Citations

Abstract OBJECTIVE: Currently, no study has assessed the performance of contrast-enhanced spectral mammography (CESM) in evaluating tumor response in breast cancer patients undergoing neoadjuvant systemic therapy (NST). This study aims to evaluate whether the accuracy of CESM is comparable to MRI in detection of residual breast cancer following NST. MATERIALS AND METHODS: Retrospective review of CESM cases at our institution between September 2014 and June 2016 identified patients who had both CESM and MRI pre- and post-NST with pathologic assessment after surgical management. Size of residual malignancy (if any) on post-neoadjuvant CESM and MRI was compared to surgical pathology (reference standard). Pathologic complete response (pCR) was documented and compared to Residual Cancer Burden (RCB) score for confirmation. Bland-Altman plots were used to visualize the differences between CESM/MRI and pathologic tumor size. RESULTS: Forty female patients met inclusion criteria. Mean age was 52.3 years (range 35-73). Type of NST included: 34 (85%) chemotherapy and 6 (15%) endocrine therapy. Histological analysis showed invasive ductal carcinoma in 38 (95%), the remaining cases consisted of one invasive lobular carcinoma, and one mixed invasive carcinoma. Mean tumor size after NST was 10.3 mm (range 0-75 mm) for CESM and 9.7 mm (range 0-60 mm) for MRI compared to 15.7 mm (range 0-100 mm) on final surgical pathology. Equivalence tests demonstrated that the mean tumor size measured by CESM or by MRI is equivalent to the mean tumor size measured by pathology within -1 and 1 cm range (p=0.0132 for CESM and p=0.0194 for MRI). Difference in Measurement Post-NST Compared to Pathology Path Tumor Size (mm)CESM Tumor Size (mm)MRI Tumor Size (mm)Mean (SD)15.7 (24.5)10.3 (18.9)9.7 (16.3)Difference Compared with Path (SD); P value -5.4 (12.6); 0.0132-6.0 (11.7); 0.0194 A complete radiologic response was seen in 25 CESM and 22 MRI cases which was confirmed by pathology in 17 and 14, respectively. Alternatively, CESM and MRI demonstrated residual disease in 15 patients and 18 patients respectively and this was confirmed on pathology in 15 and 15, respectively. Accuracy of CESM vs. MRIModalityResidual Disease by Pathology (N=23)Complete Response by Pathology (N=17)SensitivitySpecificityPPVNPVResidual Disease by CESM (N=15)150Complete Response by CESM (N=25)81765.2%100%100%68%Residual Disease by MRI (N=18)153Complete Response by MRI (N=22)81465.2%82.4%83.3%63.6% All patients who achieved a pCR had an RCB score of 0 indicating no residual cancer in lymph nodes. Among patients with residual disease, their mean RCB score was 2.6 (range 0.8-4.18). CONCLUSION: In this study, CESM was comparable to MRI in assessing residual malignancy after completion of NST, thereby offering a potentially faster and less expensive alternative to MRI for monitoring treatment response in the neoadjuvant setting. Citation Format: Hilal T, Covington M, Sugi M, Zhang N, Pockaj B, Northfelt D, Ocal IT, Patel BK. Contrast-enhanced spectral mammography is comparable to MRI in the assessment of residual breast cancer following neoadjuvant systemic therapy [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 PD2-11.

Abstract OBJECTIVE: Neoadjuvant endocrine therapy (NET) is increasingly used for the treatment of low and intermediate grade, hormone receptor positive, HER2 negative breast cancer. Several MRI phenotypes that may predict response to neoadjuvant chemotherapy (NAC) have been identified, but little data exists for phenotypes associated with response to NET. This study analyzed imaging phenotypes for all patients treated with NET with the aim to identify specific features that can be predictive of response to therapy. MATERIALS AND METHODS: The study was retrospective and included 21 patients with clinical stage I, II, and III breast cancer. The tumors were grade 1 or 2, estrogen receptor (ER) positive in >20% of cells, and HER2 non-amplified. MRI examinations were performed in all women before NET. MRI interpretation included mass shape, non-mass enhancement (NME) pattern, background parenchymal enhancement, and MRI phenotype (I well-defined unicentric mass; II well defined multilobulated mass; III area enhancement with nodularity; IV area enhancement without nodularity; V septal spreading). Type of neoadjuvant endocrine therapy included: tamoxifien alone, an aromatase inhibitor (AI) alone, AI + ovarian suppression, and AI + a non-chemotherapeutic agent. Patients received NET for a total duration ranging between 3 - 6 months, with one patient receiving therapy for 18 months. Clinically meaningful response was defined as stable or decreased tumor size by clinical exam and confirmed at resection by comparing final pathologic T stage with clinical T stage. RESULTS: Twenty-one patients were identified. Median age was 62 (range 36-84) years. Most were post-menopausal 17 (81%). Pre-neoadjuvant meadian tumor size on MRI was 3.9 (range 1.0-7.5) cm and comprised T1 3 (14.3%), T2 8 (38.1%), T3/4 10 (47.6%). Pre-treatment N stage was N0 14 (66.7%), N1 7 (33.3%) and pre-NET stage was I in 3 (14.3%), II in 8 (38.1%), and III in 10 (47.6%) patients. The majority 17 (81%) had some tumor reduction, and 4 (19%) had no response. No one achieved a complete response. Of the 17 responders, 7 (41%) had a good response defined as >25% decrease in tumor size. Median tumor size after NET was 3.1 (range 0.6-11) cm and the distribution of T stage was T1 7 (33.3%), T2 9 (42.9%), and T3/4 5 (23.8%). Eleven of 12 (92%) patients with well-defined phenotypes had a response as compared to 6 of 9 (67%) patients with non-well defined phenotypes. Phenotype was not predictive of a good response to therapy, 4 were in the well-defined phenotype and 3 were in the non-well defined phenotype groups. All 4 non-responders had moderate or marked background enhancement as compared to 5 of 17 responders (p = 0.02). CONCLUSION: A well-defined pre treatment MRI phenotype was significantly predictive of a positive response to NET, while a non well-defined MRI phenotype and higher degree of background enhancement was significantly predictive of negative response to NET. This warrants further prospective evaluation, especially in association with Ki-67 levels. If validated, pre treatment MRI phenotype can be applied in the clinical decision to either initiate NET or referral for upfront surgical resection. Citation Format: Hilal T, Covington M, Pockaj B, Northfelt D, Wu T, Zwart C, Li J, Patel BK. Pre-neoadjuavnt therapy MRI phenotype can predict response to neoadjuvant endocrine therapy [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 P4-02-03.

