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Purpose: A cross-sectional study was conducted to investigate the feasibility of implementing routine collection of the Euro-Qol 5 dimensions (EQ-5D) questionnaire, to inform drug and health technology reimbursement decision making., Methods: Women with breast cancer were recruited during scheduled clinic visits to an academic cancer centre. EQ-5D-5L was self-administered using electronic tablets. Diagnostic and treatment data were abstracted from patient charts. Feasibility was assessed primarily by the proportion of patients who fully completed EQ-5D-5L and by their willingness to complete the instrument at each clinic visit., Results: 588 women were approached for study participation, 341 were enrolled. Fully completed EQ-5D-5L questionnaires were obtained in 323 participants (95% of participants, 95% CI 92-97%). Median time for EQ-5D-5L completion was 1.5 minutes (range:0.35 to 14.7). Mean age of participants was 58 years old. Most women who completed EQ-5D were White, born outside Canada and presented a high education level; one-quarter had metastatic disease. Most participants reported "No problems" in all EQ-5D-5L dimensions. Mean EQ-5D-5L index and mean EQ-5D-5L VAS values for all participants were respectively 0.83 (SD 0.13) and 75.7 (SD 17.45), with patients with metastatic disease scoring the lowest values. Seventy-eight percent of participants were willing to complete EQ-5D-5L at each clinic visit; lower Charlson comorbidity index and higher education level were predictors of willingness to continue to answer EQ-5D-5L., Conclusions: Tablet-based collection of EQ-5D-5L in the context of routine clinical practice proved to be feasible. However, many patients declined study participation or reported being in full health, raising concerns about whether this method of collecting EQ-5D adequately represents the health status of all breast cancer patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Torres et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours., Methods: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis., Results: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%)., Conclusion: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial., Trial Registration: Clinicaltrials.gov identifier NCT00490139., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The use of endocrine therapy for early-stage breast cancer, particularly aromatase inhibitor therapy has been associated with an increased risk of osteoporosis and fracture in clinical trials. We sought to validate this observation in real-world practice., Methods: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012. Patients were classified by use of either an aromatase inhibitor or tamoxifen and followed until 2017 for a new diagnosis of an osteoporotic fracture. A multivariable analysis using a Cox proportional hazards model was adjusting for age, medical co-morbidities, medication use and duration of endocrine therapy., Results: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor as compared to 27% with tamoxifen. Our multivariable analysis did not demonstrate any significant difference in the rate of osteoporotic fracture between patients treated with an aromatase inhibitor when compared with tamoxifen [Hazard ratio (HR) = 1.09; 95% confidence interval (CI) = 0.96-1.23, p-value = 0.18]. The 5-year rate of osteoporotic fracture for patients treated with either an aromatase inhibitor or tamoxifen was 7.5% and 6.9%, respectively. A completed sensitivity analysis did observe a decreased risk of fracture associated with tamoxifen usage over time., Conclusion: We could not detect a significant difference in the rate of osteoporotic fracture among patients treated with an aromatase inhibitor versus tamoxifen. Nonetheless, the risk with tamoxifen was numerically lower and significantly decreased when accounting for total duration of endocrine therapy., Competing Interests: Declaration of competing interest KIP has received honoraria from Pfizer, Roche, Amgen, Novartis, Eisai, Genomic Health, and Myriad Genetics Laboratories. She has also consulted for Pfizer and Gilead Sciences and received royalties from UpToDate. TV has consulted for Novartis and Roche. RF has consulted for Novartis, Janssen, Pfizer and Bayer. JR has received honoraria from Roche and consulted for Lilly, Merck and Novartis. DND has received honoraria from Amgen and consulted for Novartis. All other authors report no conflicts., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials., Experimental Design: Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin + or INPP4B - ) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12., Results: Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72-3.10] when compared with non-basal (nestin - and INPP4B + ) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54-1.04; P interaction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12-1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45-0.98; P = 0.04), although the interaction test was not significant., Conclusions: The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments., (©2021 American Association for Cancer Research.)

