Citations

Abstract Purpose: Endocrine based therapy is an effective strategy to manage hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, nearly all patients exhibit/develop either de novo or acquired resistance. While prognostic biomarkers of endocrine responsiveness are well established for the adjuvant treatment in ER+ breast cancer, less is known regarding prognostic and predictive biomarkers of response in the first line ABC setting. We sought to develop a clinical calculator based on clinical criteria for predicting progression-free survival (PFS) and overall survival (OS) of women with HR+/HER2- ABC who will be receiving endocrine monotherapy as first-line treatment for ABC. Methods: The development of the clinical calculator will be based on data from modern clinical trials in women with HR+/HER2- ABC. The studies to be included in the final analyses are given in Table 1. The control arm data from trials1-6 will form the training dataset (N = 1,223) and be used to construct the clinical prediction models. Variables considered include age, race, ECOG status, disease measurability, body mass index, disease-free interval, number of metastatic sites, locations of metastatic sites, prior endocrine therapy, and prior chemotherapy. Missing values will be imputed using single imputation with all variables included in the imputation model. For continuous variables, restricted cubic splines will be used to determine if non-linear effects may be more appropriate. The Lasso regression will be used as a variable selection technique to reduce the dimensionality of covariates; initially all pairwise interactions will be included in the model. Following Lasso regression, the multivariable Cox proportional hazards models will be constructed for PFS and OS including only variables retained in Lasso. The final model will be internally validated for discrimination and calibration using 10-fold cross-validation. External validation will be performed using control arm data from EGF 30008 (N = 536). Results: To date, control arm data from four trials (trials 1-4) have been received. The preliminary results presented here are based on pooled data from C40503 and LEA, for which data elements have been harmonized. Models for predicting PFS and OS have good calibration and are associated with bias-corrected C-indices of 0.61 and 0.65, respectively. These models will be updated using pooled data from trials 1-6. Conclusions: Our preliminary data demonstrate that clinical calculators based on baseline clinical factors can provide accurate prediction of PFS and OS in patients with HR+/HER2- ABC treated with first-line ET. If validated, these tools may be used for risk stratification in future clinical trials and to identify patients who may require more or less aggressive therapy. Table 1:Studies to be includedTrial NumberTrial NameTrial PISample Size in Control Arm1C40503Maura Dickler152 (letrozole)2LEAMiguel Martin179 (letrozole)3FACTJonas Bergh188 (anastrozole)4FALCONJohn Robertson194 (anastrozole)5S0226Rita Mehta345 (anastrozole)6MONARCH 3Matthew Goetz165 (nonsteroidal AI)7EGF 30008Stephen Johnston536 (letrozole) Citation Format: Polley M-YC, Dickler MN, Johnston S, Goetz MP, de la Haba J, Loibl S, Mehta RS, Bergh J, Roberston J, Barlow W, Liu H, Tenner K, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced stage breast cancer treated with first-line endocrine therapy [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 P2-07-05.

