Boughey, JC

Abstract Background: Male breast cancer (MBC) is rare, and usually managed by extrapolation from female breast cancer. We report on the characteristics and survival outcomes of MBC patients from Mayo Clinic Rochester (MCR). Methods: Medical records of MBC patients treated at MCR during a 25-year period (1990-2015) were reviewed. Demographic variables, tumor characteristics, recurrences, and overall survival (OS) were collected. Progression free survival (PFS) and OS were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of OS. Results: One hundred sixty-seven patients were included in the final analysis, with a median follow-up of 58 months after diagnosis. Baseline characteristics are presented in Table 1. Eighty percent of patients with ER-positive tumors received endocrine therapy. Among men with stage I-III disease, approximately 90% underwent mastectomy, and 44% received adjuvant chemotherapy. The 5-year locoregional and distant recurrence rates for patients with stage I-III disease were 4.4% and 21.5%, respectively. The 5-year PFS and OS for patients with stage I-III disease were 65.5% and 80.1%, respectively. In a multivariate analysis assessing predictors of OS in patients with stage I-III disease, older age (HR 1.05; 95% CI: 1.02 – 1.09), stage II (HR 11.06; 95% CI: 3.84 – 31.85) or stage III disease (HR 14.74; 95% CI (3.99 – 54.45), and omission of surgery (HR 45.33; 95% CI: 3.97 – 517.32) were associated with poorer OS, while endocrine therapy (HR 0.21, 95% CI: 0.09 – 0.51) was associated with better OS. ER, PR, HER2 and grade were not independently prognostic. The median OS for stage IV patients was 10 months, though this 11-man cohort was too small to allow assessment of prognostic factors in advanced male breast cancer. Conclusions: MBC remains an understudied condition. Prognostic factors in this stage I-III disease are consistent with those identified in other MBC retrospective cohorts. Prospective studies are needed to better understand the unique clinical features of MBC, and to improve outcomes, particularly for advanced disease. Table 1:Baseline characteristics N=167 Median age at diagnosis (Years)64.4 Ethnicity/Race: Caucasian131 (78.4%)African American4 (2.4%)Other or unknown32 (19.2%) Overall AJCC 7th edition stage: Stage I39 (23.4%)Stage II80 (47.9%)Stage III32 (19.2%)Stage IV11 (6.6%)Unknown5 (3.0%) Grade: 18 (4.8%)247 (28.1%)3101 (60.5%)Unknown12 (7.1%) ER status: Negative8 (4.8%)Positive153 (91.6%)Unknown6 (3.6%) PR status: Negative17 (10.2%)Positive141 (84.4%)Unknown9 (5.4%) HER-2 status: Negative70 (41.9%)Positive12 (7.2%)Unknown85 (50.9%) Citation Format: Yadav S, Leon-Ferre RA, Jimenez RE, Hawse JR, Hieken TJ, Couch FJ, Boughey JC, Ruddy KJ. Clinical characteristics and survival of patients with male breast cancer: The Mayo Clinic experience [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 P6-19-05.

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 Introduction: The vast majority of cancer patients continue to receive treatments that are minimally informed by omics data. In the case of breast cancer, only ER and HER2 are routinely used for treatment selection. There is a particular need for personalized treatment in individuals with primary and secondary drug resistance or aggressive breast cancers. Emerging bioinformatics and statistical methods have made a fundamental impact on cancer research. However, challenges remains with regard to patient-centric data analysis and providing genomic data guidance to oncologists. There exists a large number of FDA approved anti-neoplastic drugs used to treat cancers other than breast and the development of innovative informatics methods and algorithms to repurpose those drugs should benefit breast cancer patients. Methods and Results: We have developed precision care systems (such as PANOPLY and CORPUS) to identify personalized therapies for an individual patient and to deliver genomic reports in a standard, searchable format so that a researcher or an oncologist can quickly navigate through molecular data and obtain prioritized drugs and targets.The PANOPLY (Precision cancer genomics report: single sample inventory) algorithm applies machine learning and topology-based network analysis methods to integrate multi-omics profiles and clinical data; individual-specific molecular alterations are identified and compared with a set of matched-controls having similar clinical data. Since there is a lack of a “gold standard” dataset to test such algorithms, we simulated 500 case-control sets and evaluated drug predictions across multiple simulation scenarios. We applied the PANOPLY algorithm to The Cancer Genome Atlas (TCGA) breast cancer cohort, which consists of multi-omics data and clinical data. In addition, PANOPLY was also applied to an in-house neoadjuvant breast cancer study (BEAUTY) that consists of multi-omics data, clinical data, and patient-derived xenografts (PDXs). In the TCGA breast cancer study we obtained survival data to determine the cases and matched-controls; and in the BEAUTY, we used pathologic complete response (pCR) as an outcome to determine responders and non-responders. Recurrent targetable alterations were not enriched in patients without pCR in the BEAUTY study. We have applied the PANOPLY to non-responder patients to identify individual specific alterations, dysregulated networks, drug targets, and drugs for each patient and stored them as case reports in CORPUS (Computational Oncology Reports and Precision therapeUticS), a web-based repository that allows clinicians to review genomic reports. Using comprehensive “omic” data derived from a triple negative breast cancer patient who had pre and post-neoadjuvant chemotherapy PDXs, PANOPLY prioritized the PARP inhibitors as the top class of drug. Using the PDX models available from this patient, we tested olaparib and confirmed the in vivo antitumor activity (more effective than vehicle with a p-value < 0.05 in the PDXs). Further studies to confirm PANOPLY findings are currently underway. Conclusions: In summary, the PANOPLY and CORPUS systems incorporate molecular data together with clinical data to provide genomic reports with proposed drug targets to advance or enable precision breast cancer care. Citation Format: Kalari KR, Sinnwell JP, Thompson KJ, Tang X, Carlson EE, Alaparthi T, Yu J, Vedell PT, Kalmbach MT, Bockol MA, Hossain A, Weinshilboum RM, Boughey JC, Wang L, Suman VJ, Goetz MP. Multiscale modeling of omics data for precision breast cancer treatment [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 P3-06-10.

Abstract Background: In women with breast cancer receiving neoadjuvant chemotherapy, residual cancer burden (RCB) predicts distant recurrence and survival. In those with high risk tumors, locoregional recurrence (LRR) remains a concern, and has been associated with type of local therapy received. We evaluated the impact of local therapy on LRR in the ISPY-2 TRIAL. Methods: Data were analyzed in Stata 14.2, using Chi2 test, log rank test, and a Cox proportional hazards model. RCB was considered a categorical variable (0/1 versus 2/3), as described in prior publications. Breast surgery categories were lumpectomy +/- radiotherapy, or mastectomy +/- radiotherapy. Axillary surgery was defined as sentinel lymph node (SLN) surgery (≤6 nodes removed) or axillary dissection (>6 nodes). Results: Follow up data from the I-SPY2 TRIAL were available for 630 patients (median follow up 2.76 yrs, range 0.4-7.2). Type of local therapy was significantly associated with clinical stage at presentation, with stage III patients most frequently undergoing mastectomy + radiation (p<0.001). Women with higher RCB were more likely to undergo mastectomy than those with lower RCB (61.3% vs 48.8% mastectomy rate, p=0.002), and more likely to receive adjuvant radiotherapy (62.0% vs 53.9%, p=0.048). There was no association between clinical stage, type of surgery, or radiotherapy and LRR (Table). Higher RCB was significantly associated with LRR, with 3 year locoregional recurrence free rate of 95.1% in RCB 0/1 versus 89.9% in RCB 2/3 (p=0.003). In a Cox model adjusting for clinical stage, tumor subtype, surgical therapy, RCB status, nodal radiation, and age, significant predictors for LRR were tumor subtype and RCB status. Hazard ratio (HR) for LRR in those with RCB 0/1 was 0.39 compared to those with RCB 2/3 (95% CI 0.17-0.87, p=0.021). There was no difference in LRR between breast conservation and mastectomy; within the breast conservation group, those who had lumpectomy alone had higher hazard of LRR compared to those having lumpectomy + radiation (HR 3.1, 95% CI 1.1-9.2, p=0.043). Conclusions: Extent of surgical therapy was not associated with local tumor control, regardless of advanced tumor stage at presentation. Rather, tumor biology and response to therapy were the best predictors of LRR. These data highlight the opportunity to minimize the morbidity of extensive surgical therapy for patients with excellent response to systemic therapy. LRR rates by clinical features and treatment status FrequencyLRR RateP valueClinical Stage 0.5I240 (47.5%)5.8% II185 (36.6%)8.7% III80 (15.8%)6.3% Tumor Subtype 0.014ER+PR+Her2-161 (26.4%)3.1% ER+PR-Her2-56 (9.2%)3.6% Her2+176 (28.9%)6.3% Triple negative216 (35.5%)11.1% Local therapy 0.169Lumpectomy85 (13.5%)11.8% Lumpectomy with radiation198 (31.4%)5.6% Mastectomy173 (27.5%)5.2% Mastectomy with radiation174 (27.6%)8.6% Axillary surgery 0.23None5 (0.8%)20% SLN329 (52.2%)5.8% ALND296 (47%)8.5% Axillary radiation 0.535Yes42 (6.7%)9.5% No588 (93.3%)7.0% Axillary management 0.2No surgery or radiation5 (0.8%)20.0% SLN312 (50%)5.3% SLN+Axillary radiation17 (2.7%)8.3% ALND271 (43%)10.3% ALND+Axillary radiation25 (4%)5.4% RCB 0.0020/1293 (50.1%)3.8% 2/3292 (49.9%)10.3% Citation Format: Silverstein J, Suleiman L, Yau C, Price ER, Singhrao R, Yee D, DeMichele A, Isaacs C, Albain KS, Chien AJ, Forero-Torres A, Wallace AM, Pusztai L, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Leyland-Jones B, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, I-SPY 2 TRIAL Consortium, Berry DA, Asare SM, Esserman LJ, Boughey JC, Mukhtar RA. The impact of local therapy on locoregional recurrence in women with high risk breast cancer in the neoadjuvant I-SPY2 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 P2-14-01.

Abstract Background The 21-gene (Oncotype DX) Recurrence Score (RS) is a multi-gene expression assay that is both prognostic and predictive of adjuvant chemotherapy (AdjCT) benefit in estrogen receptor (ER) positive/HER2 negative breast cancer (BC). Use of the RS in TNBC and HER2+ BC is not recommended by national guidelines. Using the National Cancer Database (NCDB), we sought to evaluate whether oncologists use the RS in these subtypes. Additionally, we assessed the prognostic effects of the RS in node negative patients (pts) who did or did not receive adjuvant chemotherapy. Methods Pts with TN and HER2+ BC diagnosed from 2010-2015 in the NCDB were analyzed. Pts with neoadjuvant therapy or stage IV were excluded. Cases with RS testing were classified as low (RS 0-17), intermediate (RS 18-30) or high (RS 31+). Analysis was performed using multivariable logistic regression; overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests. Results 142,330 pts were evaluable: 64,830 TNBC and 77,500 HER2+ (21,768 ER-/HER2+ and 55,732 ER+/HER2+). In these subtypes, RS was performed in 5,369 (3.8%) pts as follows: 1,479 (2.3%) TNBC, 185 (0.8%) ER-/HER2+, and 3,705 (6.6%) ER+/HER2+. Given the small ER-/HER2+ cohort, we focused on TNBC and ER+/HER2+. Within these subtypes, factors associated with RS testing included lower grade, smaller pathologic tumor size, pathologic N0 status, white race, age 60-69, and ILC or IMC histology (each p<0.005). Of the TNBC pts tested, the RS distribution was: low 16.3%, intermediate 13.1% and high 70.6%, while for ER+/HER2+ it was low 30.5%, intermediate 30.7% and high 38.8% (p<0.001). AdjCT was less frequently recommended in pts with low RS; however, this varied by tumor subtype with AdjCT recommended for 66.8% of TNBC with low RS and 37.9% of ER+/HER2+ with low RS. For intermediate RS, rates of AdjCT recommendation were 74.3% and 73.7%, and for high RS were 94.0% and 93.2% for TNBC and ER+/HER2+ respectively. In a multivariable analysis among pts with low RS, factors associated with AdjCT recommendation included younger age, larger pathologic tumor size, node positive disease, and higher grade. In AdjCT untreated TNBC, 5 yr OS did not differ for low RS (96.5%) vs intermediate RS (95.2%, p=0.82). In contrast OS was significantly worse for high RS (76.7%) than the other two groups, each p≤0.04. In AdjCT untreated ER+/HER2+, 5 yr OS was significantly better for low RS (96.7%) vs intermediate RS (92.5%, p=0.03) and vs high RS (92.1%, p=0.003), with no difference between intermediate RS vs high RS (p=0.32). Evaluating pts who did receive AdjCT, there was no significant difference in 5 yr OS for either subtype according to RS (p=0.46 and p=0.83). Interestingly, in patients with low RS, 5 yr OS was similar with or without AdjCT in both TNBC (89.5% vs 96.5%, p=0.25) and ER+/HER2+ (97.6% vs 96.7%, p=0.47). Conclusions RS testing is being conducted in a small fraction of pts with TN and HER2+ BC with lower clinical risk features. The observation that RS is prognostic for survival in AdjCT untreated patients is hypothesis generating, and suggests that further evaluation of the RS and other multigene assays in ER negative and HER2+ BC is warranted. Citation Format: Boughey JC, Hoskin TL, Cocco D, Day CN, Leon-Ferre R, Habermann EB, Goetz MP. The 21-gene recurrence score and chemotherapy use in triple negative breast cancer (TNBC) and HER2 positive breast cancer: A National Cancer Database 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 P3-08-09.

Abstract Neoadjuvant chemotherapy (NAC) is known to decrease the extent of disease in the breast and increase rates of breast conservation. In addition, NAC also can reduce the likelihood of nodal positivity and hence decrease need for axillary node dissection and its associated morbidities. Three prospective clinical trials have assessed the false negative rate (FNR) of SLN after NAC for patients with clinically node-positive disease at presentation. The American College of Surgeons Oncology Group (ACOSOG) Z1071 study reported a false negative rate (FNR) of SLN surgery of 12.6% in patients with cN1 disease with 2 or more SLNs resected. The FNR was lower at 10.6% when dual tracer technique was utilized. Additional analysis showed that when a clip was placed in the positive node at diagnosis and the clipped node was resected as one of the SLNs, the FNR was 6.8%. The Canadian study (SN FNAC - sentinel node following neoadjuvant chemotherapy) reported a FNR of 13.3% when defining SLN with isolated tumor cells (ITC) as negative and 8.4% when including ITC in the definition of a positive SLN. The SENTINA study from Europe reported an overall FNR of 14.2%, however when excluding patients with only a single SLN removed the FNR was 9.8%. Further work with preoperative localization of the clipped node with a seed and resection of the localized clipped node along with the sentinel nodes (termed targeted axillary dissection) has been shown to have a FNR of 2.4%. Surgeons are incorporating SLN after NAC into their clinical practice for patients with a good response to NAC and thus use of SLN surgery after NAC for patients with node-positive breast cancer is increasing. There are multiple methods that can decrease the FNR of the procedure in this setting. These include use of dual tracer for SLN identification, resection of the initial biopsy-proven positive node, resection of at least 2 SLNs and use of immunohistochemical staining of the SLNs. There are several different techniques to assist with ensuring resection of the initially biopsy-proven positive lymph node which include varying methods to mark the node at diagnosis and ways to identify the node at time of SLN surgery. The node can be marked at the time of percutaneous lymph node biopsy (or at a subsequent visit prior to initiation of NAC) with a clip, a radioactive seed, or tattooed with ink. At the time of surgery, if ink or a radioactive seed was placed, the node can be identified using these techniques at the time of axillary surgery. If a clip was placed at diagnosis, this can undergo preoperative localization, with a radioactive seed or wire, to maximize likelihood of identifying the clipped node during surgery. For patients with biopsy-proven node-positive breast cancer, SLN surgery after NAC allows assessment of residual nodal disease and can enable patients who have their axillary disease eradicated by NAC to avoid ALND. Citation Format: Boughey J. Methods to minimize the false negative rate of sentinel lymph node surgery after neoadjuvant chemotherapy for node positive breast cancer [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 ES7-1.

Abstract Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p<0.00001), and more effective at predicting pCR/RCB-I than predicting pCR alone (AUC: 0.72 vs. 0.65). Larger pre-surgical FTV remains associated with worse DRFS adjusting for subtype (Wald p <0.00001). The RCB index is also significantly associated with DRFS adjusting for subtype (Wald p<0.00001). Adding FTV to a model containing RCB and subtype further improves association with DRFS (LR p=0.0007). RCB-I patients have excellent DRFS (94% at 3 years compared to 95% in the pCR group). Efforts are underway to identify an optimal threshold for dichotomizing pre-surgical FTV and FTV change measures for use in combination with pCR/RCB-I class to generate integrated RCB (iRCB) groups as a composite predictor of DRFS. Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [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 P2-07-03.

Abstract Background In clinically node-negative (cN0) breast cancer patients with triple negative (TN) and HER2+ disease and breast pathological complete response (breast pCR), low rates of nodal positivity after neoadjuvant chemotherapy (NAC) have been demonstrated. In these patients, the omission of surgical axillary staging has been proposed. However, this information is not routinely known preoperatively. We aimed to validate the correlation between pathologic breast response and pathologic nodal status, and evaluate the relationship between response of the breast tumor on MRI and pathologic nodal status after NAC in cN0 patients in the I-SPY2 trial. Methods We identified all patients with cT1-4 cN0 breast cancer prior to NAC from graduated arms of the I-SPY2 trial, a prospective neoadjuvant chemotherapy trial. Absence of residual disease post-NAC was defined as longest diameter (LD) of 0 mm on MRI. Breast pCR was defined as the absence of invasive tumor in the breast at surgery. Associations between ypN0 and patient, MRI, and tumor characteristics were assessed using chi-square tests and univariate regression. Results Of 365 cT1-4 cN0 patients included, 128 had HR+/HER2- tumors (35%), 60 HR+/HER2+ tumors (16%), 34 HR-/HER2+ tumors (9%) and 143 TN tumors (39%). Overall, 283 patients (78%) were ypN0 after NAC and 152 patients (42%) had a breast pCR. ypN0 rate was higher in patients with a breast pCR than those with residual disease (93% vs 66%, p<0.001). Patients with HR-/HER2+ and TN tumors were more likely to be ypN0 (97% and 87% respectively) than patients with HR+/HER2- and HR+/HER2+ disease (66% and 71% respectively, p<0.001). Other characteristics associated with ypN0 were tumor grade (grade I 57%, grade II 66%, grade III 84%; p=0.002), MammaPrint Classification (High Risk 1 68% and High Risk 2 87%; p<0.001) and absence of residual tumor in the breast on MRI (87% vs 72% in patients with evidence of tumor on MRI post-NAC/pre-surgery; p=0.003). In patients with HR-/HER2+, HR+/HER2+, HR-/HER2+ or TN disease and a breast pCR, ypN0 rate was respectively 82%, 96%, 96% and 97% (table 1). In patients with HR+/HER2-, HR+/HER2+, HR-/HER2+ or TN disease and with no evidence of residual disease in the breast on MRI, rate of ypN0 was 71%, 80%, 94% and 96% respectively. Conclusion In cT1-4 cN0 breast cancer patients with HR+/HER2+, HR-/HER2+ and TN tumors and a breast pCR, ypN0 rates after NAC are extremely high. In patients with HR-/HER2+ and TN tumors with no residual breast disease on MRI after NAC and pre-surgery, ypN0 rates are high enough to consider omission of axillary surgery. In patients with HR+ tumors, MRI is unsufficiently predictive for pathological response and can therefore not be used to select ypN0 patients. Research on the prediction of ypN0 in cN+ I-SPY2 patients is ongoing. Nodal status in patients with pCR and absence of residual disease on MRI Number of positive nodesBreast Cancer Subtype0123AllBreast pCR HR+/HER2-27(82)2(6)4(12)033(100)HR+/HER2+24(96)01(4)025(100)HR-/HER2+24(96)1(4)0025(100)TN67(97)2(3)0069(100)Absence of residual disease on MRI HR+/HER2-24(71)7(21)3(9)034(100)HR+/HER2+16(80)3(15)01(5)20(100)HR-/HER2+15(94)1(6)0016(100)TN54(96)2(4)0056(100) Citation Format: van der Noordaa ME, Esserman L, Yau C, Mukhtar R, Price E, Hylton N, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, van 't Veer L, Hirst G, Lancaster R, Wallace A, Alvaredo M, Symmans F, Asare S, Boughey JC, I-SPY2 Consortium. Role of breast MRI in predicting pathologically negative nodes after neoadjuvant chemotherapy in cN0 patients in the I-SPY2 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 PD4-04.

Abstract Background: While TNBC remains the most aggressive type of breast cancer (BC), substantial heterogeneity in biology and outcomes exists among TNBC subtypes. Historically, risk stratification of TNBC has been based on anatomic factors such as tumor size, nodal involvement and presence of distant metastases. However, these features alone fail to accurately predict outcomes. Tumor immune infiltration (sTILs) and distribution of immune cell subsets in the perip heral blood (NLR) have emerged as variables reported to be associated with outcomes in TNBC. We sought to evaluate whether NLR and sTILs provided independent prognostic information in TNBC. Methods: From a cohort of 9,982 women who underwent BC surgery at Mayo Clinic, Rochester, MN between Jan 1985 and Dec 2012, we identified 605 centrally-confirmed TNBC tumors. Patients (pts) with prior BC, bilateral BC, non-invasive disease, stage IV, neoadjuvant therapy, endocrine therapy, or adenoid cystic histology were excluded. For eligible tumors, clinical and pathologic variables were evaluated, including peripheral blood NLR and central assessment of sTILs per the 2014 International TILs Working Group recommendations. We calculated the Pearson correlation coefficient (PCC) between NLR and sTILs and constructed Cox Proportional Hazards Models to evaluate their association with invasive-disease free (IDFS) and overall survival (OS). NLR and sTILs were both analyzed as continuous variables. Results: Most pts had T1-2 (95%) and N0-1 disease (86%). Median OS follow-up was 10.6yrs. Median IDFS was 12yrs (95%CI 10.2-16.7) and median OS was 18.8yrs (95%CI 15.6-20.8). NLR and sTILs were available in 408 and 599 pts, respectively. The median NLR and sTIL content were 2.29 (0.14-10.50) and 20% (0-90%), respectively. NLR and sTILs were poorly correlated (PCC 0.0237). On univariate analysis (UVA), a higher NLR was associated with worse IDFS (HR 1.13; 95%CI 1.02-1.26, p=0.02) and OS (HR 1.17; 95%CI 1.04-1.31, p=0.01). Each 1% increment in sTILs was associated with improved IDFS (HR 0.99; 95%CI 0.98-0.99, p<0.001) and OS (HR 0.99, 95%CI 0.98-1.00, p<0.001). Among pts with high sTILs (≥20%), a higher NLR remained significantly associated with worse IDFS (HR 1.21; 95%CI 1.05-1.38, p=0.007) and OS (HR 1.25; 95%CI 1.09-1.44, p=0.001). In contrast, among pts with low sTILs (<20%), NLR was not associated with IDFS (HR 1.07; 95%CI 0.89-1.28, p=0.49) or OS (HR 1.07; 95%CI 0.88-1.30, p=0.49). The interaction test between NLR and sTILs did not reach statistical significance. A multivariate analysis (MVA; including age, menopausal status, histologic subtype, grade, tumor size, nodal stage, Ki-67, NLR, sTILs, adjuvant chemotherapy, type of surgery and adjuvant radiation) showed that sTILs remained independently associated with IDFS (HR 0.99, 95%CI 0.97-1.0, p=0.019) and OS (HR 0.99, 95% CI 0.97-1.0, p=0.044), whereas NLR did not. Conclusions: A lower NLR and a higher sTIL content were each associated with improved IDFS and OS among pts with nonmetastatic TNBC on UVA. However, when evaluated on a MVA, only sTILs remained independently associated with IDFS and OS. Our data suggest that the effect of sTILs on outcomes may not be modified by the NLR. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Gilbert J, Cafourek V, Hillman D, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch FJ, Visscher DW, Goetz MP. Prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and its relation to stromal tumor infiltrating lymphocytes (sTILs) in triple negative breast cancer (TNBC) [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 P3-05-06.