Ductal Carcinoma In Situ Patients Research Articles

Abstract P2-08-26: Cardiovascular events and mortality in a population-based cohort treated for ductal carcinoma in situ

Abstract Background: Ductal carcinoma in situ (DCIS) patients are mostly diagnosed through cancer screening programs, suggesting that this population may have a healthy screenee effect of being more health-conscious, have lower comorbidity and belong to a higher socio-economic class. In this population-based cohort, we assessed the likelihood of cardiovascular events and mortality in DCIS patients, comparing with a control group of non-DCIS patients. Methods: Using the Korean National Health Insurance Service database, 13,740 women who were diagnosed of DCIS between 2007 and 2013 were analyzed. Control group matched by age was selected three times the number of DCIS cases (n=41,200). Follow-up for comorbidities and survival was performed up to 2016. Cox proportional hazard regression analysis was used to evaluate the association between DCIS and myocardial infarction (MI) risk, cerebrovascular stroke risk and mortality rate. The DCIS group was divided into pure DCIS patients and DCIS patients with subsequent invasive breast cancer for analysis. Results: Compared to the control group, patients with DCIS history were more likely to have hypertension, diabetes mellitus, dyslipidemia and the Charlson’s Comorbidity Index score was significantly higher. Patients with DCIS history also had higher income and were more likely to live in urban districts. Despite of higher comorbidity rate, pure DCIS patients had a trend of lower MI risk (HR 0.710; 95% CI 0.448 - 1.125) and significantly lower stroke risk (HR 0.708; 95% CI 0.492 - 1.019). Whereas, DCIS patients with subsequent invasive breast cancer had a significantly lower MI risk (HR 0.582; 95% CI, 0.371 - 0.913) and trend of lower stroke risk (HR 0.815; 95% CI 0.610 - 1.108). Mortality rate was similar between control group and pure DCIS patients, but was higher in DCIS patients with subsequent invasive breast cancer (HR 1.629; 95% CI 1.339 - 1.983). The trend of lower risk for cardiovascular events was sustained when adjusting for age, income and comorbidities (hypertension, diabetes mellitus and dyslipidemia). Conclusion: DCIS patients had a lower risk for MI and stroke compared to the control group despite of higher rate of comorbidities, which may reflect socioeconomic differences. DCIS patients with subsequent invasive breast cancer had higher mortality rate, whereas pure DCIS patients had similar survival rate compared to the control group. Citation Format: Tae-Kyung Yoo, Byung Joo Chae, Kyung Do Han, DaHye Kim, Juneyoung Ahn, Woo-Chan Park, Se Jeong Oh. Cardiovascular events and mortality in a population-based cohort treated for ductal carcinoma in situ [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-26.

Abstract P4-12-14: Has hypofractionated whole breast radiation therapy become standard of care in the United States? An updated report from national cancer database

Abstract Background: Although overwhelming results of randomized controlled trials have demonstrated that hypofractionated whole breast radiation therapy (HF-WBI) has similar recurrence rates and disease-free survival as compared to conventional fractionated whole breast radiation (CF-WBI), we and others have shown that the adoption of HF-WBI remained low in the United States by 2013. It is unknown whether the utilization of HF-WBI has changed after 2013 in the United States. Methods: Among the patients who underwent a lumpectomy, we identified 688,079 patients with early stage invasive breast cancer and 248,218 patients with ductal carcinoma in situ (DCIS) in the National Cancer Database from 2004-2016. We defined HF-WBI as 2.5-3.33 Gy/fraction to the breast, while CF-WBI as 1.8-2.0 Gy/fraction. We evaluated the trend of HF-WBI utilization and examined factors associated with HF-WBI utilization using logistic regression models. Results: Among invasive cancer patients, the usage of HF-WBI increased significantly from 0.7% in 2004 to 15.6% in 2013 and then to 38.1% in 2016. Among DCIS patients, the usage of HF-WBI has increased significantly from 0.4% in 2004 to 13.4% in 2013 and then to 34.3% in 2016. The upsurge of HF-WBI therapy did not affect the overall use of radiotherapy as there was a corresponding decrease in CF-WBI use over these years. In the analysis of factors related to HF-WBI among invasive breast cancer patients, we found that age is strongly correlated with HF-WBI utilization and it is more likely for older patients to receive HF-WBI than younger patients. The proportion of HF-WBI use was 9.3% among women younger than age 50 while 21.8% of women older than 50 years were treated with HF-WBI. Another factor found was race/ethnicity; we found that among African American women with invasive breast cancer, 12.7% used HF-WBI and among Asian women with invasive breast cancer, 23.6% used HF-WBI, while 15.6% of white women used HF-WBI. Among the invasive breast cancer patients, HF-WBI use varied widely across geographical location with the highest uptake in the Mountain census region (25.3%) and least uptake in the West South Central region (10.5%). Other factors associated with HF-WBI use for invasive breast cancer patients included nodal status, tumor size, treating facility type, treating facility volume, and distance from home to treating facility. We found that large academic facilities were more likely to administer HF-WBI (24.4%) than small community treating facilities (11.2%). Our results for DCIS patients were similar to that of the invasive breast cancer patients. Conclusions: HF-WBI utilization in the United States has more than doubled from 2013 to 2016. Although its use is close to that of conventional WBI, HF-WBI is still far from preferred standard of care in the United States. We identified several patient and facility factors that can impact the uptake of HF-WBI treatment. Citation Format: Dezheng Huo, Minji Kang, Loren Saulsberry, Yasmin Hasan. Has hypofractionated whole breast radiation therapy become standard of care in the United States? An updated report from national cancer database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-14.

