Translational Breast Cancer Research Consortium Research Articles

Patient-reported outcomes in the Translational Breast Cancer Research Consortium.

Members of the Translational Breast Cancer Research Consortium conducted an expert-driven literature review to identify a list of domains and to evaluate potential measures of these domains for inclusion in a list of preferred measures. Measures were included if they were easily available, free of charge, and had acceptable psychometrics based on published peer-reviewed analyses. A total of 22 domains and 52 measures were identified during the selection process. Taken together, these measures form a reliable and validated list of measurement tools that are easily available and used in multiple cancer trials to assess patient-reported outcomes in relevant patients.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

PurposeThis pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib’s central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance. Patients and MethodsPatients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662. ResultsWe enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples. ConclusionNeratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

Abstract OT3-04-04: A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease, with immunologic and genomic correlative studies

Abstract Background: Thirty percent of patients with breast cancer may experience chest wall recurrence, which is associated with a higher risk of developing distant metastases and a poor prognosis. Cancer cells may evade immune rejection through the programmed cell death 1 (PD-1) pathway. Pembrolizumab, an anti-PD-1 antibody, binds PD-1 and inhibits its interaction with the programmed death ligand 1 (PD-L1) to facilitate tumor immune rejection. We hypothesize that pembrolizumab may be an effective therapy in chest wall recurrence, given the inflammatory nature, and the high expression of PD-1 in tumors with lymphovascular invasion. Platinum agents may enhance anti-tumor immunity in a synergistic manner, and the combination of pembrolizumab and carboplatin has demonstrated efficacy in advanced lung cancer. In this study, the combination of pembrolizumab and carboplatin is being evaluated in breast cancer patients with chest wall disease. Methods: This is a randomized phase II study of breast cancer patients with advanced, unresectable breast cancer involving the chest wall, being conducted through the Translational Breast Cancer Research Consortium (TBCRC). Patients may have hormone resistant disease (at least 2 prior lines of hormone therapy), triple negative breast cancer, or refractory HER2+ disease for enrollment. They may have other sites of distant metastases, have received any number of prior lines of therapy, have had prior surgery, but prior chest wall radiation is not necessary. Eighty-four patients at 7 TBCRC sites will be randomized 2:1 to treatment with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks followed by pembrolizumab 200 mg IV alone every 3 weeks (Arm A, n=56) or carboplatin AUC 5 IV every 3 weeks (Arm B, n=28), with an option for patients in Arm B to cross-over to single agent pembrolizumab 200 mg IV every 3 weeks (arm Bx) on progression. Patients will undergo imaging with CT chest, abdomen, and pelvis at baseline and every 2 cycles of treatment for response evaluation. The primary endpoint is the disease control rate in the chest wall and distant sites at 18 weeks of treatment, and this study is powered to determine a 20% difference in disease control rates between arms A and B (hazard ratio of 0.52, α= 0.10, β= 0.20). After 18 patients are enrolled into Arm B, an interim analysis for futility will be conducted to enable early closure of that arm for lack of efficacy. Secondary endpoints in the study are toxicity, progression free survival, and response based on PD-L1 expression and irRECIST. Exploratory endpoints, which will be studied using peripheral blood testing and chest wall tumor biopsies at baseline and after 2 cycles of treatment, include determining associations of response with changes in tumor and peripheral blood immune composition, soluble PD-L1 expression, circulating tumor cells, cell free DNA, and tumor PD-L1 and MYC genomic expression. Ultimately this study promises to improve our understanding of checkpoint inhibition and chemotherapy for chest wall disease, and the underlying mechanism of action. This study is open for enrollment and 2 patients are currently enrolled. (NCT03095352). Citation Format: Vidula N, Goga A, Hwang J, Liu MC, Park BH, Nanda R, Pohlmann PR, Storniolo AM, Brufsky A, Abramson V, Rugo HS. A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease, with immunologic and genomic correlative studies [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-04.

Molecular determinants of post-mastectomy breast cancer recurrence

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Abstract P3-04-01: Molecular determinants of post-mastectomy breast cancer recurrence

