and menopause range), and 57 values (20.6%) were less than 0.5 ng/mL. At 1 year, 215 (77.6%) were less than 0.1 ng/mL, and 264 (95.3%) were less than 0.5 ng/mL. Postchemotherapy menses were reported by 46.2% of participants. Multivariable logistic regression found that the odds of having postchemotherapy menses increased with younger age, higher body mass index, and higher prechemotherapy AMH, but not by trastuzumab administration or by the choice of chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel vs docetaxel-cyclophosphamide). We conclude that higher prechemotherapy AMH predicts a lower risk of chemotherapy-induced amenorrhea and that AMH 1 year after chemotherapy initiation is not informative in this setting because it is likely to be very low.

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.

BACKGROUND:In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. MATERIALS AND METHODS:Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time-varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient-reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. RESULTS:The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3-4 months of receiving talazoparib. Grade 3-4 anemia lasted approximately 7 days for both arms. Overlapping grade 3-4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (

BackgroundTalazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations.MethodsEMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician's choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) or triple-negative breast cancer (TNBC) subgroups.ResultsOf 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2-: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2- and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia.ConclusionsAcross all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.

BACKGROUND:In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. MATERIALS AND METHODS:Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time-varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient-reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. RESULTS:The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3-4 months of receiving talazoparib. Grade 3-4 anemia lasted approximately 7 days for both arms. Overlapping grade 3-4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (

BACKGROUND: The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2). METHODS: We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physicians choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P

The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL). The National Surgical Adjuvant Breast and Bowel Project Protocol B-30 was a randomized trial comparing sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T) (AC→T), concurrent ACT, or AT in women with node-positive, early-stage breast cancer. The AC→T group had a higher cumulative dose of T. PN was one of the symptoms assessed in a QOL substudy. Statistical methods included simple and mixed ordinal logistic regression and general linear models. All statistical tests were two-sided. Of 1512 patients, 41.9% reported PN two years after treatment initiation. Treatment with AT and ACT was associated with less severe long-term PN compared with AC→T (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.35 to 0.58; OR = 0.59, 95% CI = 0.46 to 0.75). Preexisting PN, older age, obesity, mastectomy, and greater number of positive nodes were also associated with higher risk of long-term PN. Patients who reported worse PN symptoms at 24 months had statistically significantly worse QOL (Ptrend < .001). The administration of docetaxel is associated with long-term PN. The lower rate of long-term PN in AT and ACT patients might be an important consideration in supporting choosing these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy.

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

BackgroundNRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev.MethodsA total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry.ResultsEarly surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (

PurposeLittle is known about health-related quality of life (HRQL) in long-term survivors (LTS) of colorectal cancer (CRC).MethodsLong-term CRC survivors (≥5 years) treated in previous National Surgical Adjuvant Breast and Bowel Project trials were recruited from 60 sites. After obtaining consent, a telephone survey was administered, which included HRQL instruments to measure physical health (Instrumental Activities of Daily Living [IADL], SF-12 Physical Component Scale [PCS], SF-36 Vitality Scale), mental health (SF-12 Mental Component Scale [MCS], Life Orientation Test, and Impact of Cancer), and clinical symptoms (Fatigue Symptom Inventory [FSI], European Organization for Research and Treatment of Cancer Colorectal Module [EORTC-CR38], and Brief Pain Inventory). A multivariable model identified predictors of overall quality of life (global health rating).ResultsParticipants (N = 708) had significantly higher HRQL compared with age group-matched non-cancer controls with higher mean scores on SF-12 PCS (49.5 vs. 43.7, p =

BackgroundThe NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms.MethodsThe study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (

BackgroundDuctal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy.MethodsThe double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (

Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN.A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade.A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo.There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.

A study was conducted to evaluate and compare the efficacy of concurrent docetaxel (ACT) versus sequential regimens of ACT on survival rate in early breast cancer. Results indicated that sequential ACT far greatly improved disease free survival as well as overall survival rate in the case of such patients.