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Background: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen-progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD.Methods: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided.Results: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk.Conclusion: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects. [ABSTRACT FROM AUTHOR]

Background: Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients.Methods: Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided.Results: Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS).Conclusions: These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors. [ABSTRACT FROM AUTHOR]

Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992.Methods: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time.Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older.Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [ABSTRACT FROM AUTHOR]

Background: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis.Methods: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided.Results: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P=.02), lack of estrogen receptors (P=.008), and the number of positive lymph nodes (P=.0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors--DFS: relative risk of failure (RR)=0.60 (95% confidence interval [CI]=0.44-0.83), P=.001; survival: RR=0.66 (95% CI=0.47-0.92), P =.01; RFS: RR=0.58 (95% CI=0.42-0.82), P=.002; DDFS: RR=0.61 (95% CI=0.44-0.85), P=.003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR=0.96 (95% CI=0.75-1.23), P=.74; survival: RR =0.90 (95% CI=0.69-1.19), P=.47; RFS: RR=0.88 (95% CI=0.67-1.16), P=.37; DDFS: RR=1.03 (95% CI=0.79-1.35), P=.84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P=.02) and DDFS (P=.02) but not for survival (P= .15) or RFS (P=.06).Conclusions: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR + )/HER2-negative (HER2 - ) advanced/metastatic breast cancer., Patients and Methods: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16)., Results: Overall, 118 patients enrolled in phase IB ( n = 24) and II ( n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day ( n = 4) and 4 mg every day ( n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262)., Conclusions: Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer., (©2021 American Association for Cancer Research.)

Background: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer., Methods: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m 2 ) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review., Results: The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups., Conclusion: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR., Clinical Trial Registration: ClinicalTrials.gov, NCT01989676.

Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.

Purpose: Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care., Patients and Methods: In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified., Results: At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab., Conclusion: The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.

Purpose: registHER is a prospective, observational study of 1,023 newly diagnosed HER2-positive metastatic breast cancer (MBC) patients., Experimental Design: Baseline characteristics of patients with and without central nervous system (CNS) metastases were compared; incidence, time to development, treatment, and survival after CNS metastases were assessed. Associations between treatment after CNS metastases and survival were evaluated., Results: Of the 1,012 patients who had confirmed HER2-positive tumors, 377 (37.3%) had CNS metastases. Compared with patients with no CNS metastases, those with CNS metastases were younger and more likely to have hormone receptor-negative disease and higher disease burden. Median time to CNS progression among patients without CNS disease at initial MBC diagnosis (n = 302) was 13.3 months. Treatment with trastuzumab, chemotherapy, or surgery after CNS diagnosis was each associated with a statistically significant improvement in median overall survival (OS) following diagnosis of CNS disease (unadjusted analysis: trastuzumab vs. no trastuzumab, 17.5 vs. 3.8 months; chemotherapy vs. no chemotherapy, 16.4 vs. 3.7 months; and surgery vs. no surgery, 20.3 vs. 11.3 months). Although treatment with radiotherapy seemed to prolong median OS (13.9 vs. 8.4 months), the difference was not significant (P = 0.134). Results of multivariable proportional hazards analyses confirmed the independent significant effects of trastuzumab and chemotherapy (HR = 0.33, P < 0.001; HR = 0.64, P = 0.002, respectively). The effects of surgery and radiotherapy did not reach statistical significance (P = 0.062 and P = 0.898, respectively)., Conclusions: For patients with HER2-positive MBC evaluated in registHER, the use of trastuzumab, chemotherapy, and surgery following CNS metastases were each associated with longer survival.