Abstract Introduction The management of breast cancer (BC) patients who undergo mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated the molecular aberrations associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to controls in an effort to identify molecular predictors associated with recurrence. Methods/Materials We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy and no post mastectomy radiation therapy from 1997 to present with available FFPE tissue blocks. The cohort included 32 patients with LRR, 34 with DM, and 49 controls (without recurrence) who were matched for stage, grade, hormone receptor status, age ≤ or &amp;gt; 50, chemotherapy receipt, and margin status. Matched primary and recurrent LRR samples were available for 3 patients. Hybrid capture next generation sequencing (NGS) of 142 cancer related genes and RNAseq were performed to identify DNA/RNA alterations associated with LRR or DM. The frequency of common alterations on NGS was compared with Fisher's exact test. Expression of each gene from mRNA-Seq was treated as an explanatory variable. Immunohistochemistry (IHC) was performed for PTEN, Ki-67 and cleaved caspase 3 (CC3). PTEN loss and percentage of Ki-67 and CC3 positive cells were compared between groups with Fisher's exact test and nonparametric methods, respectively. Results RNAseq was performed on 115 patients; there was no difference in RNA expression levels between the groups. DNA analysis was performed on 57 patients (17 LRR, 15 DM and 25 controls), NF1 mutation rate was significantly elevated in both the LRR (24%) and DM (27%) samples compared to controls 0%; (p=0.0070). The mitogen activated protein kinase (MAPK) pathway was significantly mutated in both LRR (47%) and DM (40%) samples compared to the controls 0%; (p&amp;lt;0.0001). There was no significant difference in the rate of alterations of the PI3K/Akt/mTOR pathway among the three groups. Of three patients with matched primary vs LRR samples, one had concordant mutations. The second patient had additional mutations in the LRR, including gain of a NF1 mutation. The third patient had complete discordance of mutations identified in primary and LRR and had gain of HER2 amplification, suggestive of a new primary. There was no significant association between the groups and the loss of PTEN expression or CC3 expression. There was a significant difference between Ki 67 positive cells in patients with LRR (mean 29%), DM (mean 26%) versus controls (mean 14%, p= 0.0011). HR+ patients were significantly more likely to have a positive PTEN, lower Ki-67 and lower CC3 expression, p=0.0004, p&amp;lt;0.0001, and p&amp;lt;0.0001 respectively. Conclusions In this matched cohort analysis, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in this pathway are associated with a more aggressive tumor phenotype. However, there were no molecular features that discriminated between those likely to recur locally alone versus distantly. Further study is needed to validate these findings, and to determine whether targeting alterations in this pathway could decrease the risk of recurrence. Citation Format: Keene KS, King T, Hwang ES, Peng B, McGuire K, Tapia C, Zhang H, Bae S, Nakhlis F, Klauber-Demore N, Meszoely I, Sabel MS, Willey SC, Eterovic KA, Hudis C, Wolff A, De Los Santos J, Thompson A, Mills GB, Meric-Bernstam F. Molecular determinants of post-mastectomy breast cancer recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-01.

Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013.

The objective of this study was to determine whether the 21-gene Recurrence Score (RS) provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in the Translational Breast Cancer Research Consortium (TBCRC) 013. TBCRC 013 was a multicenter prospective registry that evaluated the role of surgery of the primary tumor in patients with de novo stage IV breast cancer. From July 2009 to April 2012, 127 patients from 14 sites were enrolled; 109 (86%) patients had pretreatment primary tumor samples suitable for 21-gene RS analysis. Clinical variables, time to first progression (TTP), and 2-year overall survival (OS) were correlated with the 21-gene RS by using log-rank, Kaplan-Meier, and Cox regression. Median patient age was 52 years (21 to 79 years); the majority had hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (72 [66%]) or hormone receptor-positive/HER2-positive (20 [18%]) breast cancer. At a median follow-up of 29 months, median TTP was 20 months (95% CI, 16 to 26 months), and median survival was 49 months (95% CI, 40 months to not reached). An RS was generated for 101 (93%) primary tumor samples: 22 (23%) low risk (< 18), 29 (28%) intermediate risk (18 to 30); and 50 (49%) high risk (≥ 31). For all patients, RS was associated with TTP (P = .01) and 2-year OS (P = .04). In multivariable Cox regression models among 69 patients with estrogen receptor (ER)-positive/HER2-negative cancer, RS was independently prognostic for TTP (hazard ratio, 1.40; 95% CI, 1.05 to 1.86; P = .02) and 2-year OS (hazard ratio, 1.83; 95% CI, 1.14 to 2.95; P = .013). The 21-gene RS is independently prognostic for both TTP and 2-year OS in ER-positive/HER2-negative de novo stage IV breast cancer. Prospective validation is needed to determine the potential role for this assay in the clinical management of this patient subset.

Abstract OT3-01-07: Phase II study of trastuzumab and pertuzumab alone and in combination with hormonal therapy or chemotherapy with eribulin in women aged ≥60 with HER2/neu overexpressed locally advanced and/or metastatic breast cancer

