Feasibility of Symptom Monitoring During the First Year of Endocrine Therapy for Early Breast Cancer Using Patient-Reported Outcomes Collected via Smartphone App.

PURPOSE: Treatment-associated symptoms drive early discontinuation of adjuvant endocrine therapy (ET) for breast cancer. We hypothesized that symptom monitoring with electronic patient-reported outcomes (ePROs) during adjuvant ET will enhance symptom detection, symptom management, and persistence. METHODS: Eligible patients were initiating ET for stage 0-III breast cancer. Participants completed ePRO surveys via smartphone at baseline and 1, 3, 6, and 12 months. Measures included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Fatigue, and Vaginal Discomfort; plus Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items assessing joint pain, hot flashes, vaginal dryness, concentration problems, and memory problems. Scores surpassing prespecified thresholds triggered alerts, and recommended symptom management pathways were provided to clinicians. The primary objective was to evaluate feasibility, assessed by survey completion rates, with targets of >65% for the baseline survey and ≥1 follow-up survey during the first 6 months. Secondary objectives included 12-month ET discontinuation rate (target: ≤15%), describing symptoms and evaluating pathway implementation. RESULTS: Among 250 participants, 73.2% completed the baseline survey and 69.6% completed ≥1 follow-up survey during the first 6 months. Thirty-one percent of participants had ≥1 symptom alert at baseline and 74% had ≥1 symptom alert during follow-up. The proportions of participants for whom pathway-concordant symptom management was documented at each time point ranged from 12.8% to 36.6%. Twenty-eight participants (11.2%) discontinued ET by 12 months. CONCLUSION: Symptom monitoring with ePROs during adjuvant ET is feasible. Despite infrequent documentation of pathway-concordant symptom management after symptom alerts, ePROs were associated with favorable short-term ET persistence.

Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation.

Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18-27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02-1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01-1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation.

Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes.

BACKGROUND: Poly-ADP ribose polymerase (PARP) inhibitors (PARPi) are active in patients with germline BRCA1/2 (gBRCA1/2)-mutated breast cancer, accounting for 5% to 10% of all breast cancers. Another 5% to 10% harbor somatic BRCA1/2 (sBRCA1/2) mutations or mutations in non-BRCA1/2, homologous recombination repair (HRR) genes but until recently, there were no data for the use of PARPi in these patients. This study examines the use of olaparib in patients with metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations and demonstrates potential activity of PARPi in this setting. METHODS: In this retrospective, single institution study, patients who were treated with off-label, off-protocol olaparib for metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations were identified. The primary aim was to describe these patients' demographics, tumor characteristics, mutations, safety and tolerability, response rates, progression free survival, PARPi-associated survival and subsequent treatment. RESULTS: Seven patients were treated off-label, off-trial with olaparib for sBRCA1/2-mutated cancers (n = 4) or non-BRCA1/2, HRR-mutated cancers (n = 3). All patients with sBRCA1/2-mutated cancers responded to PARP inhibition; patients with non-BRCA1/2, HRR-mutated cancers did not respond. The median progression free survival in patients with a sBRCA1/2 mutation was 6.5 months (range 5-9 months) vs. 3 months (range 2-4 months) in patients with non-BRCA1/2, HRR mutations. CONCLUSION: This single institution experience adds to recent larger reports confirming evidence for PARPi therapy in patients with metastatic breast cancer harboring sBRCA1/2 mutations. No activity was observed in patients with either germline or somatic non-BRCA1/2, HRR-mutated cancers.

A randomized intervention involving family to improve communication in breast cancer care.

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

Management of Breast Cancer During the COVID-19 Pandemic: A Stage- and Subtype-Specific Approach.

The COVID-19 pandemic has rapidly changed delivery of cancer care. Many nonurgent surgeries are delayed to preserve hospital resources, and patient visits to health care settings are limited to reduce exposure to SARS-CoV-2. Providers must carefully weigh risks and benefits of delivering immunosuppressive therapy during the pandemic. For breast cancer, a key difference is increased use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the pandemic. In some cases, this necessitates increased use of genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. Breast cancer treatment during the pandemic requires multidisciplinary input and varies according to stage, tumor biology, comorbidities, age, patient preferences, and available hospital resources. We present here the Johns Hopkins Women's Malignancies Program approach to breast cancer management during the COVID-19 pandemic. We include algorithms based on tumor biology and extent of disease that guide management decisions during the pandemic. These algorithms emphasize medical oncology treatment decisions and demonstrate how we have operationalized the general treatment recommendations during the pandemic proposed by national groups, such as the COVID-19 Pandemic Breast Cancer Consortium. Our recommendations can be adapted by other institutions and medical oncology practices in accordance with local conditions and resources. Guidelines such as these will be important as we continue to balance treatment of breast cancer against risk of SARS-CoV-2 exposure and infection until approval of a vaccine.