Aim: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial., Patients and Methods: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac)., Results: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups., Conclusion: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer., Trial Registration: clinicaltrials.gov Identifier NCT00490139., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests:, (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The association between endocrine therapy and risk of dementia remains uncertain. We investigated the association between adjuvant endocrine therapy for breast cancer and risk of developing dementia in a real-world, population-based study., Methods: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2012 with follow-up until 2017. Patients were classified by the use of either an aromatase inhibitor or tamoxifen and followed to estimate the unadjusted cumulative incidence of developing dementia. A multivariable Cox proportional hazards model was created adjusting for age, income quintile, medical co-morbidities, and duration of endocrine therapy., Results: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor and 27% with tamoxifen. Our multivariable analysis showed a lower rate of dementia in patients treated with an aromatase inhibitor as compared to tamoxifen [Hazard ratio (HR) = 0.88, 95% confidence interval (CI): 0.78-0.98, p-value = .02) at a median follow-up of 5.9 years. The 5-year dementia rate among patient treated with either an aromatase inhibitor or tamoxifen was 7.4% and 9.2% respectively. Older age, previous history of ischemic heart disease, diabetes, hypertension and history of stroke were all significantly associated with the development of dementia., Conclusion: Aromatase inhibitor therapy was associated with a decreased incidence of dementia as compared to treatment with tamoxifen among post-menopausal women with early stage breast cancer. Further prospective studies with longer-term follow-up investigating the neurocognitive effects of endocrine therapy are warranted., Competing Interests: Declaration of Competing Interest KIP has consulted for Pfizer, Roche, Amgen, Novartis, Eisai, Genomic Health and Myriad Genetics Laboratories. TV has consulted for Novartis and Roche. RF has consulted for Novartis, Janssen, Pfizer and Bayer. JR has received honoraria from Roche and consulted for Lilly. All other authors report no conflicts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI., Methods: Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors., Results: FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant., Conclusion: Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

Background: Current National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend against screening breast cancer patients for asymptomatic brain metastases. Because brain metastases are a major cause of morbidity and mortality from breast cancer, we undertook a literature review to ascertain whether there might be a role for brain metastases screening in high-risk patient subgroups., Materials and Methods: A literature search was conducted on the OvidSP platform in the MedLine database, using MeSH terms and subject headings related to breast cancer, brain metastases, and incidence. The search was conducted without language or publication restrictions, and included articles indexed from January 1, 2006 to June 10, 2018. Experimental and observational studies that reported the incidence of brain metastases in patients with nonmetastatic or metastatic breast cancer were included., Results: One hundred seventy studies were identified, with 33 included in the final analysis. Among nonmetastatic breast cancer patients, incidence of brain metastases as site of first recurrence per year of median follow-up ranged from 0.1% to 3.2%. Although incidence of brain metastases was much higher among the metastatic breast cancer population overall, it was particularly high among metastatic HER2-overexpressing (HER2 + ) and triple-negative populations, ranging between 22% and 36% for the former, and 15%-37% for the latter in the absence of screening., Conclusion: In patients with nonmetastatic breast cancer, screening for asymptomatic brain metastases cannot currently be justified. However, due to the high incidence of brain metastases among patients with metastatic HER2 + and triple-negative breast cancer, studies to determine the value of screening for brain metastases should be undertaken in these subgroups., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Adherence to adjuvant endocrine therapy among post-menopausal breast cancer patients is an important survivorship care issue. We explored factors associated with endocrine therapy adherence and survival in a large real-world population-based study., Methods: We used health administrative databases to follow women (aged ≥ 66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005 to 2010. Adherence was measured by medical possession ratio (MPR) and characterized as low (< 39% MPR), intermediate (40-79% MPR), or high (≥ 80% MPR) over a 5-year period. We investigated factors associated with adherence using a multinomial logistic regression model. Factors associated with all-cause mortality (5 years after starting endocrine therapy) were investigated using a multivariable Cox proportional hazards model., Results: We identified 5692 eligible patients starting adjuvant endocrine therapy who had low, intermediate, and high adherence rates of 13% (n = 749), 13% (n = 733), and 74% (n = 4210), respectively. Lower rates of adherence were associated with increased age [low vs. high adherence: odds ratio (OR) 1.03, 95% CI 1.02-1.05 (per year); intermediate vs. high adherence: OR 1.02, 95% CI 1.01-1.04 (per year)]. High adherence was associated with previous use of adjuvant chemotherapy (low versus high adherence OR 0.42, 95% CI 0.30-0.59) and short-term follow-up with a medical oncologist within 4 months of starting endocrine therapy (low versus high adherence OR 0.83, 95% CI 0.69-0.99). Unadjusted analysis showed increased survival among patients with high endocrine therapy adherence. However, an independent association was no longer clearly detected after controlling for confounders., Conclusion: Interventions to improve adjuvant endocrine therapy adherence are warranted. Non-adherence may be a more significant issue among elderly patients. Short-term follow-up visit by a patient's medical oncologist after starting endocrine therapy may help to improve compliance.