Abstract Her2 overexpression is both a predictive and prognostic marker with tumors overexpressing Her2 having an aggressive natural history, but also responding to targeted therapy. The standard of care for Her2 positive metastatic cancer is docetaxel paired with combined antibody therapy of pertuzumab (P) and trastuzumab (T). Older patients are known to have more difficulty tolerating traditional cytotoxic chemotherapy. Neoadjuvant studies have shown a proportion of patients have pathologic complete responses (pCR) with dual Her2 targeted therapy without chemotherapy. The NEOSPHERE trial demonstrated at 17% pCR after 3 cycles of T+P. The Translational Breast Cancer Research Consortium has shown 12-28% pCR with the combination of estrogen deprivation, trastuzumab, and lapatinib (TBCRC 006 and 023). We have designed a phase II study of T+P alone and then in combination with hormonal or chemotherapy after progression in women age ≥ 60 with Her2 overexpressed locally advanced or metastatic breast cancer (BC). As a primary endpoint, this study seeks to evaluate the overall response rate (ORR) of dual Her2 targeted therapy with T+P without chemotherapy in older patients with locally advanced or metastatic Her2 positive BC (cohort 1). At progression,depending on tumor characteristics and disease status, chemotherapy with eribulin or hormone therapy with anastrozole plus fulvestrant will be added (cohort 2 – A and B). ORR for cohorts 1, 2A and 2B will be determined. Secondary end points will evaluate clinical benefit, progression free survival, overall survival, tolerability, safety, and quality of life. Translational studies involving circulating tumor cells identified through OncoCEE – Biocept system and glycoprotein 88 expression will be performed. Eligibility includes patients' age ≥60 with locally advanced or metastatic Her2 positive BC treated with 0-3 lines of chemotherapy. Patients must have an ejection fraction &amp;gt;50% and meet set hematologic and metabolic lab criteria. Her2 status is per ASCO/ACP guidelines. Excluded patients include patients with active brain metastasis, second malignancies, anticancer treatment &amp;lt;3 weeks prior to the start of therapy. Patients must have not received pertuzumab, eribulin, anastrozole, or fulvestrant in the metastatic setting. A true ORR of 40% will be considered active. The study was designed assuming 25% of patients initially respond to T+P and 75% progress to cohort 2. With a type I error rate of 0.05 and power of 0.90, 40 patients will need to enroll in order to have 30 patients in cohort 2 (15 per arm). Data will be analyzed after eight patients are enrolled. If there are no responders in cohort 1 and 2, the accrual will be stopped and declared inefficient. After 15 patients are enrolled, if no more than 3 of the 15 respond, the therapy will be considered not promising and halted. Currently there are two patients enrolled at the University of Maryland. We are in negotiations to expand to additional sites. Questions can be directed to prosenblatt@umm.edu. Citation Format: Rosenblatt PY, Kesmodel SD, Bellavance E, Nichols EM, Feigenberg SJ, Tait N, Lewis J, Sivisailam SS, Couzi R, Goloubeva O, Tkaczuk KHR. Phase II study of trastuzumab and pertuzumab alone and in combination with hormonal therapy or chemotherapy with eribulin in women aged ≥60 with HER2/neu overexpressed locally advanced and/or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-07.

Abstract P3-05-14: A neoadjuvant window trial of endocrine response in women with invasive lobular carcinoma

Abstract Background: Patients with invasive lobular carcinoma (ILC) would be expected to have favorable outcomes compared to patients with invasive ductal carcinoma (IDC) given that ILC is more often hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, of lower grade, and displays decreased proliferation markers. Based on our preclinical studies showing differential hormone response in HR+ ILC vs. IDC and on recent studies suggesting differences in endocrine treatment response between patients with ILC vs. IDC, we designed a biomarker-driven, neoadjuvant window trial for newly diagnosed women with HR+, HER2-negative ILC. We hypothesize that Ki67 will be reduced by 85% in the fulvestrant arm compared with 60% and 75% reduction in the tamoxifen and anastrozole arms, respectively, and that Ki67 reduction will correlate with alterations in expression of ER and ER-regulated genes. Differential Ki67 effect will serve as a surrogate for outcome of patients with ILC on endocrine therapy. Trial Design: This multicenter study (NCT02206984) will enroll 150 women with HR+ and HER2-negative ILC. A mandatory research breast tumor biopsy will be performed at baseline. Fifty patients will be randomized to each of three open-label treatment arms for 21 days: fulvestrant (two 250 mg IM injections on both day 1 and day 14), anastrozole (1mg orally daily), or tamoxifen (20 mg orally daily). Biomarkers of response will be assessed on baseline and post-treatment tumor tissue. Patients will proceed to definitive surgery on day 21 after study drug exposure, or they will undergo a second research breast core biopsy if further neoadjuvant treatment is planned. Eligibility Criteria: Eligible patients include postmenopausal women with newly diagnosed, HR+, HER2-negative ILC (excluding pleomorphic subtype) measuring ≥ 1cm, with adequate organ function, ECOG PS ≥ 2, and agreeable to baseline research breast tumor biopsy. Specific Aims: The primary endpoint is percent change from baseline to post-treatment Ki67 values in ILC tissue after 21 days of endocrine treatment. Comparisons across study arms will be made using a general linear model adjusting for institutional effect, with 80% power estimated for pairwise comparisons of log2(% staining) between treatment arms, allowing for 10% attrition. Secondary endpoints include post-therapy Ki67, and change in ER and PR protein expression by IHC. Finally, planned correlative studies include evaluation of gene expression, epigenetic markers, and DNA sequence variants in ILC tissues in an effort to identify biomarkers of endocrine response and putative drivers of endocrine resistance in ILC. Target Accrual: This study will be open to enrollment by August 2015 at the University of Pittsburgh. Additional sites will be opened through the Translational Breast Cancer Research Consortium (TBCRC). We anticipate an accrual rate of 8 patients per month. (Funding from Susan G. Komen® and AstraZeneca). Citation Format: Jankowitz RC, McAuliffe PF, Sikora MJ, Butler L, Ahrendt G, Johnson R, Diego E, Bonaventura M, Puhalla S, Lembersky B, Clark B, Brufsky A, Kurland BF, Davidson NE, Dabbs DJ, Oesterreich S. A neoadjuvant window trial of endocrine response in women with invasive lobular carcinoma. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-14.