Abstract P6-15-07: Impact of increased mammary adiposity on DCIS progression

Abstract Background: The incidence of ductal carcinoma in situ (DCIS) has greatly increased since the introduction of mammographic screening. However, so far, it is still not possible to predict which patient with DCIS will further develop invasive breast cancer. Adipocyte hypertrophy and adipocyte inflammation has been associated with increased risk of developing breast cancer in postmenopausal women and with worse prognosis in breast cancer patients. In this study, we aimed 1) at evaluating the association between mammary adiposity, as assessed by digital pathology, with DCIS progression using a unique case-control series with long-term follow up and 2) study the interaction between DCIS cells and the surrounding adipocytes. Patients and methods: Mammary adipocyte size was measured in surgical specimens of 279 women with primary DCIS. These mammary adipocyte measurements were compared in 109 women with primary DCIS who subsequently developed ipsilateral invasive breast cancer (iIBC) (cases) and 170 women who did not (controls). Patients were matched for age and follow-up duration. Median follow-up time was 12.8 years. Post-menopausal patients were defined as >50 years at diagnosis and represented 220/279 (78,9%) of patients. All patients were treated with breast cancer-conserving surgery only. Intact adipocytes distant from the DCIS lesions were measured (largest diameter and area) using HALO™ image analysis software (Indica Labs, Corrales, NM) on H&E-stained whole slide images of primary DCIS. Given the specific interest in the larger adipocytes, we systematically considered the 75th percentile as unique value for each patient. An average of 4259 adipocytes (min:70, max:21107) was measured per patient. Tissue segmentation was used to measure the adipose area. Adipose triglyceride lipase (ATGL clone 2138, Cell Signaling) immunohistochemistry (IHC) was applied to study ATGL expression in DCIS cells. Her2, ER and COX-2 IHC and RNAseq of microdissected pure DCIS was already available for this series (LL. Visser et al. Clin Can Res 24 (15) 2018). Conditional logistic regression was applied to investigate differences in adipocyte hypertrophy between groups of patients (e.g., cases and controls). Results: Adipocytes were larger and the proportion of adipose tissue was higher in post-menopausal patients (both p<0.001). Mean adipocyte maximum diameter and mean adipocyte area of the 75th percentile ranged from 46.9-115.9 µm and 2016-11336 µm2 respectively. For every 1000 µm2 increase in mean adipocyte area a DCIS patient had a 1.18 increased risk for iIBC (95% CI 1.02-1.36, p= 0.028). DCIS patients with large adipocytes (above the 75th percentile) had a 2.1 increased risk for developing iIBC (95% CI: 1.18-3.72, p=0.011). This observation remained when restricting the analysis to post-menopausal patients (OR 1.19 per 1000 µm2 95% CI 1.01-1.40, p=0.038 and adipocytes above 75th percentile OR 2.2, 95% CI 1.22-3.99, p= 0.009). To further explore the potential interactions between the epithelial cells from DCIS with the adjacent adipocytes, we compared the size of the DCIS-adjacent adipocytes to those away from DCIS lesions. DCIS-adjacent adipocytes showed a reduction in size, suggesting delipidation. Adipose triglyceride lipase (ATGL) is a rate limiting lipase that can release stored free fatty acids (FFA) in DCIS cells for fatty acid ß-oxidation. In a pilot series strong ATGL expression was observed in a subset of DCIS lesions (4 of 25). Conclusion and perspective: This study is the first to demonstrate that mammary adipocyte hypertrophy is associated with an increased risk of progression for patients with DCIS. Our findings might help to distinguish potentially hazardous from harmless DCIS, enabling overtreatment of indolent DCIS. Adipocyte size will be correlated to immunohistochemical expression of ATGL, Her2, ER and COX2 in DCIS, and RNAseq data of pure microdissected DCIS. Citation Format: Mathilde Matthea Machteld Almekinders, Michael Schaapveld, Bram Thijssen, Ingrid Hofland, Marjolijn Mertz, Dennis Peters, Annegien Broeks, Lodewijk Wessels, Wilbert Zwart, Jos Jonkers, Esther Lips, Christine Desmedt, Jelle Wesseling, on behalf of the PRECISION Team. Impact of increased mammary adiposity on DCIS progression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-15-07.

Abstract P6-10-24: High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial

Abstract Background: With the introduction of mammography the detection of breast ductal carcinoma in situ (DCIS) has increased four- to sevenfold. Local recurrences occur only in a minority of patients. Radiotherapy (RT) is presently used without biomarker guidance. Therefore, novel biomarkers predicting benefit of radiotherapy are warranted to prevent overtreatment. Studies on RT response-predictive biomarkers in DCIS have focused on tumor cell features and often neglected the tumor-associated stroma, despite growing evidence of its active influence on treatment response including RT. The platelet derived growth factor receptors alpha and beta (PDGFRa and -b) signaling pathways are major regulators of stroma cells. Recent studies have indicated a loss of PDGFRa in the tumor-associated stroma of DCIS while PDGFRb remains high and patients with PDGFRa(low)/PDGFRb(high) expression had a significant increased risk for any tumor recurrence. A limitation of this study was though the usage of a population-based cohort, thus not allowing firm conclusions on the impact of the marker on natural course of the disease or benefit to treatment. Purpose: To explore if stromal expression of PDGFRb serves as prognostic as well as response-predictive biomarker for RT benefit with regard to ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) for DCIS patients within a large and clinically well-annotated randomized trial. Method: Immunohistochemical staining of PDGFRb was performed on full tissue sections of 705 patients from the SwedDCIS cohort, a randomized RT trial after breast-conserving surgery. Stromal PDGFRb expression was evaluated by two independent raters in up to ten high power fields within the tumor associated stroma region and scored as 0/negative, 1/low average stroma intensity, 2/moderate average stroma intensity or 3/high average stroma intensity. An average PDGFRb score was calculated for each tumor. The final data was split at median defining PDGFRb low and high patient groups. Outcomes were analyzed at 10 years of follow-up. Results: High stromal PDGFRb was correlated with young age (p=0.003 Spearman’s Rank correlation). In multivariable Cox regression including RT, age, size, screen detection and tumor margin status, the PDGFRb high patient group showed a trend to worse prognosis with regard to IBTR (HR 1.40, CI95% 0.96-2.04, p=0.08) and OS (HR 1.76, CI95% 1.00-3.09, p=0.05). Benefit of radiotherapy on IBTR (in situ and invasive) was absent in the PDGFRb high patient group (HR 0.76, CI95% 0.47-1.22, p=0.25)), but clearly detected in the PDGFRb low group (HR 0.29, CI95% 0.15-0.55, p<0.001) in a multivariable analysis including age, size, screen detection and tumor margin status. Interaction between RT and PDGFRb was significant (p=0.020). No differences in OS after RT were observed within the PDGFR-defined patient groups. RT benefit was also restricted to the PDGFRb low patient group in separate analyses for in situ IBTR (PDGFRb low group HR 0.27, CI95% 0.12-0.60, p=0.001, versus PDGFRb high group HR 0.66, CI95% 0.34-1.29, p=0.22) or invasive IBTR (PDGFRb low group HR 0.33, CI95% 0.11-0.98, p=0.045, versus PDGFRb high group HR 0.88, CI95% 0.45-1.73, p=0.71). Significant interactions between PDGFRb group and RT were not detected in these sub-analyses (p=0.11 for in situ and p=0.15 for invasive IBTR). Conclusion: These data suggests high stromal PDGFRb as a marker of potential clinical utility for RT resistance regarding IBTR in DCIS patients. Furthermore, the study supports the hypothesis of a fibroblast-mediated modulation of RT-sensitivity in DCIS cells. Experimental model studies, investigating the biological mechanisms and potential therapeutic relevance are therefore highly motivated. Citation Format: Carina Strell, Dick Folkvaljon, Erik Holmberg, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-24.

Abstract P6-16-04: IL6ST, a biomarker of endocrine therapy response, has potential in identifying a subgroup of women with ER+ DCIS who are more likely to benefit from adjuvant endocrine therapy

Abstract Background: Ductal carcinoma in situ (DCIS) lesions are non-obligate precursors to invasive breast cancer (IBC). With the ultimate goal of preventing the development of invasive disease, DCIS is typically treated by breast-conserving surgery (BCS). Adjuvant radiotherapy (RT) is given for high-grade disease to reduce the risk of in-breast tumour recurrence (IBTR). The use of endocrine therapy (ET) for DCIS varies, as studies show a modest benefit but no survival improvement; in the UK, guidelines recommend ET for DCIS in some scenarios but only instead of, rather than in addition to, RT. This project sought to characterise the biology of ER+ DCIS and identify a group of women who are likely to gain the most benefit from the addition of adjuvant ET. Patients: Cohort A - 77 women with ER+ (Allred 7/8) high-grade DCIS treated with BCS plus RT, 20 of whom developed IBTR.Cohort B - 70 women with ER+ (Allred 7/8) low/intermediate-grade DCIS treated with BCS alone, 12 of whom developed IBTR.Cohort C - 68 women with ER+ (Allred 7/8) DCIS treated with BCS plus ET. All patients were treated locally between 2000 and 2016 and the median follow-up is 6 years. Methods: We performed whole-genome transcriptomic QuantSeq sequencing of samples from cohort A. Sequencing of cohort B and C is currently underway. IL6ST levels were validated using immunohistochemistry and RNAScope. Results: In cohort A, only a subset (34/77) of tumours had gene expression profiles consistent with active ER signalling. Levels of IL6ST, a biomarker for ET response, could differentiate these two subgroups and this was validated at protein level using immunohistochemistry. The low ER signalling subgroup were associated with higher levels of EGFR, HER2 and MAPK signalling. 20/77 high-grade DCIS cases recurred within 10 years. 50% of these recurred as IBC (rather than DCIS) and these were associated with higher levels of IL6ST, had active ER signalling and higher levels of proliferation-associated and estrogen receptor target genes, known to be decreased by ET, in the primary DCIS lesion. Discussion: Our findings suggest that some high-grade ER+ DCIS patients have active ER signalling while in others ER signalling remains low despite highly expressing the ER protein. IL6ST, a biomarker of endocrine therapy response can be used to differentiate these two groups of ER+ DCIS. DCIS lesions which recurred as IBC had active ER signalling and also higher levels of proliferation genes known to be decreased by ET compared with DCIS which recurred as further DCIS. These findings suggest that IL6ST may have a role in identifying a subset of ER+ DCIS which are at a higher risk of developing advanced disease and are also more likely to benefit from the addition of adjuvant ET, with a better risk-to-benefit ratio than observed in previous studies that considered a less targeted use of this treatment strategy, thus potentially reducing the risk of IBC recurrence. These findings will be validated in a cohort of low/intermediate-grade DCIS who received no adjuvant RT (cohort B) and a cohort of patients who received adjuvant ET as part of their treatment (cohort C). Citation Format: Carlos Martinez-Perez, Charlene Kay, Rebecca Swan, Gregory E Ekatah, Laura M Arthur, James Meehan, Mark Gray, Andrew H Sims, Olga Oikonomidou, Arran K Turnbull, J Michael Dixon. IL6ST, a biomarker of endocrine therapy response, has potential in identifying a subgroup of women with ER+ DCIS who are more likely to benefit from adjuvant endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-04.

Abstract P5-06-15: Computer extracted features of nuclear shape, orientation disorder and texture from H&E Whole slide images are associated with disease-free survival in ductal carcinoma in situ (DCIS)

Abstract Background: Ductal Carcinoma in Situ (DCIS) of the breast comprises a diverse group of cancerous lesions confined to the breast ducts. About 25% of all breast cancers in the US are DCIS and women with DCIS have a 10 times higher lifetime risk of progressing to invasive breast cancer (IBC). While DCIS is treated routinely with breast conserving therapy which includes a lumpectomy followed by adjacent radiation therapy (RT). However, studies have shown that RT can be omitted in women with a lower risk of recurrence/progression. Gene expression methods like Oncotype Dx can be used to risk stratify patients but are expensive, tissue-destructive and time consuming. Recently, there has been substantial interest in developing computerized approaches to quantitatively extract tumor histomorphometric (QH) features from digitized images of tissue slides to predict cancer outcome. In this work, we evaluate the role of QH features related to the architecture, shape, orientation disorder and texture of cancer nuclei from lumpectomy specimens of DCIS to predict disease-free survival (DFS). Methods: H&E whole slide images (WSI) and corresponding outcome information for 121 DCIS patients (61 with progression/recurrence and 60 without) from the no adjuvant treatment arm of the UK/ANZ DCIS trial were retrieved and collected from Queen Mary university of London. WSIs were scanned by 3DHistech scanner at 43x magnification. For each image, a deep learning based generative adversarial network model was employed to segment the cancer nuclei, following which 379 nuclear features from four feature families including architecture, shape, orientation disorder and Haralick texture features were extracted within each candidate breast duct in the WSI and averaged across the multiple cancerous breast ducts for each patient. The dataset was randomly split into training (D1, n=60) and a hold-out validation set (D2,n=61) with events split equally in the two sets. For each of the four feature families, a set of 6 top features was identified by an elastic Cox Model to predict DFS (time from diagnosis to recurrence/invasive breast cancer or death whichever is sooner) onD1. The feature sets giving significant prognostic value (assessed by log rank test between the feature derived risk groups) were combined, from which 6 top features were further identified by a Cox Model to predict DFS on D1. Results: The top ranked QH features included features from three feature families: 2 shape features, 1 orientation disorder feature and 3 texture features. The Elastic Cox model predicted DFS on D1 with hazard ratio (HR) of 7.29 (95% CI = 2.94 ~18.05, p=1.75e-05) and on D2 with HR of 2.07 (95% CI = 1.02 ~2.94, p=0.045). Conclusion: Computer extracted nuclear histomorphometric features pertaining to shape, orientation disorder and texture were associated with disease free survival for DCIS. Additional independent multi-site validation of the approach is planned to further confirm the preliminary findings presented here. Citation Format: Haojia Li, Kaustav Bera, Hannah Gilmore, Zelin Zhang, Jack Cuzick, Mangesh A Thorat, Anant Madabhushi. Computer extracted features of nuclear shape, orientation disorder and texture from H&E Whole slide images are associated with disease-free survival in ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-15.

Abstract OT3-09-03: The PREDICT registry: A prospective registry study to evaluate the effect of the DCISionRT test on treatment decisions in patients with DCIS following breast conserving therapy

Abstract Background: The benefits of adjuvant radiation therapy (RT) in DCIS patients treated with breast conserving surgery (BCS) remains controversial. Although there is level I evidence supporting the role of RT in reducing the risk of local recurrence, the incremental absolute benefit is variable. Current treatment guidelines generally recommend RT for all patients having BCS. When considered in the context of the economic, health-related, and quality-of-life costs associated with RT, it is critical to identify patients who are at low enough risk to consider foregoing RT. It is important to develop prognostic tools to better assess risk and understand the impact such a tool would have on treatment decisions. The DCISionRT™ Test (PreludeDx, Laguna Hills, CA) is a biologic signature that provides a validated score for assessing 10-year risk of recurrence and RT benefit using individual tumor biology in conjunction with clinical and pathologic risk factors. Trial Design: This is a prospective cohort study for patients diagnosed with ductal carcinoma in situ (DCIS) of the breast. Treating physicians complete a treatment recommendation survey before and after receiving DCISionRT test results. Test results, treatment recommendations, patient preferences and clinicopathologic features are stored in a de-identified registry for future analysis of data across participating institutions from a variety of geographic regions in the US. The study will also collect 5- and 10-year recurrence and survival data. Eligibility Criteria: The study includes females over the age of 25 who are candidates for BCS and eligible for RT and/or systemic treatment with sufficient tissue to generate test results. Subjects must not have been previously treated for DCIS or have previous or current invasive or micro-invasive breast cancer. Specific Aims: The primary objective of this study is to create a de-identified database of patients, test results, treatment decisions and outcomes that can be queried to determine the clinical utility of the DCISionRT Test in actual clinical use for the management of DCIS. The primary endpoints are changes in treatment recommendations for surgical, radiation and hormonal therapy after the physician and patient have reviewed the DCISionRT test results, including subgroup analysis by physician type (surgeon, radiation oncologist or tumor board). Secondary endpoints are identification of the key drivers for treatment recommendations, including age, size, grade, architecture, necrosis, palpability, presentation, hormone receptor status, race, ethnicity, family history, etc. Statistical Methods: Study results will be analyzed by summary descriptive statistics, such as patient counts, percentages, means, etc. Changes in treatment recommendations will be assessed using McNemar's chi-squared test for symmetry of rows and columns in a two-dimensional contingency table with an alpha level of 0.05. Differences in recurrence-free and overall survival will be evaluated by Kaplan-Meier survival analysis using the logrank test and/or the Cox Proportional Hazards model. A planned early interim analysis based on the first 200 patients has been recently completed and reported - data are available upon request (contact Steven Shivers, PhD, sshivers@preludedx.com.) Accrual: As of July 1, 2019, 319 patients have been accrued from 56 physicians at 25 institutions. Twenty-two additional institutions are currently in the process of joining the study. We are planning to accrue up to 2,500 patients from up to 100 institutions. Contact Information: We are actively recruiting institutions for participation. For more information, please contact: Mary Kay Hardwick, mkhardwick@tmebcn.com. Citation Format: Steve C Shivers, Pat Whitworth, Rakesh Patel, Troy Bremer, Charles E Cox. The PREDICT registry: A prospective registry study to evaluate the effect of the DCISionRT test on treatment decisions in patients with DCIS following breast conserving therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-03.

FAP-a and GOLPH3 Are Hallmarks of DCIS Progression to Invasive Breast Cancer.

Biological markers that could predict the progression of ductal carcinoma in-situ (DCIS) to invasive breast cancer (IDC) are required urgently for personalized therapy for patients diagnosed with DCIS. As stroma was invaded by malignant cells, perturbed stromal-epithelial interactions would bring about tissue remodeling. With the specific expression of the fibroblast activation protein-alpha (FAP-a), Carcinoma-associated fibroblasts (CAFs) are the main cell populations in the remodeled tumor stroma. Golgi phosphoprotein 3 (GOLPH3), a documented oncogene possessing potent transforming capacity, is not only up-regulated in many tumors but also an efficient indicator of poor prognosis and more malignant tumors. The present study aimed to retrospectively evaluate the pathological value of FAP-a and GOLPH3 in predicting the recurrence or progression of DCIS to invasive breast cancer. Immunohistochemical techniques were applied to investigate the expression of FAP-a GOLPH3 in 449 cases of DCIS patients received extensive resection and with close follow-up, but not being treated with any form of chemo- or radio-therapy. The combination of FAP-a and GOLPH3 in predicating the recurrence or progression of DCIS into invasive breast cancer was specifically examined. The study demonstrated that the overexpression of FAP-a in stromal fibroblasts and GOLPH3 in carcinoma cells are highly predictive of DCIS recurrence and progression into invasive breast cancer. Both FAP-a and GOLPH3 have high specificity and sensitivity to predict the recurrence of DCIS. Moreover, the combination of FAP-a and GOLPH3 tends to further improve the specificity and sensitivity of DCIS recurrence by 9.72–10.31 and 2.72–3.63%, respectively. FAP-a and GOLPH3 serve as novel markers in predicting the recurrence or progression of DCIS into invasive breast cancer.

Predictive factors for the presence of invasive components in patients diagnosed with ductal carcinoma in situ based on preoperative biopsy

BackgroundIn patients diagnosed with ductal carcinoma in situ (DCIS) with needle biopsy before surgery, invasive component (IC) is often found in the postoperative tissue, which results in altered post-surgical care. However, there are no clinically available factors to predict IC, and few MRI studies are available for the detection of IC in DCIS patients. The purpose of this study was to evaluate which risk factors can predict IC preoperatively.MethodsPatients with a DCIS diagnosis based on preoperative biopsy, who underwent breast surgery Kangbuk Samsung Hospital between Jan 2005 and June 2018, were retrospectively evaluated. Clinico-pathological and breast MRI factors were compared between DCIS and DCIS with IC in postsurgical specimens.ResultsOf the 431 patients with a preoperative diagnosis of DCIS, 34 (7.9%) showed IC during the postoperative pathological investigations, and 217 (50.3%) underwent breast MRI. Among MRI-related factors, Mass-like enhancement on MRI was the sole but significant predictor of IC (HR = 0.26, C.I. = 0.07–0.93, p = 0.038), while nipple-areolar complex invasion, enhancement peak and pattern were not statistically significant. Nuclear grade was the only significant predictor of IC in the analysis of other clinico-pathological factors (HR = 2.39, C.I. = 1.05–5.42, p = 0.038 in univariate analysis, HR = 2.86, C.I. = 1.14–7.14, p = 0.025 in multivariate analysis).ConclusionsMass-like enhancement on MRI and high nuclear grade were associated with IC in patients with preoperative diagnosis of DCIS. Considering the high sensitivity of breast MRI for IC, further evaluation of the predictive value of MRI in preoperative DCIS patients is desirable.

Quantitative nuclear histomorphometric features are predictive of Oncotype DX risk categories in ductal carcinoma in situ: preliminary findings

BackgroundOncotype DX (ODx) is a 12-gene assay assessing the recurrence risk (high, intermediate, and low) of ductal carcinoma in situ (pre-invasive breast cancer), which guides clinicians regarding prescription of radiotherapy. However, ODx is expensive, time-consuming, and tissue-destructive. In addition, the actual prognostic meaning for the intermediate ODx risk category remains unclear.MethodsIn this work, we evaluated the ability of quantitative nuclear histomorphometric features extracted from hematoxylin and eosin-stained slide images of 62 ductal carcinoma in situ (DCIS) patients to distinguish between the corresponding ODx risk categories. The prognostic value of the identified image signature was further evaluated on an independent validation set of 30 DCIS patients in its ability to distinguish those DCIS patients who progressed to invasive carcinoma versus those who did not. Following nuclear segmentation and feature extraction, feature ranking strategies were employed to identify the most discriminating features between individual ODx risk categories. The selected features were then combined with machine learning classifiers to establish models to predict ODx risk categories. The model performance was evaluated using the average area under the receiver operating characteristic curve (AUC) using cross validation. In addition, an unsupervised clustering approach was also implemented to evaluate the ability of nuclear histomorphometric features to discriminate between the ODx risk categories.ResultsFeatures relating to spatial distribution, orientation disorder, and texture of nuclei were identified as most discriminating between the high ODx and the intermediate, low ODx risk categories. Additionally, the AUC of the most discriminating set of features for the different classification tasks was as follows: (1) high vs low ODx (0.68), (2) high vs. intermediate ODx (0.67), (3) intermediate vs. low ODx (0.57), (4) high and intermediate vs. low ODx (0.63), (5) high vs. low and intermediate ODx (0.66). Additionally, the unsupervised clustering resulted in intermediate ODx risk category patients being co-clustered with low ODx patients compared to high ODx.ConclusionOur results appear to suggest that nuclear histomorphometric features can distinguish high from low and intermediate ODx risk category patients. Additionally, our findings suggest that histomorphometric features for intermediate ODx were more similar to low ODx compared to high ODx risk category.

Preoperative Delays in the Treatment of DCIS and the Associated Incidence of Invasive Breast Cancer

BackgroundAlthough treatment delays have been associated with survival impairment for invasive breast cancer, this has not been thoroughly investigated for ductal carcinoma in situ (DCIS). With trials underway to assess whether DCIS can remain unresected, this study was performed to determine whether longer times to surgery are associated with survival impairment or increased invasion.MethodsA population-based study of prospectively collected national data derived from women with a clinical diagnosis of DCIS between 2004 and 2014 was conducted using the National Cancer Database. Overall survival (OS) and presence of invasion were assessed as functions of time by evaluating five intervals (≤ 30, 31–60, 61–90, 91–120, 121–365 days) between diagnosis and surgery. Subset analyses assessed those having pathologic DCIS versus invasive cancer on final pathology.ResultsAmong 140,615 clinical DCIS patients, 123,947 had pathologic diagnosis of DCIS and 16,668 had invasive ductal carcinoma. For all patients, 5-year OS was 95.8% and unadjusted median delay from diagnosis to surgery was 38 days. With each delay interval increase, added relative risk of death was 7.4% (HR 1.07; 95% CI 1.05–1.10; P < 0.001). On final pathology, 5-year OS for noninvasive patients was 96.0% (95% CI 95.9–96.1%) versus 94.9% (95% CI 94.6–95.3%) for invasive patients. Increasing delay to surgery was an independent predictor of invasion (OR 1.13; 95% CI 1.11–1.15; P < 0.001).ConclusionsDespite excellent OS for invasive and noninvasive cohorts, invasion was seen more frequently as delay increased. This suggests that DCIS trials evaluating nonoperative management, which represents infinite delay, require long term follow up to ensure outcomes are not compromised.

Risk of Contralateral Breast Cancer in Women with Ductal Carcinoma In Situ Associated with Synchronous Ipsilateral Lobular Carcinoma In Situ.

Lobular carcinoma in situ (LCIS) is a risk factor for breast cancer, but the effect of LCIS found in association with ductal carcinoma in situ (DCIS) is unknown. In this study, we compared contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) rates among women with DCIS with or without synchronous ipsilateral LCIS treated with breast-conserving surgery (BCS). DCIS patients undergoing BCS from 2000 to 2011 with a contralateral breast at risk were stratified by the presence or absence of synchronous ipsilateral LCIS with the index DCIS (DCIS + LCIS vs. DCIS). Those with contralateral, bilateral, or prior ipsilateral LCIS were excluded. Associations of patient, tumor, and treatment factors with CBC and IBTR were evaluated. Of 1888 patients identified, 1475 (78%) had DCIS and 413 (22%) had DCIS + LCIS. At median follow-up of 7.2 (range 0-17) years, 307 patients had a subsequent first breast event; 207 IBTR and 100 CBC. The 10-year cumulative incidence of IBTR was similar in both groups: 15.0% vs. 14.2% (log-rank, p = 0.8) for DCIS + LCIS vs. DCIS, respectively. The 10-year cumulative incidence of CBC was greater in the DCIS + LCIS group: 10.9% vs. 6.1% for DCIS (log-rank, p < 0.001). After adjustment for other factors, CBC risk remained higher in DCIS + LCIS compared with DCIS (hazard ratio 2.06, 95% confidence interval 1.36-3.11, p = 0.001); there was no significant difference in IBTR risk. Compared with DCIS alone, DCIS + LCIS is associated with similar IBTR risk but double the risk of CBC. This finding should inform treatment decisions, in particular regarding endocrine therapy for risk reduction.

Fractionation in adjuvant radiotherapy for invasive breast cancer and ductal carcinoma in situ in Ontario, Canada from 2009 to 2015.

The use of hypofractionated radiotherapy (HFRT) in patients with breast cancer and ductal carcinoma in situ (DCIS) in Ontario, Canada, from 2009 to 2015 was reported. A retrospective cohort study was conducted using data from the Institute for Clinical Evaluative Sciences (ICES). Patients with a breast cancer or DCIS diagnosis between 2009 and 2015 who received adjuvant breast or chest wall radiation were included. Trends in HFRT use (≤16 fractions) and factors associated with HFRT use in a multivariable logistic regression model with physician-level random effect were reported. The approximate number of hours that could be saved if all patients were to receive HFRT was calculated. A total of 42072 patients were included. All included characteristics were significantly associated with HFRT use. Hypofractionated radiotherapy use in patients with breast cancer and DCIS increased to around 75% in 2015. In stage I/II patients with mastectomy and chest wall radiation, HFRT use increased to 40% in 2015. Hypofractionated radiotherapy use in patients with regional nodal radiation or reconstruction has increased but remains under 20%. For breast cancer patients with breast-conserving surgery (BCS) and breast radiation, 56265 visits corresponding to 7200hours of treatment or 3500 additional HFRT courses could have been saved. In conclusion, HFRT use in Ontario has increased in all patient populations but is nonuniform among physicians and institutions. Use of HFRT in chest wall and regional nodal radiation remains relatively lower than in breast cancer and DCIS patients with BCS.

A single-center retrospective study on axillary evaluation in 1 557 breast ductal carcinoma in situ patients between 2006 and 2016

Objectives: To examine the influence factors on axillary evaluation in ductal carcinoma in situ (DCIS) patients, and the prognosis of different choices of axillary evaluation in a single-center retrospective study. Methods: Totally 1 557 DCIS patients admitted in Department of Breast Surgery, Fudan University Shanghai Cancer Center from January 2006 to November 2016 were retrospectively enrolled. All patients were female. The median age was 49 years (range: 21 to 85 years). Surgical methods included modified radical mastectomy, simple mastectomy (with or without axillary evaluation) and breast conservation surgery (with or without axillary evaluation). Axillary evaluation included axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB). T tests, χ(2) test and Logistic regression analysis was used to analyze influence factors on axillary evaluation, respectively. Kaplan-Meier curve and Log-rank analysis were used to evaluate recurrence-free survival (RFS) and loco-regional recurrence-free survival (LRRFS) in patients with different surgical methods. Results: Among the 1 557 DCIS patients, there were 1 226 cases received axillary evaluation, while 331 cases not received axillary evaluation. Patients were separated into 3 groups by different axillary evaluation choices: SLNB group (957 cases, 61.46%), ALND group (197 cases, 12.65%) and no evaluation group (403 cases, 25.88%). The patients in SLNB group increased significantly (P=0.000), from 3.85% (60/1 557) in 2006 to 75.19% (1 170/1 557) in 2016. The independent influence factors of receiving axillary evaluation were high nuclear grade (OR=3.191, 95%CI: 1.722 to 5.912, P=0.001) and tumor size>15 mm (OR=1.698, 95%CI: 1.120 to 2.573, P=0.012). Also, patients received breast conservation surgery were more likely to refuse axillary evaluation (OR=0.155, 95%CI: 0.103 to 0.233, P=0.000). There were no significant differences in RFS and LRRFS in patients with different axillary evaluation choices. Conclusions: The investigation in trends and influence factors of different axillary evaluation choices provided basis on surgical precision medicine in DCIS patients. Patients received SLNB increased significantly. The independent influence factors of axillary evaluation were nuclear grade, tumor size and surgical methods. There was no significant differences in prognosis among the groups receiving different axillary evaluations.

Genomic landscape of ductal carcinoma in situ and association with progression.

The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS. Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features. We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05). PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

A whole slide image-based machine learning approach to predict ductal carcinoma in situ (DCIS) recurrence risk

BackgroundBreast ductal carcinoma in situ (DCIS) represent approximately 20% of screen-detected breast cancers. The overall risk for DCIS patients treated with breast-conserving surgery stems almost exclusively from local recurrence. Although a mastectomy or adjuvant radiation can reduce recurrence risk, there are significant concerns regarding patient over-/under-treatment. Current clinicopathological markers are insufficient to accurately assess the recurrence risk. To address this issue, we developed a novel machine learning (ML) pipeline to predict risk of ipsilateral recurrence using digitized whole slide images (WSI) and clinicopathologic long-term outcome data from a retrospectively collected cohort of DCIS patients (n = 344) treated with lumpectomy at Nottingham University Hospital, UK.MethodsThe cohort was split case-wise into training (n = 159, 31 with 10-year recurrence) and validation (n = 185, 26 with 10-year recurrence) sets. The sections from primary tumors were stained with H&E, then digitized and analyzed by the pipeline. In the first step, a classifier trained manually by pathologists was applied to digital slides to annotate the areas of stroma, normal/benign ducts, cancer ducts, dense lymphocyte region, and blood vessels. In the second step, a recurrence risk classifier was trained on eight select architectural and spatial organization tissue features from the annotated areas to predict recurrence risk.ResultsThe recurrence classifier significantly predicted the 10-year recurrence risk in the training [hazard ratio (HR) = 11.6; 95% confidence interval (CI) 5.3–25.3, accuracy (Acc) = 0.87, sensitivity (Sn) = 0.71, and specificity (Sp) = 0.91] and independent validation [HR = 6.39 (95% CI 3.0–13.8), p < 0.0001;Acc = 0.85, Sn = 0.5, Sp = 0.91] cohorts. Despite the limitations of our cohorts, and in some cases inferior sensitivity performance, our tool showed superior accuracy, specificity, positive predictive value, concordance, and hazard ratios relative to tested clinicopathological variables in predicting recurrences (p < 0.0001). Furthermore, it significantly identified patients that might benefit from additional therapy (validation cohort p = 0.0006).ConclusionsOur machine learning-based model fills an unmet clinical need for accurately predicting the recurrence risk for lumpectomy-treated DCIS patients.

Survival benefit of postoperative radiotherapy for ductal carcinoma in situ after breast-conserving surgery: a Korean population-based cohort study.

It has been accepted that radiation therapy (RT) for ductal carcinoma in situ (DCIS) has no survival benefit despite increasing local control. However, a recent large database study reported a small but significant benefit. Using a Korean population-based large database, we examined the survival benefit of RT for DCIS after breast-conserving surgery (BCS) and analyzed which subgroup might derive benefit from it. Data from 6038 female DCIS patients who underwent BCS with or without RT between 1993 and 2012 were included in this study. We used propensity score analysis to control for differences in baseline characteristics. Before adjusting, patients who received RT were more likely to have a large-sized tumor, poor histologic grade, poor nuclear grade, and less hormone receptor positivity. Ten-year overall survival (OS) rates were 95.0% in the non-RT group and 97.1% in the RT group (p < 0.001). After adjusting, previously noted differences of characteristics were substantially reduced, and then ten-year OS rates were 94.3% in the non-RT group and 97.6% in the RT group (p = 0.001). When examining the benefit of RT according to proposed prognostic scores, patients with a score of 0 showed no difference in OS by adding RT after BCS, whereas those with high scores demonstrated a significant benefit. We demonstrated the significant OS benefit of postoperative RT after BCS based on a large database, and for the first time beyond the western population. The omission of RT for selected patients to prevent overtreatment needs to be more elaborately studied.

DCIS with Microinvasion: Is It In Situ or Invasive Disease?

Ductal carcinoma in situ (DCIS) with microinvasion (DCISM) can be challenging in balancing the risks of overtreatment versus undertreatment. We compared DCISM, pure DCIS, and small volume (T1a) invasive ductal carcinoma (IDC) as related to histopathology, treatment patterns, and survival outcomes. Women ages 18-90years who underwent breast surgery for DCIS, DCISM, or T1a IDC were selected from the SEER Database (2004-2015). Multivariate logistic regression and Cox proportional hazards models were used to estimate the association of diagnosis with treatment and survival, respectively. A total of 134,569 women were identified: 3.2% DCISM, 70.9% DCIS, and 25.9% with T1a IDC. Compared with invasive disease, DCISM was less likely to be ER+ or PR+ and more likely to be HER2+. After adjustment, DCIS and invasive patients were less likely to undergo mastectomy than DCISM patients (DCIS: OR 0.53, 95% CI 0.49-0.56; invasive: OR 0.86, CI 0.81-0.92). For those undergoing lumpectomy, the likelihood of receiving radiation was similar for DCISM and invasive patients but lower for DCIS patients (OR 0.57, CI 0.52-0.63). After adjustment, breast-cancer-specific survival was significantly different between DCISM and the other two groups (DCIS: HR 0.59, CI 0.43-0.8; invasive: HR 1.43, CI 1.04-1.96). However, overall survival was not significantly different between DCISM and invasive disease, whereas patients with DCIS had improved OS (HR 0.83, CI 0.75-0.93). Although DCISM is a distinct entity, current treatment patterns and prognosis are comparable to those with small volume IDC. These findings may help providers counsel patients and determine appropriate treatment plans.

Surgical management of ductal carcinoma in situ of the breast: A large retrospective study from a single institution.

Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasize on re-operation rates and outcome. Breast ductal carcinoma in situ cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n=1249). Clinicopathological data were collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumor in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analyzed. 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumor grade, size >40mm, and associated with comedo necrosis and Paget's disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumor tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast-conserving surgery (BCS) were reduced from approximately 70% to 23%, and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing.

Abstract 1451: HER2 peptide pulsed dendritic cell vaccine induce senescence and eliminates disseminated cancer cells in a preventive model of transgenic HER2/neu breast cancer

Abstract HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. The detection of disseminated cancer cells (DCCs) in early-stage DCIS likely to become invasive and manifests prominent role in metastasis and recurrence. The HER2-positive DCCs can easily escape targeted therapies and become a source of tumor recurrence suggesting that targeting these cells may provide eminent benefits in HER2 positive breast cancer patients. Unfortunately, the conventional therapies that target these DCCs are limited. Previous studies from our lab have shown that HER2 peptide pulsed-DC1 (HER2-DC1) vaccine induced 30% complete response (pCR) in DCIS patients. However, little is known about the effect of HER2-DC1 vaccine on DCCs. Here, we investigated the efficacy of HER2-DC1 vaccine on DCCs in a transgenic HER2 mammary cancer model (neuT). The key features of this model are each one of ten mammary glands develops an independent carcinoma that slowly progresses from a microscopic lesion to an invasive tumor and metastasis is mainly driven by DCCs. Since this model mimics some of the most critical features of human disease, we evaluated the efficacy of HER2-DC1 vaccine on DCCs. Mice received six doses of HER2-DC1 vaccine subcutaneously twice a week. The spontaneous tumor development in the mammary glands of NeuT mice was examined once a week by ultrasound until the age of week 16. HER2-DC1 vaccine significantly prevented spontaneous tumor growth in NeuT mice. Remarkably, HER2-DC1 vaccine treatment significantly decreased HER2+CYT8/18+Ki-67+ proliferative DCCs (2%, p&amp;lt;0.002) in the bone marrow (BM-DCCs) compared to untreated mice (6%) by flow cytometry. We also observed increased senescent DCCs (82%, p&amp;lt;0.0001 compared to untreated mice, 37%) by a β-gal assay. BM-DCCs in HER2-DC1 vaccinated mice had reduced expression of Ki-67 compared to untreated mice. Multicolor flow cytometry demonstrated elevated levels of CD4 T cells (2 fold increase) and CD8 T cells (1 fold increase) in the bone marrow after HER2-DC1 vaccination compared to untreated mice. Importantly, accumulation of CD4 T cells (5 fold increase), CD8 T cells (19 fold increase) and B cells (100 fold increase) was observed in the mammary glands of HER2-DC1 vaccinated mice with strong anti-HER2 Th1 immune responses. Notably, HER2-DC1 vaccine led to an increased in the M1 macrophage phenotype (3 fold increase) and decreased M2 type (8 fold decrease) at the tumor site. Treatment of DCCs with Th1 cytokines, IFN-γ or TNF-α significantly induced senescence (76.3%, p&amp;lt;0.0001) in cultured DCCs compared to untreated cells (26%) in vitro. These results describe the novel role of HER2-DC1 vaccine in targeting DCCs and a possible role in prevention of metastasis and recurrence. Citation Format: Ganesan Ramamoorthi, Krithika Kodumudi, Colin Synder, William Dominguez-Viqueira, Scott Kidd, Shari Pilon-Thomas, Brian Czerniecki. HER2 peptide pulsed dendritic cell vaccine induce senescence and eliminates disseminated cancer cells in a preventive model of transgenic HER2/neu breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1451.