Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.

BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.

Novel hyaluronan formulation for preventing acute skin reactions in breast during radiotherapy: a randomized clinical trial.

PURPOSE: We conducted a randomized, double-blind, vehicle-controlled clinical trial to investigate the use of a new proprietary hyaluronan (HA) formulation for the prevention of acute skin toxicity in breast cancer patients undergoing radiotherapy (RT). METHODS: Thirty women with breast cancer undergoing whole breast RT were enrolled. Each patient was randomly assigned to HA formulation (study cream, S) on the medial or lateral half of the irradiated breast and the control cream (placebo, P) on the other half. The primary endpoint was physician's evaluation of skin symptoms at week 5 during RT and week 2 post-RT. We also collected patients' independent assessment of skin after RT, patient's product preference, and an independent physician panel assessment of skin reactions based on photographs. RESULTS: Twenty-eight patients were evaluable. On physician's evaluation, there was no significant difference in radiation dermatitis between S and P and no overall preference to either cream at week 5 during or week 2 post-RT. More patients preferred S in evaluating skin appearance and skin reactions, but this did not reach statistical significance. Univariate analysis showed that physicians had an overall preference to the S cream at week 2 post-RT in patients with larger breasts. On the independent panel assessment, 3 reviewers saw no significant difference in radiation toxicity, whereas one reviewer reported better skin outcome with S cream at week 5. CONCLUSIONS: We found a nonstatistically significant patient preference but overall no significant radioprotective effects for this HA formulation compared with placebo except in patients with larger breasts. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02165605).

Adaptive Randomization of Neratinib in Early Breast Cancer.

BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

The Promoting Activity in Cancer Survivors (PACES) trial: a multiphase optimization of strategy approach to increasing physical activity in breast cancer survivors.

BACKGROUND: Despite the significant, empirically supported benefits of physical activity, the majority of breast cancer survivors do not meet recommended guidelines for physical activity. A variety of effective strategies to increase physical activity in breast cancer survivors have been identified. However, it is unknown which of these strategies is most effective or how these strategies might be combined to optimize intervention effectiveness. METHODS: The proposed trial uses multiphase optimization strategy (MOST) to evaluate four evidence-based intervention strategies for increasing physical activity in breast cancer survivors. We will enroll 500 breast cancer survivors, age 18 and older, who are 3-months to 5 years post-treatment. Using a full-factorial design, participants will be randomized to receive a combination: 1) supervised exercise, 2) facility access, 3) self-monitoring, and 4) group-based active living counseling. The primary outcome, moderate-to-vigorous physical activity (MVPA) will be measured at baseline, 3 months, and 6 months using an Actigraph GT3X+. To evaluate intervention effects, a linear mixed-effects model will be conducted with MVPA as the outcome and with time (3 months and 6 months) as the within-subjects factor and intervention (i.e., supervised exercise, facility access, self-monitoring, and active living counseling) as the between subjects factor, along with all two-way interactions. DISCUSSION: The purpose of the PACES study is to evaluate multiple strategies for increasing physical activity in breast cancer survivors. Results of this study will provide in an optimized intervention for increasing physical activity in breast cancer survivors. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03060941 . Registered February 23, 2017.

Genetic Ancestry using Mitochondrial DNA in patients with Triple-negative breast cancer (GAMiT study).

BACKGROUND: Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. METHODS: Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. RESULTS: A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P<.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry). CONCLUSIONS: Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society.

Housing Assistance and Blood Lead Levels: Children in the United States, 2005-2012.

OBJECTIVES: To compare blood lead levels (BLLs) among US children aged 1 to 5 years according to receipt of federal housing assistance. METHODS: In our analyses, we used 2005 to 2012 data for National Health and Nutrition Examination Survey (NHANES) respondents that were linked to 1999 to 2014 administrative records from the US Department of Housing and Urban Development (HUD). After we restricted the analysis to children with family income-to-poverty ratios below 200%, we compared geometric mean BLLs and the prevalence of BLLs of 3 micrograms per deciliter or higher among children who were living in assisted housing at the time of their NHANES blood draw (n = 151) with data for children who did not receive housing assistance (n = 1099). RESULTS: After adjustment, children living in assisted housing had a significantly lower geometric mean BLL (1.44 µg/dL; 95% confidence interval [CI] = 1.31, 1.57) than comparable children who did not receive housing assistance (1.79 µg/dL; 95% CI = 1.59, 2.01; P < .01). The prevalence ratio for BLLs of 3 micrograms per deciliter or higher was 0.51 (95% CI = 0.33, 0.81; P < .01). CONCLUSIONS: Children aged 1 to 5 years during 2005 to 2012 who were living in HUD-assisted housing had lower BLLs than expected given their demographic, socioeconomic, and family characteristics.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer.

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor ß signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Cardiac mechanisms for low aerobic power in anthracycline treated, older, long-term breast cancer survivors.