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50mg/day and 2.5mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease>6months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA+ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90% of patients, only 17 (57%) patients ever achieved MPA trough concentrations>50ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7%) had stable disease for>6months. Skin Nm23 expression increased after 4weeks of MPA+ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Abstract P1-04-01: Significance of circulating tumor cells in metastatic triple negative breast cancer: Results of an open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 tigatuzumab (TBCRC 019)

Abstract Background: Circulating Tumor cells (CTCs) are prognostic at baseline and first follow-up in patients with metastatic breast cancer (MBC). Using the most commonly used assay (CellSearch®), we have previously reported the ability to detect apoptotic vs. non-apoptotic CTCs in patients with MBC. However, there has been concern regarding the performance of the CellSearch® assay in patients with triple negative (TN) MBC. We hypothesized that CellSearch® is an effective assay in patients with TN MBC, and that CTC-apoptosis might further separate prognosis. Therefore, we studied CTCs in patients with TN MBC who participated in a prospective randomized phase II trial testing for activity of tigatuzumab (TIG) in combination with nanoparticle albumin-bound paclitaxel (nab-PAC) conducted by the Translational Breast Cancer Research Consortium (overall results reported by Forero A., et al, ASCO 2013). Methods: Whole blood (WB) was drawn into a CellSave tube at baseline, day 15, and day 29 and CTC counts were determined using the CXC CellSearch® kit. Apoptosis was characterized by staining with a monoclonal antibody that detects a neo-epitope on fragmented cytokeratin (M-30) and independently by visual inspection (nucleic condensation and/or fragmentation, as well as granular cytokeratin). Association between levels of CTCs and CTC-apoptosis with the overall response rate (ORR) and progression free survival (PFS) at baseline, day 15, and day 29 was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Of the 60 patients entered into the trial, 52 were evaluable for CTCs. Of these, 19/52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) had elevated CTCs (≥5CTC/7.5 ml WB) at baseline, day 15, and day 29, respectively. Patients with elevated CTCs at each time point had worse PFS than patients with low or no CTCs. Hazard rates (HR) at baseline, day 15, and day 29 were 2.38 (95% CI: 1.27-4.45, p = 0.007), 2.87 (95% CI: 1.46-5.66, p = 0.002), and 3.40 (95% CI: 1.68-6.89, p = 0.001), respectively. The odds of overall response for those who had elevated CTCs compared to those who did not at baseline, day 15, and day 29, were 0.25 (95% CI: 0.073-0.81, p = 0.024), 0.18 (95% CI: 0.04-0.67, p = 0.014), and 0.06 (95% CI: 0.01-0.28, p = 0.001), respectively. There was no apparent prognostic effect comparing the degree of CTC-apoptosis vs. non-apoptosis. Conclusions: Similar to observations in other intrinsic subgroups, CTCs were detected in a large fraction of TN MBC patients at baseline using CellSearch® assay, and reductions in CTC levels reflected response. In these homogenously prospectively enrolled TN MBC patients, regardless of treatment, CTCs are prognostic at baseline, day 15, and day 29. It does not appear that analysis of CTC-apoptosis is prognostic. Supported by Susan G. Komen for the Cure, Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP), Triple Negative Breast Cancer Foundation, The AVON Foundation, and The Breast Cancer Research Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-01.

Radiation-induced increases in PARP1 activity to predict for long-term radiosensitization by PARP1 inhibition in preclinical breast cancer models.

1025 Background: Sustained locoregional (LR) control of breast cancer (BCa) is a significant issue for patients with inflammatory disease or chest wall recurrences. Inhibition of poly(adenosine diphosphate-ribose) (PAR) polymerase 1 (PARP1), a DNA damage response protein, is a promising strategy for radiosensitization (RS). We investigated RS by PARP1 inhibition and aimed to identify early biomarkers (BMs) predictive of long-term treatment efficacy in preclinical BCa models. Methods: Clonogenic survival assays in 12 BCa and normal epithelial cell lines were used to determine the degree of RS conferred by the PARP1 inhibitor ABT-888 and to optimize the sequencing of therapy. Immunoblots, immunofluorescent staining, flow cytometery, and xenograft studies were used to evaluate for pre-/intra-treatment BMs predicting for subsequent response to therapy. Results: ABT-888 preferentially radiosensitized BCa (vs. normal) cells (enhancement ratios (EnhR) up to 2.3 across different subtypes). The highest EnhRs resulted from concurrent and adjuvant ABT-888. The degree of RS did not correlate with pretreatment markers of PARP1 activity (e.g., PAR levels), DNA damage/repair (e.g. gamma-H2AX &amp; RAD51 foci), or cell cycle distribution. However, increases in PARP1 activity from pretreatment to 24 hours after RT, was associated with long-term clonogenic death after treatment with ABT-888 + radiation (RT) (Spearman's coefficient=0.8, p=0.002). The four cell lines significantly radiosensitized by PARP1 inhibition (EnhR&gt;1.5) averaged a 2-fold increase in PAR levels following RT. Findings were also confirmed in SKBR3 and MDA-231 BCa xenograft models. Conclusions: Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT in BCa cell lines. Treatment-induced increase in PARP1 activity 24 hours after RT predicts for long-term radiosensitization by PARP1 inhibition and is a potential biomarker of response. These studies have led to a clinical trial, incorporating intratreatment BM analyses, of PARP inhibitors and RT in BCa patients currently open for accrual through the Translational Breast Cancer Research Consortium.

Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Hormonal Therapy for the Treatment of Primary HER2-Positive Breast Cancer: One More Step Toward Chemotherapy-Free Therapy

During the last decade, the introduction of agents that target the human epidermal growth factor receptor 2 (HER2), such as the monoclonal antibody trastuzumab (Herceptin; Roche, Basel, Switzerland) or the tyrosine kinase inhibitor lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC), in combination with chemotherapy, has changed the course of HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to taxanes increases progression-free survival (PFS) and overall survival (OS), whereas the addition of lapatinib to capecitabine increases PFS after treatment with regimens that include an anthracycline, a taxane, and trastuzumab. In the adjuvant setting, trastuzumab increases diseasefree survival and OS. In addition to these impressive advances, clinical research to improve the outcome in HER2-positive breast cancer is as vibrant as it has ever been. A number of important questions are being addressed at this time, including the delineation of the role of neoadjuvant (presurgical) therapy, theconceptofdualHER2receptorblockade, theidentificationof markers of sensitivity or resistance to therapy, and, finally, the study of new agents. As reported in the article that accompanies this editorial, the timely Neoadjuvant Translational Breast Cancer Research Consortium 006 (TBCRC 006) trial by Rimawi et al has addressed three of these questionsandhas identifiedonemorepiece in thepuzzle: the importance ofaddinghormonal therapyinthesubsetofpatientswithHER2-positive/ hormone receptor (HR) –positive tumors. To place this study in context, let us look at what we know today. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy and maintenance for 1 year increases pathologic complete response (pCR) rates and 3-year event-free survival (EFS). And there is increasing evidence that there is a good correlation between pCR and EFS in HER2-positive disease, which has led to the acceptance of pCR as the primary end point in a number of neoadjuvant studies. If some of these studies, such as the Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Organisation (NeoALTTO) study, further confirm that pCR is a surrogate marker of EFS, improved pCR in HER2-positive breast cancer could lead to regulatory approval of novel agents in this disease. In terms of dual HER2 blockade, laboratory studies have shown that a more complete blockage of the HER2 and/or the HER signaling pathway by combining two or three inhibitors with nonoverlapping mechanisms of action improves cell death and tumor shrinkage in HER2-positive models. These preclinical findings have now been confirmed in the clinical setting. Trastuzumab and lapatinib (or trastuzumab and pertuzumab [Perjeta; Genentech, South San Francisco, CA], a humanized monoclonal antibody binding to the HER2 dimerization domain), in combination with chemotherapy, results in pCR rates of 45.8% to 51.3% compared with pCR rates of 24.0% to 29.5% with a single anti-HER2 agent combined with the same chemotherapy schedule. Moreover, the addition of pertuzumab to trastuzumab and docetaxel increases PFS and OS in first-line metastatic HER2-positive disease. These results have led to regulatory approval of pertuzumab and have placed the dual HER2 blockade with pertuzumab and trastuzumab in combination with chemotherapy as the standard of care in first-line metastatic disease. Furthermore, dual HER2 blockade strategies could also become standard of care in other settings. For example, the ongoing Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) phase III trial is evaluating the adjuvant dual HER2 blockade with trastuzumab and lapatinib afterchemotherapy,andAStudyofPertuzumabinAdditiontoChemotherapy and Herceptin (Trastuzumab) As Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer (APHINITY), a phase III trial, is also currently evaluating adjuvant trastuzumab and pertuzumab with chemotherapy. Given that the dual HER2 blockade is more efficacious that single-agent HER2 therapy, a question that arises is whether the dual blockade may eliminate the need for chemotherapy in a subset of patients. In support of this proposal, the dual HER2 blockade without chemotherapy has shown high activity in a group of patients with metastatic and primary HER2-positive breast cancer. In HER2-positive metastatic breast cancer that was previously treated with trastuzumab, the addition of pertuzumab or lapatinib to trastuzumab showed higher clinical benefit than either pertuzumab or lapatinib alone. In treatment-naive JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 14 MAY 1

Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) to predict response to preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer: Translational breast cancer research consortium (TBCRC008).

10509 Background: PST allows for improved surgical outcomes and response assessment without compromising long term outcomes. PST is an attractive model for assessing surrogate markers of response to therapy. We hypothesized that changes in tumor standardized uptake values corrected for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of therapy would predict pathological complete response (pCR) to PST in women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: TBCRC008 is a multicenter placebo-controlled trial that investigates pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat. FDG-PET followed by tumor biopsies were performed at baseline and C1D15. We correlated % reduction in SULmax on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no invasive cancer in breast/axilla). We compared % reduction in SULmax between responders (pCR) and non responders (no pCR) using nonparametric Wilcoxon rank sum test. We explored association of % reduction in SULmax at pre-specified cutoff with response using Fisher’s exact test and logistic regression. We correlated baseline, C1D15, and % change in Ki67 at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled (10/2009-11/2011), 40 have completed study PST and surgery (median age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an intent to treat analysis (n=39), we observed a significant difference in median % reduction in SULmax between responders vs not (66.6% vs 32.4%, p &lt;0.001). We observed a higher proportion of reduction in SULmax ≥ 60% in responders vs not (80% vs 3.5%, p &lt;0.001). The differences in baseline, C1D15 and % change in Ki67 were not significant between responders and non-responders. Conclusions: Change in SULmax on FDG-PET 15 days after initiating PST was significantly greater in patients with pCR versus no pCR. Future studies will determine whether altering therapy based on early changes in SULmax will improve pCR. Unblinded data from all participants will be presented at the meeting.

OT3-02-04: TBCRC 012: ABCDE, a Phase II Randomized Study of Adjuvant Bevacizumab, Metronomic Chemotherapy (CM), Diet and Exercise after Preoperative Chemotherapy for Breast Cancer.

Abstract Background Patients (pts) with residual breast cancer after neoadjuvant chemotherapy are at increased risk of recurrence; no proven risk-reduction strategies exist, supporting exploration of novel therapies in the post-preoperative setting. Bevacizumab (B) combined with chemotherapy is active in metastatic disease; ongoing studies are exploring the efficacy of adjuvant combination chemotherapy and B. DFCI 05–055 (Mayer et al, ASCO 2007, 2008) demonstrated the feasibility of 1 year B after preoperative chemotherapy. Also, increasing data support risk reduction through lifestyle interventions (Segal, Ligibel et al, ASCO 2011). The ABCDE trial was designed to evaluate extended adjuvant B in a high risk post-preoperative cohort, and also assess the contribution of exercise to a dietary intervention. Eligibility Criteria Eligible pts have HER2− breast cancer and have received preoperative anthracycline and/or taxane-based chemotherapy with residual invasive disease at surgery. Acceptable stages include: triple negative if preop stages I-III, or ER+/PR+ if stage III preop or IIB postop. Acceptable organ function and standard B exclusions apply. Registration must occur between 28–180 days after last surgery. Specific Aims Primary endpoint is recurrence-free survival at a median follow-up of 6 years. Secondary endpoints include B pharmacogenomics, evaluation of the impact of exercise on quality of life and biomarkers associated with recurrence, and prospective examination of cardiac toxicity. Residual tissue-based predictors of outcome will be extensively explored, including PAM50, Ki67, and VEGF hypoxia signature. Methods This is a 2 × 2 randomized study with a first randomization to 6 months (mo) B 15 mg/kg every 3 weeks (wks) plus 6 mo CM (C 50 mg daily, M 2.5 mg twice daily days 1, 2 each wk), followed by 2.5 years B 15 mg/kg every 6–8 wks, versus observation. A second randomization is to a 1 year telephone-based lifestyle intervention, offering dietary modification alone, or in combination with a structured exercise program. Statistical Methods and Accrual Total sample size is 660 pts within the Translational Breast Cancer Research Consortium. Overall power is 0.80 to detect a hazard ratio of 0.59−0.68, depending on pt population. Accrual initiated early 2011 and is expected to continue for the next 36 months. Conclusions Patients with residual disease after preoperative chemotherapy are at high risk of recurrence and have unmet medical needs. To our knowledge, this is the only trial testing a prolonged but less intensive adjuvant B schedule in this clinical setting. Results of this study could have critical implications for the management of this patient population and for the design of future clinical trials with anti-angiogenic agents. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-02-04.