In identifying research priorities it is important to take the needs and prospective of patients with breast cancer into account., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Fulvestrant, a selective estrogen receptor degrader, is approved for first- and second-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (ABC)., Methods: Meta-analysis of randomized controlled trials (RCTs) evaluating fulvestrant 500 mg in postmenopausal hormone receptor-positive ABC, to evaluate differences in clinical benefit rate (CBR; proportion of patients experiencing best overall response of complete response, partial response, or stable disease for ≥ 24 weeks) between fulvestrant 500 mg and comparator endocrine therapies. Odds ratios (OR) and 95% confidence intervals (CI) for CBR were calculated; fixed effects (FE) models were constructed (first- and second-line data, alone and combined)., Results: Six RCTs were included. Four studies evaluated fulvestrant 500 mg vs. fulvestrant 250 mg; two evaluated fulvestrant 500 mg vs. anastrozole 1 mg. In total, 1054 and 534 patients were included (first- and second-line treatment, respectively). Analysis of OR and 95% CI of CBR by therapy line favored fulvestrant 500 mg vs. comparator therapy. Assessing all results combined in the FE model indicated significant improvement in CBR with fulvestrant 500 mg vs. comparator treatments (OR 1.33; 95% CI 1.13-1.57; p = 0.001). Restricting the FE model to therapy line demonstrated significant improvement in CBR vs. comparator treatments (OR 1.33; 95% CI 1.02-1.73; p = 0.035) for first-line, and a trend to improvement vs. comparator treatments (OR 1.27; 95% CI 0.90-1.79; p = 0.174) for second-line., Conclusions: In postmenopausal patients with hormone receptor-positive ABC, fulvestrant 500 mg first-line was associated with significantly greater CBR (more patients benefiting from treatment) vs. comparator endocrine therapy.

Background: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known., Methods: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger., Results: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%)., Conclusions: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)., (Copyright © 2019 Massachusetts Medical Society.)

Aromatase inhibitors (AIs) play an important role in the adjuvant treatment of hormone receptor-positive breast cancer, but they are associated with bone loss and increased fracture risk. Although several guidelines for the management of osteoporosis and osteopenia exist, their algorithms do not account for the use of AIs. In this article, we describe the role of bone-targeted therapies, specifically for managing early breast cancer, by reviewing their bone-specific and cancer-specific benefits.

Background: Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence., Methods: In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor-positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease-free survival (DDFS); and overall survival (OS). All statistical tests were two-sided., Results: Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years' follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non-aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01)., Conclusion: Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased "all-cause" mortality, presumably because of higher preexisting cardiovascular risks.

Background: The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score., Methods: We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death)., Results: Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25., Conclusions: Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

Background: The 21-gene Recurrence Score (RS) assay is only reimbursed in Ontario for node-negative and micrometastatic node-positive (N+) early-stage breast cancer (EBC). We carried out a prospective study to evaluate the impact of the assay on treatment decisions for women with N+ EBC., Subjects, Materials, and Methods: Women with estrogen receptor-positive, human epidermal growth receptor 2-negative EBC and one to three positive axillary lymph nodes, who were candidates for adjuvant chemotherapy in addition to hormonal treatment, but in whom the benefit of chemotherapy was uncertain, were eligible. The primary objective was to characterize how the results of the RS assay affected physicians' recommendations for adjuvant chemotherapy. Secondary objectives were to characterize changes in the physicians' and patients' level of confidence in treatment recommendations, to determine whether the results of the RS assay affected patients' treatment preferences, and to determine the final treatment administered., Results: Seventy-two patients were recruited; the mean age was 61. RS was <18 in 55%, between 18 and 30 in 36%, and ≥31 in 9% of patients. Treatment recommendations changed in 36% of all evaluable patients. The most significant change was in the group with a low RS. Physicians' and patients' confidence in treatment recommendations increased in 49% and 54% of cases, respectively. Upfront chemotherapy was recommended to 79% of patients before the assay; 42% ultimately received chemotherapy., Conclusion: The RS assay resulted in a substantial decrease in the number of patients who received chemotherapy and in an increase in physicians' and patients' confidence in the adjuvant treatment recommendations., Implications for Practice: This is the first decision impact study to include exclusively women with ER-positive, HER2-negative, early-stage breast cancer with 1-3 positive lymph nodes, a population typically treated with adjuvant chemotherapy. This study provides evidence that, in these patients, the Oncotype Dx Recurrence Score assay influences systemic treatment decisions. Most of the changes in treatment recommendation resulted in withdrawal of chemotherapy or change in recommendation from a chemotherapy regimen with anthracyclines to a taxane-only regimen. If prospective studies confirm that these decisions result in good outcomes, a reduction in the use of chemotherapy might result in pharmacoeconomic savings., (© AlphaMed Press 2018.)