Abstract Background: The LAR subtype is a genomically distinct subset of TNBC. Using a large cohort of non-metastatic TNBC patients (pts) with long term follow-up, we sought to further characterize the clinicopathologic features and outcomes of LAR vs non-LAR TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, 605 met criteria for TNBC (ER/PR<1% and HER2-negative) by central pathology. RNA extracted from 304 FFPE tumor specimens using the HighPure RNA extraction kit was subjected to TruSeq RNA Access library preparation and sequencing on a HiSeq2500. Adequate RNA was available for 283 pts. Tumors were classified as LAR or non-LAR using a shrunken centroid model, CABAL (Clustering Among BAsal and Luminal androgen receptor). In addition to previously described analyses [Leon-Ferre et al, Breast Cancer Res Treat 2017], immunohistochemical (IHC) androgen receptor (AR) staining was performed and the impact of various parameters on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: 58 (20%) tumors were classified as LAR and 225 (80%) as non-LAR. Compared to non-LAR, LAR pts were older (mean age 65 vs 54) and more often postmenopausal (79%vs53%), both p=0.01. Apocrine histology was more common among LAR tumors (21%vs0%), which were also lower grade (grade3: 69%vs95%) and had lower Ki-67 (Ki-67>15%: 64%vs82%), all p<0.01. Additionally, LAR tumors had lower median stromal tumor infiltrating lymphocytes (TILs, 20%vs25%) and were less frequently lymphocyte-predominant [≥50% stromal or intratumoral TILs (19%vs32%)], although neither reached statistical significance. AR IHC was available for 223 of 283 tumors. Median AR IHC score in LAR was 65% (range 0-100%) vs 0% (range 0-90%) in non-LAR. T/N stage, surgery type, and receipt of adjuvant chemotherapy (AdjCT) or radiotherapy were similar between LAR and non-LAR. LAR pts had shorter IDFS and OS compared to non-LAR (5.6 vs 11.8 yrs and 10.8 vs 20.8 yrs, respectively), although this did not reach statistical significance. Test of proportional hazard assumption was not significant for IDFS or OS (p = 0.30 and 0.09). IDFS estimates were numerically higher in LAR vs non-LAR (80.2%vs70.5%,p = 0.92) at 3yrs post-diagnosis; whereas the opposite was true (40.9%vs55.6%,p = 0.07) after 10yrs. OS estimates at 3 and 5yrs were similar between LAR and non-LAR, but at 10yrs OS was inferior in LAR (40.9%vs66.4%,p = 0.24). In a univariate analysis including both LAR and non-LAR, older age, higher N stage, lower TILs and absence of AdjCT were associated with poorer IDFS and OS. In a multivariate analysis, higher N stage and absence of AdjCT remained associated with both poorer IDFS and OS; while lower stromal TILs were associated with poorer IDFS (p=0.01), and with a trend towards poorer OS (p=0.07). Conclusions: LAR TNBCs occurred in older women, were lower grade, and had lower TIL density than nonLAR tumors. While significant differences in IDFS or OS were not demonstrated, LAR pts exhibited a numerically lower risk of a disease event at 3yrs, but higher risk by 10yrs compared to nonLAR pts. In the entire cohort, higher N stage, absence of AdjCT and lower TILs were independently associated with poorer outcomes. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Kalari KR, Boughey JC, Liu MC, Cafourek V, Negron V, Ingle JN, Thompson KJ, Tang X, Barman P, Carlson E, Visscher DW, Carter JC, Couch FJ, Goetz MP. Characteristics, outcomes and prognostic factors of luminal androgen receptor (LAR) triple-negative breast cancer (TNBC) [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 P3-08-01.

Abstract Background High mammographic breast density is the primary reason for missed cancers or delayed detection on mammography, and is associated with a higher rate of advanced and interval cancers which increase breast cancer mortality. Digital breast tomosynthesis (DBT) has been shown to reduce false positive findings relative to 2D mammography but does not eliminate the potential for tumor masking in dense breasts due to the similar x-ray attenuation characteristics of tumors and normal fibroglandular tissue. Molecular Breast Imaging (MBI) performed with a dedicated gamma camera to detect functional uptake of a radiotracer, Tc-99m sestamibi, has been shown to reveal breast cancers obscured by density on mammography. In single-institution studies, adding MBI to 2D mammography in women with dense breasts detected an additional 5 to10 invasive cancers per 1000 screened, with modest increases in recall rate (6 to 8%) at a lower cost-per-cancer detected than mammography alone. Despite this promising evidence, the lack of multicenter trial data has limited wider acceptance. Also, MBI has yet to be compared to DBT, which in some centers has replaced 2D mammography screening. We present interim results from a multicenter trial comparing cancer detection rate of DBT and MBI in screening of women with mammographically dense breasts. Methods In this ongoing, prospective, multicenter clinical trial, asymptomatic women aged 40-75 years with dense breasts on prior mammogram and no prior history of supplemental screening are invited to undergo two annual rounds of concurrent DBT and MBI. MBI is performed with injection of 300 MBq Tc-99m sestamibi with a dual-head semiconductor-based gamma camera. Screening tests are interpreted independently. Here, preliminary cancer detection rates (cancers per 1000 women screened), recall rates, and biopsy rates of DBT and MBI for initial screening are reported. Results In 537 women out of a planned 3000 who have completed the first round of screening, 7 cancers were detected: one by DBT only and 6 by MBI only, giving cancer detection rates of 1.9 for DBT vs. 11.2 for MBI and incremental cancer detection rate of 9.3 for MBI. The one DBT-only cancer was a node-negative 0.8 cm invasive lobular carcinoma. All 6 cancers detected by MBI were invasive; 5 of 6 were node negative (median size 1.0 cm; range 0.6 to 2.6 cm). Recall rate was 11% (60/537) for DBT alone; 16% (84/537) for MBI alone, and 21% (115/537) for the combination. Biopsy was prompted by DBT in 13 patients (PPV 8% [1/13]); by MBI in 23 patients (PPV 26% [6/23]); and by the combination of modalities in 33 (PPV 21% [7/33]). Conclusion These preliminary results demonstrate that MBI detects invasive breast cancers occult on DBT in dense breasts. Data from a second screening round will allow calculation of sensitivity and specificity, and determination of the impact of screening MBI in reducing advanced (> 2 cm) and interval cancers. Additional planned analyses will evaluate a denoising algorithm for further reduction in MBI radiation dose to match that of DBT. Citation Format: Rhodes D, Hunt K, Conners A, Zingula S, Whaley D, Ellis R, Gasal Spilde J, Mehta R, Polley M-Y, O'Connor M, Hruska C. Molecular breast imaging and tomosynthesis to eliminate the reservoir of undetected cancer in dense breasts: The Density MATTERS trial [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 PD4-05.