Collecting tissue for research purposes: A survey of 16 institutions in the Translational Breast Cancer Research Consortium (TBCRC).

10615 Background: In order to understand the pathogenesis of breast cancer, many institutions are routinely requesting patients to donate tissue for current or future research. However, little is known about established processes for collecting tissue specimens for research studies. Methods: The Patient Advocate Working Group of the TBCRC, a collaborative group of 16 US academic breast cancer programs, conducted a two-part study to learn how patients are approached for tissue/biospecimen banking in its sites. Advocates from each institution contacted the appropriate person at each site to complete the surveys, explain their purposes, and ensure completion of the 2 online surveys (40 questions). Questions covered current practices, identified best practices, and recommended areas of improvement. One survey focused on the processes and staff involved in obtaining consent, the other focused on the information obtained from the consent form. Results: 16 invitations to respond were sent out and 12 sites completed the surveys. In all, a median of 80% (range, 20-100%) of patients were approached to obtain consent for tissue/biospecimen banking with an average patient refusal rate of 20%. 40% of the institutions limited the number of times a patient could be approached for consent and 20% of the institutions reported an annual goal for obtaining consents. 1 institution offered courses on interviewing skills, cultural or sensitivity training. The entire consent form was reviewed with patients about 80% of the time over an average of 20 minutes (range, 5-60). Only 1 TBCRC institution collected data from patients on their experience with consenting. Consent form differences included length (2-13 pages), permission for future contact (70%), permission to draw blood (65%) and donation of tissue without linkage to clinical data (43%). Conclusions: Development of patient educational materials on biospecimen donation, specialized training for staff, and a systematic approach to obtaining patient feedback may lead to a better patient experience and possibly a higher consent rate. Simplified consent forms that provide patients with necessary information for informed decision-making are needed.

Translational Breast Cancer Research Consortium (TBCRC) Patient Advocate Working Group (PAWG): An approach to research advocacy.

e19539 Background: Cancer research patient advocates act as a connection between the patient population and the research community, bringing the patient perspective to the research table and the re...

Abstract P6-15-02: A Phase Ib Study Evaluating Safety, Tolerability, Pharmacokinetics (PK), and Activity of the Phosphoinositide-3 Kinase (PI3K) Inhibitor GDC-0941 in Combination with Trastuzumab-MCC-DM1 (T-DM1) in Patients with Advanced HER2-Positive Breast Cancer

Abstract Background: Aberrant activation of the PI3K pathway has been hypothesized to reduce the efficacy of trastuzumab-based therapy in patients with HER2-positive breast cancer. Inhibition of the PI3K pathway in combination with continued suppression of HER2 signaling is one strategy that may enhance sensitivity to HER2-directed therapy. GDC-0941 is a potent and selective oral pan-inhibitor of class I PI3K (in vitro IC50 for the p110-alpha subunit is 3 nM) and demonstrates single-agent activity in preclinical xenograft models. T-DM1 is a novel antibody-drug conjugate that combines the biological properties of trastuzumab with the highly potent anti-microtubule agent DM1 and has shown promising activity in two Phase II studies in heavily pretreated patients with advanced HER2- positive breast cancer. In vivo studies of GDC-0941 dosed in combination with T-DM1 have shown increased anti-tumor activity relative to either T-DM1 or GDC-0941 alone in trastuzumab-resistant and PI3K mutant breast cancer xenograft models. Material and Methods: Patients with histologically confirmed advanced HER2-positive breast cancer who have progressed on prior trastuzumab therapy were enrolled in a Phase Ib study (GDC4627g) of GDC-0941 and T-DM1 using a 3+3 dose escalation design. Treatment consists of T-DM1 IV on a 21-day schedule (q3wks) and GDC-0941 orally given daily for 14 of 21 days. Objectives include an evaluation of the safety, tolerability and PK of GDC-0941 administered with T-DM1, as well as determining the maximum tolerated dose of this combination. Results: Thirteen patients have been enrolled in three successive cohorts. Starting doses of T-DM1 and GDC-0941 were 3.6 mg/kg and 80 mg, respectively (T-DM1 administered one day after GDC-0941, cycle 1 only). A dose-limiting toxicity (DLT) of Grade 4 thrombocytopenia was seen in the first cohort. The cohort was expanded without any additional DLTs. Two DLTs were observed in the second cohort (T-DM1 3.6 mg/kg and GDC-0941 115 mg): Grade 4 thrombocytopenia in one patient and Grade 3 fatigue in a second patient in the setting of newly diagnosed brain metastases. A third cohort was enrolled with a reduced dose of T-DM1 of 3.0 mg/kg and GDC-0941 at 100 mg (both starting the same day on cycle 1). No DLTs were observed and dose escalation continues. Preliminary PK for GDC-0941, T-DM1 and free DM1 were similar to historical profiles from previous studies of these molecules. Evidence of clinical activity has been reported in a number of participants. Conclusions: This trial represents the first report of a regimen combining a HER2-targeted agent with a PI3K inhibitor. DLTs observed with this combination to date have been Grade 4 thrombocytopenia and Grade 3 fatigue. Encouraging evidence of clinical activity has been observed. Dose-escalation continues and updated PK/PD, safety and efficacy data will be presented. Data from this study will inform plans for a subsequent Translational Breast Cancer Research Consortium clinical trial. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-02.