Breast cancer survivors have reduced peak aerobic capacity (VO2peak) which may be related to latent or lingering chemotherapy induced cardiac damage. Nine, older (67 ± 3 years), long-term survivors (9.8 years) of anthracycline based chemotherapy and age- and sex-matched healthy controls were recruited and tested to determine whether: i) VO2peak remains reduced in long-term survivorship; and ii) reductions in VO2peak are due to cardiac dysfunction. VO2peak was significantly reduced in breast cancer survivors relative to healthy controls (15.9 ± 2.0 vs 19.9 ± 3.1 ml/kg/min, p = 0.006), however the heart rate and stroke volume responses to exercise were normal (heart rate reserve; 88 ± 9 vs 85 ± 10 bpm, p = 0.62: stroke volume reserve; 13 ± 6 vs 13 ± 9 ml,p = 0.94). These findings indicate low-normal ventricular size in long-term breast cancer survivors, but normal reserve function.

Preliminary Results of Multi-Institutional Phase 1 Dose Escalation Trial Using Single-Fraction Stereotactic Partial Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. METHODS AND MATERIALS: Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival. RESULTS: From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence. CONCLUSIONS: This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline.

A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609).

PURPOSE: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). PATIENTS AND METHODS: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines was 2 (0-5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. CONCLUSIONS: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.

Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registration: www.clinicaltrials.gov/ct2/show/NCT01042379.

A Phase I/Ib Trial of PD 0332991 (Palbociclib) and T-DM1 in HER2-Positive Advanced Breast Cancer After Trastuzumab and Taxane Therapy.

BACKGROUND: Preclinical breast cancer models with acquired HER2 resistance exhibit decreased proliferation with CDK4/6 inhibition in tumors with intact Rb and low p16 levels. Adding cytotoxic agents like T-DM1 enhances the inhibitory CDK4/6 cytostatic effect. PATIENTS AND METHODS: A phase I/Ib 3+3 dose escalation/expansion trial of palbociclib and T-DM1 identified 150 mg on days 5 to 18 as the palbociclib maximal tolerated dose combined with day 1 intravenous T-DM1 in 21-day treatment cycles. Patients were previously treated with trastuzumab and a taxane with no limitation on prior therapy lines, including prior pertuzumab, lapitinib, neratinib, and T-DM1. Median age was 54 years and two-thirds were estrogen receptor positive. Primary objectives included maximum tolerated dose as determined by dose-limiting toxicity, and secondary end points of safety, toxicity, response rate, response duration, and progression-free survival. RESULTS: From May 2014 to August 2018, 18 total patients were treated. The median number of cycles was 6.5 (1-22). A maximum tolerated dose was not reached. The most common G3 toxicity of more than 10% incidence was hematologic. Overall response rate (complete response + partial response) was 33% (95% confidence interval, 13%-59%). Median duration of response in responders was not reached and median-progression free survival was 6 months (95% confidence interval, 2.5-11.6). CONCLUSIONS: The combination of day 1 T-DM1 and days 5 to 18 palbociclib is safe, tolerable, and active in previously treated HER2-positive relapsed patients. Observed hematologic toxicity is manageable. The trial response rate confirms that a CDK 4/6 inhibitor can resensitize HER2-resistant breast cancer.

Electronic Health Records-Based Cardio-Oncology Registry for Care Gap Identification and Pragmatic Research: Procedure and Observational Study.

BACKGROUND: Professional society guidelines are emerging for cardiovascular care in cancer patients. However, it is not yet clear how effectively the cancer survivor population is screened and treated for cardiomyopathy in contemporary clinical practice. As electronic health records (EHRs) are now widely used in clinical practice, we tested the hypothesis that an EHR-based cardio-oncology registry can address these questions. OBJECTIVE: The aim of this study was to develop an EHR-based pragmatic cardio-oncology registry and, as proof of principle, to investigate care gaps in the cardiovascular care of cancer patients. METHODS: We generated a programmatically deidentified, real-time EHR-based cardio-oncology registry from all patients in our institutional Cancer Population Registry (N=8275, 2011-2017). We investigated: (1) left ventricular ejection fraction (LVEF) assessment before and after treatment with potentially cardiotoxic agents; and (2) guideline-directed medical therapy (GDMT) for left ventricular dysfunction (LVD), defined as LVEF<50%, and symptomatic heart failure with reduced LVEF (HFrEF), defined as LVEF<50% and Problem List documentation of systolic congestive heart failure or dilated cardiomyopathy. RESULTS: Rapid development of an EHR-based cardio-oncology registry was feasible. Identification of tests and outcomes was similar using the EHR-based cardio-oncology registry and manual chart abstraction (100% sensitivity and 83% specificity for LVD). LVEF was documented prior to initiation of cancer therapy in 19.8% of patients. Prevalence of postchemotherapy LVD and HFrEF was relatively low (9.4% and 2.5%, respectively). Among patients with postchemotherapy LVD or HFrEF, those referred to cardiology had a significantly higher prescription rate of a GDMT. CONCLUSIONS: EHR data can efficiently populate a real-time, pragmatic cardio-oncology registry as a byproduct of clinical care for health care delivery investigations.