Introduction: Elderly patients make up a significant proportion of patients with metastatic breast cancer. With several options available in the metastatic setting for hormone positive breast cancer, these patients require an individualized approach to decision-making that considers multiple factors beyond performance status and chronologic age., Areas Covered: The authors review the literature on endocrine monotherapy and combinations for hormone positive metastatic breast cancer, with specific commentary on the efficacy and toxicity for elderly patients. The authors describe the role of comprehensive geriatric assessment (CGA) and highlight the considerations for the use of bone modifying agents, and HER2-targeted therapy for hormone positive/HER2+ patients., Expert Opinion: Evidence for elderly patients is largely based on subgroup analyses, which should be interpreted with caution. Nonetheless, elderly patients with metastatic hormone receptor positive breast cancer appear to derive similar benefit from treatments as younger patients. Similarly, for most drugs, these patients have no significant worsening of toxicity compared to younger patients. In addition to tumor biology, patient values and information from the CGA should be used to guide treatment decisions.

Phosphoinositide 3-kinase (PI3K) inhibitors may overcome drug resistance and improve advanced breast cancer (ABC) outcomes. We conducted a systematic review and meta-analysis to assess the efficacy and safety of adding a PI3K inhibitor to the standard of care (SOC) treatment in ABC. The electronic databases Ovid, PubMed, Cochrane Central Register of Controlled Trials and Embase, were searched for relevant randomised trials. Pooled hazard ratios (HRs) for progression-free survival (PFS) and pooled risk ratios (RRs) for objective response rates (ORRs), disease control rates (DCRs) and toxicity were meta-analysed using the Mantel-Haenszel method and generic inverse variance. Five studies were included. In unselected patients, the addition of a PI3K inhibitor decreased the risk of progression by 21% (2329 participants, HR = 0.79; 95% confidence interval [CI], 0.71-0.88). A marginal improvement in ORR (2329 participants, RR = 1.26; 95% CI, 1.01-1.57) and no improvement in DCR (2146 participants, RR = 1.05; 95% CI, 0.94-1.18) were achieved with a significant increase in toxicity of any grade (2386 participants, RR = 1.05; 95% CI, 1.03-1.06) and of grade III and higher (2386 participants, RR = 1.91; 95% CI, 1.76-2.08). A PFS benefit was seen in patients with and without PI3K pathway activation assessed on tumour and only in patients with an activated PI3K pathway when it was assessed from the plasma using circulating tumour DNA (ct-DNA) analysis. The addition of a PI3K inhibitor decreases the risk of progression in unselected ABC patients and particularly in patients with an activated PI3K pathway detected on ct-DNA analysis. However, their significant dose-limiting toxicity is a limiting factor. Selective PI3K inhibitors are being tested to assess whether these better-tolerated agents have a role in ABC treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose MA.17R was a Canadian Cancer Trials Group-led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor-positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL.

Background: The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment., Methods: In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years., Results: Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively., Conclusions: After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).

Background: Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes., Methods: The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05., Results: Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31)., Conclusions: Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples., Methods: VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables., Results: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L., Conclusions: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) -positive and node-positive early breast cancer (eBC). Methods Postmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for letrozole versus 82.9% for anastrozole arm (hazard ratio, 0.93; 95% CI, 0.80 to 1.07; P = .3150). Exploratory analysis showed similar DFS with letrozole and anastrozole in all evaluated subgroups. The 5-year estimated overall survival rate was 89.9% for letrozole versus 89.2% for anastrozole arm (hazard ratio, 0.98; 95% CI, 0.82 to 1.17; P = .7916). Most common grade 3 to 4 adverse events (> 5% of patients) reported for letrozole versus anastrozole were arthralgia (3.9% v 3.3%, and 48.2% v 47.9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR-positive, node-positive eBC.

Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor-positive (HR+) tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR+/HER- advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients. Although the safety profiles of these combinations are generally predictable and manageable, both everolimus and palbociclib are associated with an increased risk of potentially serious or early-onset toxicities requiring individualized a priori adverse event risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Although each of these combinations improves progression-free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. PI3K catalytic-α mutations assessed from circulating tumor DNA represent the first potentially viable serum biomarker for the selection of ET combinations, and new data demonstrate the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis. Therapeutic ratios of select ET combinations support their use in first- and second-line settings, but optimal sequencing has yet to be determined., The Oncologist: 2017;22:12-24 IMPLICATIONS FOR PRACTICE: Emerging data show that new endocrine therapy (ET) combinations can improve progression-free and overall survival outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER-) advanced breast cancer. Level 1 evidence supports consideration of dual ET regimens, particularly in ET-naïve patients, or palbociclib plus letrozole as first-line therapy, as well as the addition of mTOR or CDK4/6 inhibitors to established ET in the second-line setting and in select first-line patients. Some combinations are associated with increased risk of class-specific toxicities that will require individualized risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Recent data on a noninvasive biomarker assay that predicts response to a phosphoinositide 3-kinase inhibitor demonstrates the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis., (© AlphaMed Press 2016.)

Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. Cancer Res; 76(23); 7012-23. ©2016 AACR., Competing Interests: No potential conflicts of interest were disclosed by the authors., (©2016 American Association for Cancer Research.)

Introduction: Elderly women with early breast cancer require an individualized approach to risk assessment and treatment. Unfortunately, there are limited data to inform optimal adjuvant therapy decisions in this population. Cytotoxic chemotherapy, biologic treatments and endocrine agents, while important in reducing breast cancer recurrence and mortality, are associated with the potential for adverse effects that may be of particular significance to elderly patients., Areas Covered: In this review, we summarize the evidence for geriatric assessment in elderly patients with early breast cancer, outline special considerations for the use of chemotherapy and trastuzumab in older adults, and describe the age-specific risks of endocrine therapy in the adjuvant breast cancer setting., Expert Opinion: The treatment of elderly women with early breast cancer should take into account cancer risk, life expectancy, comorbidities, functional status, physiologic changes, and patient values. Formal geriatric assessment may better inform treatment recommendations for individual patients. In general, there is no strong evidence to suggest that older women benefit less from standard adjuvant therapies than do their younger counterparts. When choosing between endocrine therapies, the differential risks associated with each agent should be considered and particular attention to the fracture risk on aromatase inhibitors (AIs) is warranted. Enrolment of women over 70 years of age into breast cancer clinical trials should be encouraged to better inform treatment guidelines.

Endocrine-based treatments are the mainstay of therapy for postmenopausal women with breast cancer; yet concern has been raised about potential adverse cognitive effects. We performed a systematic review of the published literature to evaluate whether endocrine-based treatments for breast cancer are associated with changes in cognitive domains and whether these effects are more pronounced with advanced age. An electronic database search was performed. Original investigations that examined the effects of endocrine treatment on cognitive function were identified. Data were abstracted and studies were assessed for risk of bias. A total of 21 unique studies (n = 2398) were identified. Ten were short-term (duration ≤ 2 years) and 11 were long-term (duration > 2 years). Nine (43 %) studies had a sample size ≤100 subjects; 9 (43 %) were longitudinal, with baseline measurement before treatment initiation. No studies were primary randomized clinical trials. While there was heterogeneity in the neuropsychological measures used, tests could be grouped into the cognitive domains that they assessed. Compared to breast cancer or healthy controls, endocrine therapy was associated with impaired performance on neuropsychological testing. No study explored the association between age and changes in cognitive performance. Overall, endocrine therapies were associated with greater cognitive deficits compared to surgical and healthy controls; yet, lack of randomized trial data and heterogeneity in design of many studies limited any definitive conclusions. Despite older women being at highest risk for the development of cognitive impairment, advanced age has not been adequately explored.

Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence., Methods: We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival., Results: We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P=0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P=0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life., Conclusions: The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov numbers, NCT00003140 and NCT00754845.).

Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.

Background: Previously we have shown that early development of rash is associated with a higher chance of achieving pathological complete response to neoadjuvant lapatinib. In the current analysis, we investigate its impact on survival in the ALTTO phase III adjuvant trial., Methods: In ALTTO, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomly assigned to adjuvant trastuzumab, lapatinib, their sequence, or their combination for a total duration of one year. We evaluated whether the development of early lapatinib-related rash (ie, within 6 weeks) is associated with disease-free (DFS) and overall survival (OS). Landmark analysis at eight weeks and time-dependent analysis were tested in a multivariable model stratifying on trial's stratification factors. All statistical tests were two-sided., Results: Out of 6098 lapatinib-treated patients, 3973(65.2%) were included in the landmark analysis, of whom 1389 (35.0%) had developed early rash. After median follow-up of 4.5 years, the development of early rash was associated with a trend of improved DFS (multivariable: hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.73 to 1.03,P= .10) and statistically significantly improved OS (multivariable: HR = 0.63, 95% CI = 0.48 to 0.82,P< .001) compared with subjects without early rash. Compared with patients randomly assigned to trastuzumab (n = 2051), patients who were randomly assigned to trastuzumab/lapatinib combination and developed early rash (n = 692) had superior DFS (multivariable: HR = 0.72, 95% CI = 0.55 to 0.92,P= .01) and OS (multivariable: HR = 0.59, 95% CI = 0.39 to 0.90,P= .01). Time-dependent analysis suggests that the occurrence of rash is predictive of lapatinib benefit, both when given in combination or sequential to trastuzumab., Conclusions: Our results indicate that early development of rash identifies patients who derive superior benefit from lapatinib-based therapy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death.

Purpose: To evaluate the 21-gene recurrence score (RS) on decision-making in a population-based cohort., Patients and Methods: Patients with axillary node-negative or nodal micrometastases, estrogen receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer being considered for chemotherapy were eligible. All cancer treatment centers in Ontario, Canada, participated. Oncologists made a preliminary recommendation for endocrine therapy with or without chemotherapy on the basis of Adjuvant! Online (AOL) risk estimation. Patients were asked for their preference regarding chemotherapy. After RSs were available, patients returned for final decision-making. Patient satisfaction was measured by using the decisional conflict scale., Results: Between January 2012 and July 2013, 1,000 patients were recruited. RSs were available for 979 patients. In 58% of patients, risk was categorized as low (RS, 0 to 18); in 33%, intermediate (RS, 19 to 30); and in 9%, high (RS, ≥ 31). Oncologists' recommendations pretest and post-test remained the same in 464 patients (48%), changed from unsure or chemotherapy to no chemotherapy in 365 (38%), and changed from unsure or no chemotherapy to chemotherapy in 143 (15%). After the test, oncologists recommended chemotherapy for 236 patients, 81% of whom received chemotherapy. Of 151 patients in whom risk was classified as intermediate by means of AOL, 41% were a low risk and 44% intermediate risk with RS. Of 298 patients at high risk with AOL, 16% had a high risk RS. None of 236 patients with grade I tumors had a high-risk RS. Mean total decisional conflict scale score significantly improved from pretest to post-test from 34 to 19 (P < .001)., Conclusion: The RS substantially influenced both oncologists' recommendations and patients' preferences for chemotherapy. The major effect was avoidance of chemotherapy when AOL indicated high or intermediate risk., (© 2015 by American Society of Clinical Oncology.)

Background: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain., Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T., Results: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms., Conclusion: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care., (© 2015 by American Society of Clinical Oncology.)

Background: Fatigue and sleep problems are prevalent in cancer patients and can be associated with disruption of circadian rhythmicity. In this prospective phase II trial, we sought to assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in breast cancer patients., Methods: Thirty-two patients with metastatic breast cancer, receiving hormonal or trastuzumab therapy, took 5 mg of melatonin at bedtime for 2 months. Before starting and after 2 months on melatonin therapy, sleep and circadian rhythmicity were assessed by actigraphy, diurnal patterns of serum cortisol, and the expression of the core clock genes PER2 and BMAL1 in peripheral blood mononuclear cells. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was completed for subjective parameters., Results: Bedtime melatonin was associated with a significant improvement in a marker of objective sleep quality, sleep fragmentation and quantity, subjective sleep, fatigue severity, global quality of life, and social and cognitive functioning scales. Morning clock gene expression was increased following bedtime melatonin intake. Melatonin did not affect actigraphy measure of circadian rhythmicity, or the diurnal cortisol pattern., Conclusion: These results invite further investigation of melatonin as a potentially useful therapeutic agent for improving sleep and quality of life in cancer patients.

In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial. To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors. Hormone receptor negative (HR-) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR- patients on placebo (hazard ratio 0.64, P=0.003). For patients with HR- disease, starting treatment with lapatinib ≤1 year from diagnosis improved DFS by 12.1% [2.1-22.1] at 2 years and 15.7% [4.1-27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients <1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA). In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR- patients are in range with those reported from up-front adjuvant trastuzumab trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: To explore the genetic landscape of tumors from patients enrolled on the BOLERO-2 trial to identify potential correlations between genetic alterations and efficacy of everolimus treatment. The BOLERO-2 trial has previously demonstrated that the addition of everolimus to exemestane prolonged progression-free survival by more than twofold in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer previously treated with nonsteroidal aromatase inhibitors., Patients and Methods: Next-generation sequencing was used to analyze genetic status of cancer-related genes in 302 archival tumor specimens from patients representative of the BOLERO-2 study population. Correlations between the most common somatic alterations and degree of chromosomal instability, and treatment effect of everolimus were investigated., Results: Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components. However, quantitative differences in everolimus benefit were observed between patient subgroups defined by the exon-specific mutations in PIK3CA (exon 20 v 9) or by different degrees of chromosomal instability in the tumor tissues., Conclusion: The data from this exploratory analysis suggest that the efficacy of everolimus was largely independent of the most commonly altered genes or pathways in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The potential impact of chromosomal instabilities and low-frequency genetic alterations on everolimus efficacy warrants further investigation., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Background: Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999)., Methods: Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis., Results: Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002)., Conclusions: BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.

Background: Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker., Methods: We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence)., Results: Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6)., Conclusions: Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Chromosome instability (CIN) in solid tumours results in multiple numerical and structural chromosomal aberrations and is associated with poor prognosis in multiple tumour types. Recent evidence demonstrated CEP17 duplication, a CIN marker, is a predictive marker of anthracycline benefit. An analysis of the BR9601 and MA.5 clinical trials was performed to test the role of existing CIN gene expression signatures as predictive markers of anthracycline sensitivity in breast cancer. Univariate analysis demonstrated, high CIN25 expression score was associated with improved distant relapse free survival (DRFS) (HR: 0.74, 95% CI 0.54-0.99, p = 0.046). High tumour CIN70 and CIN25 scores were associated with aggressive clinicopathological phenotype and increased sensitivity to anthracycline therapy compared to low CIN scores. However, in a prospectively planned multivariate analysis only pathological grade, nodal status and tumour size were significant predictors of outcome for CIN25/CIN70. A limited gene signature was generated, patients with low tumour CIN4 scores benefited from anthracycline treatment significantly more than those with high CIN4 scores (HR 0.37, 95% CI 0.20-0.56, p = 0.001). In multivariate analyses the treatment by marker interaction for CIN4/anthracyclines demonstrated hazard ratio of 0.35 (95% CI 0.15-0.80, p = 0.012) for DRFS. This data shows CIN4 is independent predictor of anthracycline benefit for DRFS in breast cancer.

NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.

Background: Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes., Methods: We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival., Results: Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001)., Conclusions: Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.).

Most patients with hepatitis B virus (HBV) have no symptoms, and many are unaware of the infection. However, HBV can reactivate with immunosuppression; chemotherapy causes reactivation in 22 % of hepatitis B surface antigen-positive patients. HBV reactivation can be fatal. HBV reactivation can be prevented, provided that HBV is recognized prior to chemotherapy. The objective of this study is to estimate the health and economic effects of HBV screening strategies in patients receiving adjuvant chemotherapy for breast cancer. We developed a state-transition microsimulation model to examine the cost-effectiveness of three HBV screening strategies: (1) "No screening"; (2) "Screen-and-Treat to prevent reactivation" (screen-all) with either lamivudine/tenofovir (LAM/TDF) or entecavir (ETV); and (3) "Screen-and-Treat high-risk only" (screen-HR) and treat with either LAM/TDF or ETV. Model data were obtained from the published literature. We used a payer's perspective, a lifetime horizon, and a 5 % discount rate for the analysis. "Screen-all" would prevent at least 38 severe reactivations per 100,000 persons screened over the lifetime of the cohort. "Screen-all" was associated with an increase of 0.0034-0.0035 QALYs and an additional cost of C$164-C$266 per person, which translated into an incremental cost-effectiveness ratio of C$47,808/QALY-C$76,527/QALY gained compared with "No screening" depending on the antiviral therapy received. "Screen-all" was the most cost-effective strategy, while "Screen-HR" was inferior in all scenarios tested. HBV screening before adjuvant chemotherapy for breast cancer patients would prevent a significant number of reactivations, would likely be moderately cost-effective, and may extend the lives of breast cancer patients.

Purpose: The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown., Patients and Methods: The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors., Results: From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03)., Conclusion: As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane., (© 2015 by American Society of Clinical Oncology.)

Introduction: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described., Methods: Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy., Results: Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+ HR- (ER-/PR-) disease (hazard ratio 0.72, P=0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+ HR- compared to HER2+ HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P=0.002 for years 1 to 5). The high early risk of recurrence of HER2+ HR- patients declined sharply over time, so that it was similar to that seen in HER2+ HR+ patients in years 6 to 10 (hazard ratio 0.97, P=0.92 for years 6 to 10)., Conclusions: Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+ HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+ HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy.

Background: To evaluate health related quality of life (HRQOL) in TEACH, a phase III randomized placebo controlled trial of 12 months of adjuvant lapatinib in HER2 positive (HER2+) early breast cancer which demonstrated marginal benefit in disease-free survival., Methods: Women on TEACH completed the Short Form 36-item health survey (version2; SF-36v2) at the baseline, six and 12 months after therapy initiation and six monthly thereafter. Mean changes were compared between treatment groups for two summary measures (Physical and Mental Component Summary scores; PCS and MCS) and eight domain measures (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), and in patients discontinuing therapy. A five-point change was deemed a Minimally Clinically Important Difference (MCID). Response analysis compared the proportion of patients demonstrating a MCID in HRQOL, and a regression analysis identified predictors of worsening HRQOL., Findings: 3074 (97%) subjects completed baseline SF-36v2. During the initial 12 months, summary SF-36v2 scores decreased in both arms but did not reach Minimally Clinically Important Difference (MCID) despite significant incidences of diarrhoea and rash in lapatinib treated patients. At six months, women receiving lapatinib had more significant reductions (p < 0.01 versus placebo) in social functioning. Early treatment discontinuations were more frequent on lapatinib (32% versus 18%), and were associated with more substantial decrements of HRQOL in both arms. For those discontinuing primarily due to adverse events, decrements in HRQOL reached MCID in Mental Summary scores (MCS) only. Lower baseline HRQOL was a significant predictor of worsening HRQOL (p < 0.05)., Interpretation: Despite frequent but usually mild toxicities, adjuvant lapatinib is not associated with clinically significant decreases in overall HRQOL. These placebo-controlled results may also help to inform physicians and patients using lapatinib in metastatic HER2 positive breast cancer., Funding: GlaxoSmithKline. The AVON Foundation NY supported PEG, DF and BM and The Friends of the Mater Foundation supported FB., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Low vitamin D levels have been associated with poor breast cancer outcomes in observational studies. We examined the association of vitamin D blood levels with relapse-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) in the MA.21 randomized clinical trial. Fasting blood was collected pre-chemotherapy in 934/2104 (44.4 %) of subjects; 25 hydroxy vitamin D was measured (radioimmunoassay, Diasorin) in one batch. Vitamin D was assessed as a transformed continuous factor, and categorically (quartiles and clinical classifications). Univariate and multivariate prognostic analyses (adjusted for treatment, stratification factors, and baseline imbalances) were performed using Cox models. Most patients were young (median 47.8 years), white (91.6 %) and premenopausal (69.4 %) with grade III (52 %), HER2 negative or missing (89.5 %), ER positive (61.9 %), T1-2 (89.4 %), N + (72.7 %) breast cancer. Compared to the full population, those with vitamin D levels were more likely to be white, PS 1 or 2, to have undergone mastectomy, and to have an ER + tumor. Mean vitamin D was 69.7 nmol/L (27.9 ng/ml) and did not vary by tumor subtype. The majority (80.5 %) had levels >50 nmol/L (20 ng/ml), considered adequate by Institute of Medicine. Continuous vitamin D was not multivariately associated with RFS, BCSS, or OS (p = 0.36, 0.26, 0.33, respectively); categorical vitamin D was also not associated with outcome. Vitamin D associations with RFS did not differ within ER/HER2 subgroups. There was no evidence that vitamin D blood level was associated with RFS, BCSS, and OS in MA.21; the majority of subjects had adequate vitamin D levels at study entry.

Background: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples., Methods: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided., Results: Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin., Conclusions: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)