Pilot Trial of Preoperative (Neoadjuvant) Letrozole in Combination With Bevacizumab in Postmenopausal Women With Newly Diagnosed Estrogen Receptor— or Progesterone Receptor—Positive Breast Cancer

Introduction Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of antiestrogen adjuvant therapy. We designed a pilot study to assess the feasibility and short-term efficacy of neoadjuvant letrozole and bevacizumab (anti-VEGF) in postmenopausal women with stage II and III estrogen receptor/progesterone receptor—positive breast cancer. Patients and Methods Patients were treated with a neoadjuvant regimen of letrozole orally 2.5 mg/day and bevacizumab intravenously 15 mg/kg every 3 weeks for a total of 24 weeks before the surgical treatment of their breast cancer. Patients were followed for toxicity at 3-week intervals, and tumor assessment (a physical examination and ultrasound) was performed at 6-week intervals. Positron emission tomography (PET) scans were performed before therapy and 6 weeks after the initiation of therapy. Results Twenty-five evaluable patients were treated. The regimen was well-tolerated, except in 2 patients who were taken off the study for difficulties controlling their hypertension. An objective clinical response occurred in 17 of 25 patients (68%), including 16% complete responses (CRs) and 52% partial responses. The 4 patients with clinical CRs manifested pathologic CRs in their breasts (16%), although 1 patient had residual tumor cells in her axillary nodes. Eight of 25 patients (32%) attained stage 0 or 1 status. The PET scan response at 6 weeks correlated with clinical CRs and breast pathologic CRs at 24 weeks ( P < .0036). Conclusion Combination neoadjuvant therapy with letrozole and bevacizumab was well-tolerated and resulted in impressive clinical and pathologic responses. The Translational Breast Cancer Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.

TBCRC 012: ABCDE, a phase II randomized study of adjuvant bevacizumab, metronomic chemotherapy (CM), diet and exercise after preoperative chemotherapy for breast cancer.

TPS103 Background: Patients (pts) with residual breast cancer after neoadjuvant chemotherapy (C) are at increased risk of recurrence; no proven risk-reduction strategies exist, supporting exploration of novel therapies in the post-preoperative setting. Bevacizumab (B) combined with chemotherapy (C) has an established role in the treatment of metastatic disease; E5103 is exploring the efficacy of adjuvant combination C and B. DFCI 05-055 (Mayer et al, ASCO 2007, 2008) demonstrated the feasibility of 1 year B after preoperative C. Also, increasing data support risk reduction through lifestyle interventions. The ABCDE trial was designed to evaluate extended adjuvant B in a high risk cohort, in addition to assessing the contribution of exercise to a dietary intervention. Methods: Eligible pts have HER2- breast cancer and have received preop anthracycline and/or taxane with residual disease at surgery. Accrual goal is 660 pts, to begin 3/2010 within the Translational Breast Cancer Research Consortium. Acceptable stages include, for triple negative, preop stages I-III, or if ER/PR+, stage III preop or IIB postop. Therapy must be initiated between 28-180 days after last surgery. This is a 2 × 2 randomized study with a first randomization to 6 months (mo) B 15 mg/kg every 3 weeks (wks) plus 6 mo CM followed by 2.5 years B 15 mg/kg every 6-8 wks, versus observation, and a second randomization to a 1 year telephone-based lifestyle intervention, offering dietary modification alone, or in combination with a structured exercise program. Primary endpoint is recurrence-free survival at a median follow-up of 6 years; overall power is 0.80 to detect a hazard ratio of 0.59-0.68, depending on pt population. Correlative studies include B pharmacogenomics, evaluation of the impact of exercise on biomarkers associated with recurrence, exploration of tissue-based predictors of outcome, and prospective examination of cardiac toxicity. To our knowledge, this is the only trial testing a prolonged but less intensive adjuvant B schedule in high risk pts. Results of this study could have critical implications for the design of future clinical trials with antiangiogenic agents. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech/Roche Genentech/Roche Genentech/Roche