Background: Botanical therapies are often used by breast cancer patients yet few clinical trials have evaluated their safety and efficacy. We studied mechanisms of activity and performed a phase I clinical trial in patients with advanced breast cancer to evaluate BZL101, an aqueous extract from Scutellaria barbata., Methods: Preclinical studies were conducted in vitro to characterize cell death induced by BZL101. In a phase I trial, eligible patients had histologically confirmed, measurable metastatic breast cancer. Treatment consisted of 350 ml per day of oral BZL101, administered as sole cancer therapy until disease progression, toxicity or personal preference to discontinue. Primary endpoints were safety, toxicity and tumor response., Results: BZL101 extract induced strong growth inhibition and apoptosis of breast cancer cell lines. In the phase I trial, 21 patients received BZL101. Mean age was 54 years (30-77) and mean number of prior treatments for metastatic disease was 3.9 (0-10). There were no grade III or IV adverse events (AEs). The most frequently reported BZL101-related grade I and II AEs included: nausea (38%), diarrhea (24%), headache (19%) flatulence (14%), vomiting (10%), constipation (10%), and fatigue (10%). Sixteen patients were evaluable for response. Four patients had stable disease (SD) for >90 days (25%) and 3/16 had SD for >180 days (19%). Five patients had objective tumor regression, one of which was 1 mm short of a PR based on RECIST criteria., Conclusions: BZL 101 inhibits breast cancer cell lines by inducing apoptosis. In a phase I clinical trial, BZL101 was safe and had a favorable toxicity profile. BZL101 demonstrated encouraging clinical activity in this heavily pretreated population.

Purpose: Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss., Patients and Methods: Patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (LS) or total hip (TH) T score decreased to less than -2.0 or when a nontraumatic fracture occurred. The primary end point of this study was to compare the change in LS BMD at month 12 between the groups. Secondary end points included change in TH BMD and changes in serum bone turnover markers at month 12., Results: The upfront and delayed groups each included 301 patients. At month 12, LS BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P < .0001), and TH BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P < .0001). In the upfront group, mean serum N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 15.1% (P < .0001) and 8.8% (P = .0006), respectively, at month 12, whereas concentrations increased significantly in the delayed group by 19.9% (P = .013) and 24.3% (P < .0001), respectively., Conclusion: With 1 year of follow-up, results of the primary end point of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) indicate that upfront zoledronic acid therapy prevents bone loss in the LS in postmenopausal women receiving adjuvant letrozole for early-stage breast cancer.

Purpose: Locoregional failure after breast-conserving surgery is associated with increased risk of distant disease and death. The magnitude of this risk in patients receiving chemotherapy has not been adequately characterized., Patients and Methods: Our study population included 2,669 women randomly assigned onto five National Surgical Adjuvant Breast and Bowel Project node-positive protocols (B-15, B-16, B-18, B-22, and B-25), who were treated with lumpectomy, whole-breast irradiation, and adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated. Kaplan-Meier curves were used to estimate distant-disease-free survival (DDFS) and overall survival (OS) after IBTR or oLRR. Cox models were used to model survival using clinical and pathologic factors jointly with IBTR or oLRR as time-varying predictors., Results: Four hundred twenty-four patients (15.9%) experienced locoregional failure; 259 (9.7%) experienced IBTR, and 165 (6.2%) experienced oLRR. The 10-year cumulative incidence of IBTR and oLRR was 8.7% and 6.0%, respectively. Most locoregional failures occurred within 5 years (62.2% for IBTR and 80.6% for oLRR). Age, tumor size, and estrogen receptor status were significantly associated with IBTR. Nodal status and estrogen and progesterone receptor status were significantly associated with oLRR. The 5-year DDFS rates after IBTR and oLRR were 51.4% and 18.8%, respectively. The 5-year OS rates after IBTR and oLRR were 59.9% and 24.1%, respectively. Hazard ratios for mortality associated with IBTR and oLRR were 2.58 (95% CI, 2.11 to 3.15) and 5.85 (95% CI, 4.80 to 7.13), respectively., Conclusion: Node-positive breast cancer patients who developed IBTR or oLRR had significantly poorer prognoses than patients who did not experience these events.

Purpose: Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines., Patients and Methods: National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms., Results: Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity., Conclusion: Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.