Abstract Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)>4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the >50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM, CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection of individuals in the general population who may benefit from genetic testing and associated risk management strategies. Citation Format: Couch FJ, Hu C, Hart SN, Gnanaolivu RD, Lilyquist J, Lee KY, Gao C, Eckloff B, Samara R, Klebba J, Auer P, Bernstein L, Gaudet M, Haiman C, Palmer JR, Yao S, Domchek SM, Weitzel JN, Goldgar DE, Nathanson KL, Kraft P, Polley EC. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study [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 GS2-01.

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

11599 Background: It is unclear whether survival varies among breast cancer molecular subtypes without systemic and locoregional therapy. This study aims to evaluate the survival profile by molecular subtypes after surgery. Methods: In total, we evaluated 301 women with invasive breast cancer with stage I, II or III disease. Patients were classified into four major breast cancer subtypes by immunohistochemistry/FISH classifiers: luminal-A (ER+ and/or PR+/HER2-), luminal-B (ER+ and/or PR+/HER2+), HER2-enriched (HER2+/ER-/PR-) or basal-like (ER-/PR-/HER2-; triple-negative). Overall survival (OS) was analyzed by Kaplan-Meier analysis, and log-rank test for differences. Association between clinical outcome and subtype adjusting for breast cancer prognostic factors was assessed by multivariable Cox proportional hazards model. Results: All patients did not receive systemic chemotherapy and hormone therapy as well as radiation therapy. Luminal A was the most common subtype (N = 224), followed by basal-like (N = 43), luminal B (N = 21) and HER2-enriched (N = 13). Median follow-up for OS was 197 months (range: 1 – 273 months). Age at diagnosis was statistically different among the subtypes, with basal-like and luminal B having high proportions less than 50 years (P = 0.047). Patients with basal-like and HER2-enriched had more high grade tumors (P < 0.001). Notably, there was no difference in OS among the four subtypes (log-rank P = 0.983). In multivariable analysis, the adjusted hazard ratio (HR) was 1.1 for luminal A vs. luminal B (P = 0.781), 0.62 in luminal A vs. HER2-enriched (P = 0.273), or 0.67 in luminal A vs. basal-like (P = 0.158). In contrast, the adjusted HR were 2.2 in age less than 50 years (P = 0.0017), and 1.1 for number of positive nodes (P = 0.00074). Conclusions: OS, through long-term clinical follow-up, is not significantly different among molecular subtypes if not controlling for other prognostic factors in patients who only received surgery. Age and number of positive nodes are independent prognostic factors in patients with no systemic and locoregional treatments.

533 Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER < 1%, PR < 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 > 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p < 0.01), lower sTILs (p = 0.01) and no AdjCT (p < 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p < 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.