The Effects of a Remote-based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial.

PURPOSE: We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length. EXPERIMENTAL DESIGN: Women with stage 0-III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m2 were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at 6 months. We assessed baseline and 6-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNFα, MCP1, IL1ß, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells. RESULTS: From 2013 to 2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At 6 months, 51% of women randomized to POWER-remote lost ≥5% of their baseline body weight, compared with 12% in the self-directed arm [OR, 7.9; 95% confidence interval (CI), 2.6-23.9; P = 0.0003]; proportion were similar at 12 months (51% vs 17%, respectively, P = 0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at 6 months. CONCLUSIONS: A remotely delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.

Sharing in care: engaging care partners in the care and communication of breast cancer patients.

PURPOSE: Family is often overlooked in cancer care. We developed a patient-family agenda setting intervention to engage family in cancer care communication. METHODS: We conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family "care partner." Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks. RESULTS: At baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients' MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001). CONCLUSIONS: A patient-family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.

A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.

PURPOSE: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS. METHODS: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively. RESULTS: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density. CONCLUSIONS: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories.

Heterogeneity within and among tumors in a metastatic cancer patient is a well-established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores. Pathological features of the patients' disease were assessed by immunohistochemical analyses. Our data support a monoclonal origin of metastasis in 3 cases, but in 2 cases, metastases arose from at least 2 distinct subclones in the primary tumor. In the latter 2 cases, the primary tumor presented with mixed histologic and pathologic features, suggesting early divergent evolution within the primary tumor with maintenance of metastatic capability in multiple lineages. We used genetic and histopathological evidence to demonstrate that metastases can be derived from a single or multiple independent clones within a primary tumor. This underscores the complexity of breast cancer clonal evolution and has implications for how best to determine and implement therapies for early- and late-stage disease.

Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study.

Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. ©2016 AACR.

Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer.

Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or ≤ 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk.

TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer.

UNLABELLED: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes. METHODS: Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR. RESULTS: In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not. CONCLUSION: Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.

Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS. PATIENTS AND METHODS: Premenopausal women with axillary node-negative, hormone receptor-positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were disease-free survival (DFS) and overall survival (OS). Secondary end points included toxicity and patient-reported outcomes. Patient-reported outcome data included health-related quality of life, menopausal symptoms, and sexual function. These were evaluated at baseline, 6 months, 12 months, and then annually for up to 5 years after registration. RESULTS: In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for DFS (5-year rate: 87.9% v 89.7%; log-rank P = .62) or OS (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up. CONCLUSION: When added to tamoxifen, OFS results in more menopausal symptoms and sexual dysfunction, which contributes to inferior self-reported health-related quality of life. Because of early closure, this study is underpowered for drawing conclusions about the impact on survival when adding OFS to tamoxifen.

A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burden and immune tolerance. Cyclophosphamide augments vaccine activity in tolerant neu mice and in patients with metastatic breast cancer. HER2-specific monoclonal antibodies (mAb) enhance vaccine activity in neu mice. We hypothesized that cyclophosphamide-modulated vaccination with HER2-specific mAb safely induces relevant HER2-specific immunity in neu mice and patients with HER2+ metastatic breast cancer. Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice. We, therefore, conducted a single-arm feasibility study of cyclophosphamide, an allogeneic HER2+ GM-CSF-secreting breast tumor vaccine, and weekly trastuzumab in 20 patients with HER2+ metastatic breast cancer. Primary clinical trial objectives were safety and clinical benefit, in which clinical benefit represents complete response + partial response + stable disease. Secondary study objectives were to assess HER2-specific T-cell responses by delayed type hypersensitivity (DTH) and intracellular cytokine staining. Patients received three monthly vaccinations, with a boost 6 to 8 months from trial entry. This combination immunotherapy was safe, with clinical benefit rates at 6 months and 1 year of 55% [95% confidence interval (CI), 32%-77%; P = 0.013] and 40% (95% CI, 19%-64%), respectively. Median progression-free survival and overall survival durations were 7 months (95% CI, 4-16) and 42 months (95% CI, 22-70), respectively. Increased HER2-specific DTH developed in 7 of 20 patients [of whom 4 had clinical benefit (95% CI, 18-90)], with a trend toward longer progression-free survival and overall survival in DTH responders. Polyfunctional HER2-specific CD8+ T cells progressively expanded across vaccination cycles. Further investigation of cyclophosphamide-modulated vaccination with trastuzumab is warranted.

Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer.