Cosmetic Outcomes of a Phase 1 Dose Escalation Study of 5-Fraction Stereotactic Partial Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: Our purpose was to evaluate cosmetic changes after 5-fraction adjuvant stereotactic partial breast irradiation (S-PBI). METHODS AND MATERIALS: Seventy-five women with in situ or invasive breast cancer stage 0, I, or II, with tumor size ≤3 cm, were enrolled after lumpectomy in a phase 1 dose escalation trial of S-PBI into cohorts receiving 30, 32.5, 35, 37.5, or 40 Gy in 5 fractions. Before S-PBI, 3 to 4 gold fiducial markers were placed in the lumpectomy cavity for tracking with the Synchrony respiratory tracking system. S-PBI was delivered with a CyberKnife robotic radiosurgery system. Patients and physicians evaluated global cosmesis using the Harvard Breast Cosmesis Scale. Eight independent panelists evaluated digital photography for global cosmesis and 10 subdomains at baseline and follow-up. McNemar tests were used to evaluate change in cosmesis, graded as excellent/good or fair/poor, from baseline to year 3. Wilcoxon signed rank tests were used to evaluate change in subdomains. Cohen's kappa (κ) statistic was used to estimate interobserver agreement (IOA) between raters, and Fleiss' κ was used to estimate IOA between panelists. RESULTS: Median cosmetic follow-up was 5, 5, 5, 4, and 3 years for the 30, 32.5, 35, 37.5, and 40 Gy cohorts. Most patients reported excellent/good cosmesis at both baseline (86.3%) and year 3 (89.8%). No dose cohort had significantly worsened cosmesis by year 3 on McNemar analysis. No cosmetic subdomain had significant worsening by year 3. IOA was fair for patient-physician (κ = 0.300, P < .001), patient-panel (κ = 0.295, P < .001), physician-panel (κ = 0.256, P < .001), and individual panelists (Fleiss κ = 0.327, P < .001). CONCLUSIONS: Dose escalation of S-PBI from 30 to 40 Gy in 5 fractions for early stage breast cancer was not associated with a detectable change in cosmesis by year 3. S-PBI is a promising modality for treatment of early stage breast cancer.

Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.

IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379.

Risk Factors for Fat Necrosis After Stereotactic Partial Breast Irradiation for Early-Stage Breast Cancer in a Phase 1 Clinical Trial.

PURPOSE: This study reports predictive dosimetric and physiologic factors for fat necrosis after stereotactic-partial breast irradiation (S-PBI). METHODS AND MATERIALS: Seventy-five patients with ductal carcinoma-in situ or invasive nonlobular epithelial histologies stage 0, I, or II, with tumor size <3 cm were enrolled in a dose-escalation, phase I S-PBI trial between January 2011 and July 2015. Fat necrosis was evaluated clinically at each follow-up. Treatment data were extracted from the Multiplan Treatment Planning System (Cyberknife, Accuray). Univariate and stepwise logistic regression analyses were conducted to identify factors associated with palpable fat necrosis. RESULTS: With a median follow-up of 61 months (range: 4.3-99.5 months), 11 patients experienced palpable fat necrosis, 5 cases of which were painful. The median time to development of fat necrosis was 12.7 months (range, 3-42 months). On univariate analyses, higher V32.5-47.5 Gy (P < .05) and larger breast volume (P < .01) were predictive of any fat necrosis; higher V35-50 Gy (P < .05), receiving 2 treatments on consecutive days (P = .02), and higher Dmax (P = .01) were predictive of painful fat necrosis. On multivariate analyses, breast volume larger than 1063 cm3 remained a predictive factor for any fat necrosis; receiving 2 treatments on consecutive days and higher V45 Gy were predictive of painful fat necrosis. Breast laterality, planning target volume (PTV), race, body mass index, diabetic status, and tobacco or drug use were not significantly associated with fat necrosis on univariate analysis. CONCLUSIONS: Early-stage breast cancer patients treated with breast conserving surgery and S-PBI in our study had a fat necrosis rate comparable to other accelerated partial breast irradiation modalities, but S-PBI is less invasive. To reduce risk of painful fat necrosis, we recommend not delivering fractions on consecutive days; limiting V42.5 < 50 cm3, V45 < 20 cm3, V47.5 < 1 cm3, Dmax ≤ 48 Gy and PTV < 100 cm3 when feasible; and counseling patients about the increased risk for fat necrosis when constraints are not met and for those with breast volume >1000 cm3.