Abstract Background: Late recurrence 5 or more years after diagnosis accounts for least one-half of all breast cancer recurrences, especially in hormone receptor (HR)+ disease. Biomarkers prognostic for late recurrence offer potential to more accurately identify subjects who might benefit from extended adjuvant endocrine therapy, or novel strategies to reduce late recurrence risk. Methods: CTCs were assessed at a single time point using the CELL SEARCH® assay in patients without clinical evidence of recurrence between 4.5-7.5 years after an initial diagnosis of HER2- stage II-III breast cancer and enrolled in trial E5103; all patients received surgery plus adjuvant chemotherapy and endocrine therapy for at least 5 years if HR+ disease. Patients were followed for evidence of clinical recurrence in accordance with standard care, and the association between CTCs and clinical recurrence was evaluated. Results: 546 patients without clinical evidence of recurrence enrolled between 2/25/13-7/29/16 and provided a blood sample that yielded a CTC result; 16 (2.9%) subsequently had a recurrence, of whom 15 had HR-positive disease. The median time between enrollment on E5103 and CTC assay was 5.2 years, and median/mean followup after the CTC assay was 1.6 years (range 0-3.9 years). The CTC assay was positive in 27 (4.9%) (median CTC count 1/7.5 ml blood, range 1-15). There were no significant differences in patient characteristics in the CTC+ vs. CTC- cases, including age < 50 years at initial diagnosis (52% vs. 44%), tumor size > 2 cm (63% vs. 59%), >/= 1 positive axillary node (81% vs. 72%), ER and/or PR+ (70% vs. 64%) or poor histologic grade (44% vs 55%). The recurrence rate per person-year in the CTC+ vs. CTC- groups was 19.6% vs. 1.1%, respectively (P<0.01). The median/mean time to recurrence after a positive CTC assay was 2.8 years. In multivariate analysis adjusted for clinical covariates (see table), a positive CTC assay was associated with an 18.3-fold increased risk of recurrence. Univariate and Multivariate Analysis - Association Between CTC Status and RecurrenceCovariateHazard Ratio for Recurrence - Univariate Analysis (95% CI)Hazard Ratio for Recurrence - Multivariate Analysis (95% CI)Age < 50 years3.4 (0.95-11.8)3.0 (0.8-10.9)Tumor size > 2 cm4.2 (0.98-19.2)2.9 (0.6-13.2)>/= 1+ node2.6 (0.59-11.5)0.7 (0.1-3.8)ER and/or PR+8.3 (1.1-63.5)7.7 (0.7-79.9)Poor grade0.43 (0.14-1.2)1.2 (0.4-3.8)CTC -pos vs CTC-neg20.9 (7.5-58.3)18.3 (5.7-58.2) Conclusions: A single positive CTC assay in patients without clinical evidence of recurrence 5 years after diagnosis of stage II-III HR+, HER2- breast cancer provides independent prognostic information for late recurrence, providing proof of concept for using liquid-based biomarkers for late relapse risk assessment. These findings provide a foundation for further evaluation of this new risk assessment paradigm using CTC and other blood-based assays in this setting, and designing clinical trials to tailor therapeutic risk interventions. Supported by Breast Cancer Research Foundation (J. Sparano; R. Comis) and Susan G. Komen Foundation (J. Sparano), and by the National Cancer Institute (CA180820, CA180794, CA180790, CA180791, CA180795, CA180802, CA180816, CA180821, CA189859). Citation Format: Sparano JA, O'Neill A, Alpaugh K, Wolff AC, Northfelt DW, Dang C, Sledge, Jr. GW, Miller KD. Circulating tumor cells (CTCs) five years after diagnosis are prognostic for late recurrence in operable stage II-III breast cancer [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 GS6-03.

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (> 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p<0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [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 GS3-08.

Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.