The pro-drug capecitabine is approved for treatment of anthracycline- and paclitaxel-resistant metastatic breast cancer. However, toxicity and large interpatient pharmacokinetic variability occur despite body surface area (BSA)-dosing. We hypothesized that a fixed-dose schedule would simplify dosing and provide an effective and safe alternative to BSA-based dosing. We conducted an open label, single-arm, two-stage study of oral capecitabine with fixed starting dose (3,000 mg total daily dose in two divided doses × 14 days q21 days) in patients with metastatic breast cancer. We correlated pharmacodynamic endpoints [e.g., efficacy (response) per RECIST and toxicity], adherence and pharmacokinetics/pharmacogenetics. Sample size of 45 patients was required to detect a 25 % response rate from null response rate of 10 % using a Simon two-stage design. Twenty-six patients were enrolled in the first-stage and 21 were evaluable after a median of four cycles of capecitabine. Two thirds of patients received either the same dose or a dose 500 mg lower than what would have been administered with a commonly used 2,000 mg/m(2) BSA-dosing schedule. Eight patients had stable disease but progressed after a median of seven cycles. Despite a clinical benefit rate of 19 %, no RECIST responses were observed following the first stage and the study was closed. Dose-reductions were required for grade 2 hand-foot syndrome (28 %) and vomiting (5 %). Adherence was similar when using both patient-reported and Medication Event Monitoring System methods. High interpatient variability was observed for capecitabine and metabolite pharmacokinetics, but was not attributed to observed pharmacogenetic or BSA differences. Single agent activity of capecitabine was modest in our patients with estrogen receptor-positive or -negative metastatic breast cancer and comparable to recent studies. BSA was not the main source of pharmacokinetic variability. Fixed-dose capecitabine is feasible, and simplifies dosing.

GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.

GATA3 plays an integral role in breast luminal cell differentiation and is implicated in breast cancer progression. GATA3 immunohistochemistry is a useful marker of breast cancer; however, its use in specific subtypes is unclear. Here, we evaluate GATA3 expression in 86 invasive ductal carcinomas including triple-negative, Her-2, and luminal subtypes, in addition to 13 metaplastic carcinomas and in 34 fibroepithelial neoplasms. In addition, we report GATA3 expression in matched primary and metastatic breast carcinomas in 30 patients with known estrogen receptor (ER), progesterone receptor (PR), and Her-2 status, including 5 with ER and/or PR loss from primary to metastasis. Tissue microarrays containing 5 to 10 cores per tumor were stained for GATA3, scored as follows: 0 (0-5%), 1+ (6%-25%), 2+ (26%-50%), 3+ (51%-75%), and 4+ (>75%). GATA3 labeling was seen in 67% (66/99) of primary ductal carcinomas including 43% of triple-negative and 54% of metaplastic carcinomas. In contrast, stromal GATA3 labeling was seen in only 1 fibroepithelial neoplasm. GATA3 labeling was seen in 90% (27/30) of primary breast carcinomas in the paired cohort, including 67% of triple-negative carcinomas. GATA3 labeling was overwhelmingly maintained in paired metastases. Notably, GATA3 was maintained in all "luminal loss" metastases, which showed ER and/or PR loss. In conclusion, GATA3 expression is maintained between matched primary and metastatic carcinomas including ER-negative cases. GATA3 can be particularly useful as a marker for metastatic breast carcinoma, especially triple-negative and metaplastic carcinomas, which lack specific markers of mammary origin. Finally, GATA3 labeling may help distinguish metaplastic carcinoma from malignant phyllodes tumors.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: little evidence of improvement over the past 30 years.

BACKGROUND: Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy. METHODS: Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group that accrued patients between 1978 and 2002 were reviewed. Survival after distant disease recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model. RESULTS: Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (25%) developed distant disease recurrence; the median survival after recurrence was 20 months (95% confidence interval, 19 months-21 months). Factors associated with inferior survival included a shorter distant recurrence-free interval (DRFI), estrogen receptor-negative and progesterone receptor-negative disease, the number of positive axillary lymph nodes present at the time of diagnosis, and black race (P < .0001 for all). When the time period of recurrence was added to the model, it was not found to be significantly associated with survival for the general population with disease recurrence. Survival improved over time only in those patients with hormone receptor-negative disease with a DRFI ≤ 3 years, both among the 5 most recent and the entire trial data sets (P = .01 and P = .05, respectively). CONCLUSIONS: In contrast to reports from population-based studies, no general improvement in survival was observed over the last 30 years for patients who developed distant disease recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for patients with hormone receptor-negative disease with a short DRFI suggests a benefit from trastuzumab.

Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer.

BACKGROUND: Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated. METHODS: The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided. RESULTS: When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥ 30 kg/m(2)) and overweight (BMI, 25-29.9 kg/m(2)) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/neu-overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS (P = .02) and showed a strong trend for DFS (P = .07). Similar results were found in 2 other trials (E5188, E3189). CONCLUSIONS: In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy.