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Purpose:Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).Patients and Methods:Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.Results:Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.Conclusions:Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.

PDF - 160KB, Supplementary Figure 1 -Histograms of BUM model to the P-values from the ANOVA test of race/ethnicity by breast cancer subtype in 177 proteins. Supplementary Figure 2 - Histograms of BUM model to the P-values from the ANOVA test of race/ethnicity by breast cancer subtype in 16,438 probe sets. Supplementary Figure 3 - Unsupervised clustering of the significant 384 probe sets with FDR

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Background: Differences in gene or protein expression patterns between breast cancers according to race/ethnicity and cancer subtype.Methods: Transcriptional profiling was performed using Affymetrix HG-U133A platform in 376 patients and reverse phase protein array analysis (RPPA) was done for 177 proteins in 255 patients from a separate cohort. Unsupervised clustering was conducted, as well as supervised comparison by race and tumor subtype. Standard statistical methods, BRB-Array tools, and Ingenuity Pathways software packages were used to analyze the data.Results: Median age was 50 years in both the cohorts. In the RPPA cohort, 54.5% of the tumors were hormone receptor–positive (HR-positive), 20.7% HER2-positive, and 24.71% triple-negative (TNBC). One hundred and forty-seven (57.6%), 47 (18.43%), and 46 (18.1%) of the patients were White, Hispanic, and Black, respectively. Unsupervised hierarchical clustering of the protein expression data showed no distinct clusters by race (P values were 0.492, 0.489, and 0.494 for the HR-positive, HER2-positive, and TNBC tumors respectively). In the gene expression cohort, 54.2% of the tumors were HR-positive, 16.5% HER2-positive, and 29.3% TNBC. Two hundred and sixteen (57.5%), 111 (29.52%), and 32 (8.52%) patients were White, Hispanic, and Black, respectively. No probe set with a false discovery rate (FDR) of Conclusions: We did not detect a significant variation in RNA or protein expression comparing different race/ethnicity groups of women with breast cancer.Impact: More research on the complex network of factors that result in outcomes differences among race/ethnicities is needed. Cancer Epidemiol Biomarkers Prev; 23(2); 316–23. ©2013 AACR.

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Background: (Neo) Adjuvant chemotherapy decreases the risk of recurrence and improves overall survival among breast cancer patients, however, delays in chemotherapy initiation are associated with adverse outcomes. While the determinants of such delays are not clearly understood, delays are more likely to occur in those: with additional comorbidities, belonging to a low social economic status, without a partner, enrolled in public health insurance, or who identify as Latino/Hispanic or Black/African Americans. The causes of disparities in the delivery of care among breast cancer patients are complex and include interrelated social, economic, cultural, environmental, and health system factors. The goal of Project Start was to conduct a qualitative investigation to assess and identify the multilevel factors contributing to the barriers and facilitators of initiating chemotherapy in the context of breast cancer treatment. Methods: We enrolled English or Spanish speaking women, ≥18 years, diagnosed with primary invasive breast cancer who experienced a ≥ 60 days delay to chemotherapy initiation, whether adjuvant or neoadjuvant (determined from the date of surgery or the date of histopathologic diagnosis). Participants were identified through electronic medical record review and approached in clinic to participate. Semi-structured interviews were conducted in-person or over the phone to explore participants’ perceptions about individual, community, and system level barriers and facilitators contributing to starting chemotherapy. Interviews were audio-recorded, transcribed verbatim, and coded using the Sort and Sift, Think and Shift qualitative approach to identify concepts and topics within and across transcripts. Participants completed brief questionnaires collecting sociodemographic characteristics, health literacy and numeracy, physician trust, and social support to supplement the qualitative data. Quantitative data were summarized using descriptive statistics. Results: Seventeen participants completed semi-structured interviews and questionnaires (mean age 49.9 years; range 30-70 years). Participants identified as: Latina (n=7); Black (n=2); and non-Latina White (n=8). Most completed interviews in English (n=15) and over half had lower educational attainment (i.e., middle school, high school, associate’s degree; n=10). While the interview included questions addressing chemotherapy delays, explicit insight into chemotherapy delay was rare among participants. When discussing their process to chemotherapy, participants described barriers and facilitators at the patient, family, medical, and community levels contributing to their timeline to start chemotherapy. At the patient level, participants discussed their fear and anxiety, the command over their diagnosis, and the importance of playing an active role in treatment. Within the family realm, participants described their family roles (e.g., caregiving, income), treatment costs, and the need for emotional support (e.g., not shutting family members out). Participants sought out and relied heavily on support from their communities (e.g., churches, other patients, survivors). Finally, patients described their reliance on the medical team for information, the trust needed to navigate their treatment process, and the challenge of managing information associated with their treatment. Conclusions: Women expressed the importance of managing individual stressors, family roles and support, medical information, and community support. Activating women to be engaged in the treatment process at multiple levels appeared to facilitate initiating chemotherapy. Multilevel interventions that engage the patient, family, medical team, and community may provide the supports to enable the initiation of timely chemotherapy. Citation Format: Ashley J. Housten, Edna Paredes, Cassandra L. Harris, Mariana Chavez-MacGregor. Why do women experience a delay to chemotherapy? A qualitative analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-75.

Background: Triple negative breast cancer (TNBC) disproportionally impacts Black and Hispanic women and is suggested to be partly responsible for disparities observed in breast cancer mortality. We sought to evaluate the impact of race/ethnicity on TNBC molecular subtype, immune profile, pathologic complete response (pCR) and recurrence free survival (RFS). Methods: The ARTEMIS trial (NCT02276443) uses imaging response and molecular profiling to personalize neoadjuvant chemotherapy in early stage TNBC. After 4 cycles of AC, patients with chemo-sensitive disease receive standard taxane-based therapy, while those with chemo-resistant disease are offered therapeutic trials based upon molecular profiling. Pathologic response was assessed at surgery. Patients self-reported race/ethnicity was categorized as Asian, Black/African-American, Hispanic/Latino and White (non-Hispanic). Patients were excluded if no race or ethnicity was reported. Clinical and pathologic factors were recorded and compared. Gene expression profiling was performed by RNAseq to determine Vanderbilt signature. PD-L1 and Androgen Receptor (AR) were determined by immunohistochemistry. Frequencies at which various factors were observed by race/ethnicity were calculated and Fisher’s exact test performed to determine statistical significance. Kaplan-Meier analysis was used to estimate survival stratified by pCR status and race/ethnicity. Results: Among 321 women enrolled in ARTEMIS, 26 (8.1%) were classified as Asian, 50 (15.6%) as Black, 59 (18.4%) as Hispanic and 186 (57.9%) as White. Demographic and clinical features were similar, except Black women were more likely to have BMI ≥30 (70.0%, p Conclusion: Among this population of patients with TNBC treated with neoadjuvant chemotherapy there was no statistically significant difference observed in TNBC Vanderbilt signature, PD-L1 staining, sTIL, pCR or RFS by race/ethnicity. Asian women were found to have a higher incidence of AR-positive subtype. Numerically higher rates of N3 stage in Black women and RCB-III classification in Black and Hispanic women were identified, however not statistically significant. Larger cohorts of patients are needed to further investigate these findings. Table 1. TNBC profiling compared by race/ethnicity.Total n (%)Asian n (%)Black n (%)Hispanic/Latino n (%)White n (%)p valueVanderbilt signature n (%) Basal like (BL1) Basal like 2 (BL2) Immunomodulatory (IM) Luminal androgen receptor (LAR) Mesenchymal (M) Mesenchymal stem-like (MSL) Unstable (UNS)231 50 (21.6) 25 (10.8) 42 (18.2) 22 (9.5) 48 (20.8) 14 (6.0) 30 (13.0)21 (9.1) 0 (0.0) 4 (19.0) 5 (23.8) 3 (14.3) 5 (23.8) 1 (4.8) 3 (14.3)35 (15.2) 9 (25.7) 5 (14.3) 6 (17.1) 2 (5.7) 7 (20.0) 1 (2.9) 5 (14.3)43 (18.6) 14 (32.5) 3 (7.0) 10 (23.2) 5 (11.6) 6 (14.0) 2 (4.7) 3 (7.0)132 (57.1) 27 (20.5) 13 (9.8) 21 (15.9) 12 (9.1) 30 (22.7) 10 (7.6) 19 (14.4)NSAndrogen Receptor n (%) Positive (>=10%) Negative (1298 212 (71.1) 86 (28.9)24 (8.1) 15 (62.5) 9 (37.5)47 (15.8) 33 (70.2) 14 (29.8)57 (19.1) 40 (70.2) 17 (29.8)170 (57.0) 124 (72.9) 46 (27.1)NSStromal tumor infiltrating lymphocytes (sTIL) n (%) High (>=20%) Low ( Citation Format: Mediget Teshome, Ryan Sun, Elizabeth E. Ravenberg, Abenaa Brewster, Mariana Chavez-MacGregor, Jason B. White, Stacy Moulder. Impact of race/ethnicity on triple negative breast cancer molecular features, treatment response and clinical outcomes in patients receiving neoadjuvant therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-12.

BACKGROUND: Delays in adjuvant chemotherapy initiation have a detrimental effect in outcomes and are more frequently seen among racial/ethnic minorities, uninsured patients and those with low socioeconomic status. A provision in the Affordable Care Act called for expansion of Medicaid eligibility in order to cover more low-income Americans. In this study we evaluate the impact of Medicaid expansion on racial disparities in time to adjuvant chemotherapy administration in a large cohort of BC patients.METHODS: Women (aged 40-64) diagnosed with primary invasive BC (stage I-III) between 01/01/2007 and 12/31/2016 were identified in the National Cancer Database. All patients underwent surgery as initial treatment modality and received adjuvant chemotherapy within 6 months of surgery. Chemotherapy delay was defined as >60 days from surgery to the first dose of chemotherapy. The cohort was limited to those residing in states that underwent Medicaid expansion in 2014 (KY, NV, CO, OR, NM, WV, AR, RI, AZ, MD, MA, ND, OH, IA, IL, VT, HI, NY, DE). For comparison purposes, 2007-2013 was considered the pre-expansion period and 2014-2016 the post-expansion period. We calculated difference-in-difference (DID) estimates using multivariable linear regression models. Results are presented as adjusted differences (in % points) between race/ethnicity groups in the pre and post-expansion periods, and as adjusted DID with 95% CI. A negative DID estimate indicates that Medicaid expansion reduces the racial/ethnic disparity in chemotherapy administration delay. The parallel trend assumption was tested. Variables in the final model included age, comorbidities, BC subtype, insurance status, distance to treatment facility, region, education, household income, facility type and facility case volume. RESULTS: 105,385 patients were included (median age 53), of them 75,663 (71.8%) were diagnosed in the pre- and 29,722 (28.2%) in the post-expansion period. 77.5% of the patients were White, 11.7% Black and 4.9% Hispanic. The proportion of patients experiencing chemotherapy initiation delays was greater among Blacks and Hispanics in both study periods compared to Whites. The proportion of chemotherapy delays decreased for all races between the pre and the post-expansion period. We observed a statistically significant decrease in the chemotherapy initiation racial disparity. The adjusted DID was -2% (95%CI -3.8 to -0.3, P=0.02) between Whites and Blacks was and -3% (95%CI -5.5 to -0.5, P=0.02) between Whites and Hispanics. In a subgroup analysis among 10,777 Medicaid patients the parallel trend assumption was not valid, therefore we estimated the DID between Whites and Blacks using a propensity-score based weight sample, identifying a reduction in the racial disparity of even greater magnitude (DID -9.1% [-14.4 to -3.8, P CONCLUSIONS: We demonstrate that Medicaid expansion reduced racial disparities by decreasing the proportion of Blacks and Hispanics experiencing delays in adjuvant chemotherapy initiation and decreasing the gap that exists when compared to Whites. These important results highlight the positive impact of policies aimed at improving equity and increasing access to health care. Pre-ExpansionPost-ExpansionRaceNAdjusted Rate of Delayed Chemo > 60 daysAdjusted Difference Between White Race (% points)NAdjusted Rate of Delayed Chemo > 60 daysAdjusted Difference Between White Race, (%points)Adjusted DID (95% CI), Percentage PointsPWhite5930527.202232524.20RefRefBlack856036.18.9372031.16.9-2.0 (-3.8 to -0.3)0.02Hispanic343232.35.1170426.32.1-3.0 (-5.5 to -0.5)0.02 Citation Format: Mariana Chavez-MacGregor, Xiudong Lei, Hui Zhao, Tina Shih, Sharon H Giordano. Impact of Medicaid expansion on racial disparities in time to adjuvant chemotherapy administration among breast cancer (BC) patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS1-10.

Purpose: Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane). Patients and Methods: Postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy. Results: Patients (N = 116) received triplet therapy (n = 83 in the dose-escalation phase; n = 33 in the dose-expansion phase). A dose-dependent drug–drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher ESR1 gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response. Conclusions: Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR+, HER2− ABC.

Background: Early stage breast cancer patients benefit from adjuvant chemotherapy, but delays in initiation of treatment can negatively impact outcomes. Delays may be more common in older women. In this study we evaluate the survival impact of delays in adjuvant chemotherapy initiation in patients over 65 years of age and identify factors associated with delays. Methods: Patients age 66 years and older diagnosed between 2001 and 2013 with localized or regional breast cancer were identified in the SEER-Medicare and Texas Cancer Registry-Medicare databases. All patients received adjuvant chemotherapy within 9 months of surgery. Patients were required to have continuous Medicare Parts A and B coverage and no HMO enrollment 12 months before and 12 months after diagnosis. We grouped patients according to time from surgery to chemotherapy in 4 groups: 0-30, 31-60, 61-90, and > 90 days. Delayed chemotherapy initiation was defined as > 90 days. We used multivariable logistic regression to identify predictors of delayed chemotherapy. We estimated overall survival (OS) and breast cancer-specific survival (BCSS) using Kaplan-Meier method. Inverse probability treatment weights were applied to survival analyses. Cox proportional hazard models were used to determine the association between delays in chemotherapy and outcome after adjustment for other variables. Results: 25,902 women were included in the analysis, and the median age was 71 years. The median time from surgery to chemotherapy was 43 days. From 2001-2013 this interval increased from 38 days to 47 days (p < 0.001). Chemotherapy delays were observed in 10.6% of the patients. In multivariable analysis, factors associated with an increased risk in chemotherapy delays included: older age, black or Hispanic race/ethnicity, being single, more comorbidities, hormone receptor positivity, mastectomy, Oncotype DX testing, and having a full state buy-in Medicare plan. Chemotherapy delay was associated with worse OS. The 5 year OS estimates for patients receiving chemotherapy 0-30, 31-60, 61-90 and > 90 days after surgery were 0.82, 0.81, 0.80 and 0.73 respectively (p < 0.001). A similar trend was seen with BCSS (p < 0.001). After multivariable adjustment chemotherapy delay was associated with worse OS (HR=1.32, 95%CI 1.24-1.40) and BCSS (HR=1.38, 95%CI 1.24 - 1.52) compared with patients in the 0-30 day category. In a stratified analysis among patients with known breast cancer subtype, we observed that a delay in adjuvant chemotherapy initiation was associated with worse OS among patients with hormone receptor-positive (HR=1.45, 95%CI 1.05-2.01), HER2-positive (HR=1.52, 95%CI 1.03-2.23), and triple negative (HR=1.90, 95%CI 1.32-2.73) breast cancer. Discussion: Delays in initiating adjuvant chemotherapy in older women with breast cancer are associated with worse OS and BCSS. Our data demonstrates that delays should be avoided and should encourage providers to initiate chemotherapy ≤ 90 days after surgery. In addition, the multidisciplinary medical team should be aware of the socioeconomic factors that may impact patients’ ability to receive timely treatment. Further studies should seek to elucidate the causes of these inequities in care. Citation Format: Demetria Smith-Graziani, Xiudong Lei, Sharon Giordano, Hui Zhao, Meghan Karuturi, Mariana Chavez-MacGregor. Delayed initiation of adjuvant chemotherapy in older women with breast cancer [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 P2-14-04.

BACKGROUND: Raloxifene is a selective estrogen receptor modulator that has demonstrated to reduce breast cancer risk and reduce the incidence of vertebral fractures. Based on these effects, raloxifene is used as a risk reduction agent and to prevent osteoporosis in postmenopausal women. Little is known about the raloxifene adherence rates or the relationship between adherence and breast cancer incidence. METHODS: Women 60 years or older without a breast cancer history were identified in the MarketScan database (2008-2015). We identified women who received raloxifene by searching for prescription claims. Proportion of days covered (PDC) were calculated, adherence was defined as a PDC >80% in the first year after initial prescription claim. We identified factors associated with adherence. ICD-9 codes were used to identify incident cases of invasive breast cancer and cumulative incidence rates were calculated. A multivariable Cox model with propensity score method (matching variables included year of claim, age, comorbidities and family history of breast cancer) was used to evaluate the association between raloxifene adherence and breast cancer risk. All statistical tests were two-sided. RESULTS: A total of 16,179 women were included in the analysis. We identified that during the first year of treatment 6,716 (40.2%) women had a PDC >80% and thus were considered to be adherent. Factors associated with increased adherence included the use of generic drug, mail order of 90 days supply and family history of breast cancer (all p CONCLUSIONS: Among women 60 years of age or older receiving raloxifene, adherence to therapy was associated with lower risk of invasive breast cancer. Efforts to ensure adherence and compliance are crucial so patients can receive full benefit from this therapy. Citation Format: Chavez-MacGregor M, Lei X, Zhao H, Bevers TB, Brewster A, Giordano SH. Impact of raloxifene adherence in breast cancer risk [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 P4-10-02.

Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is FDA-approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The goal of this study was to evaluate the pathologic complete response (pCR) rate for neoadjuvant HP-containing regimens compared to H-containing regimens and report the 3-year relapse-free survival (RFS) for patients who had a pCR compared to those with residual disease (RD). Methods: All patients with stage II-III non-inflammatory HER2+ BC who received neoadjuvant H-containing or HP-containing therapy and underwent definitive breast and axillary surgery were identified from 2005 to 2016 through an institutional database. Medical records were examined for patient demographics, breast cancer stage, pathology results, surgical outcomes, and treatment details. pCR was defined as ypT0/is, ypN0. RFS was defined as the interval from surgery to date of last followup or death from any cause. Descriptive statistics, Cox proportional hazards, and Kaplan-Meier estimates were used for statistical analysis. Results: Patient characteristics and results by pCR or RD status are shown in the table below. The median age was 51 (22-84) years for the HP group and 50 (21-87) years for the H group. The median follow-up time was 1.9 (0-4.2) years for the HP group and 5.3 (0.1-12) years for the H group. For the HP group, the 3-year RFS was 98% (95% CI: 95, 100) for the pCR group and 90% (95% CI: 83, 97) for the RD group; HR 0.17 (0.04, 0.82), p=0.012. For the H group, the 3-year RFS was 91% (95% CI: 88,94) for the pCR group and 75% (95% CI: 71-79) for the RD group; HR 0.31 (0.22, 0.44), p Conclusion: Patients who achieve pCR have an improved 3-year RFS compared to patients who have RD. Treatment with HP-containing neoadjuvant regimens is associated with a high 3-year RFS. VariableHP (n=215)H (n=807) pCR n=121RD n=94pCR n=399RD n= 408Age at Diagnosis Citation Format: Murthy RK, Raghavendra AS, Hess KR, Barcenas CH, Lim B, Moulder SL, Giordano SH, Mittendorf EA, Thompson A, Ueno NT, Valero V, Litton JK, Tripathy D, Chavez-Macgregor M. 3-year relapse-free survival of stage II-III HER2-neu positive breast cancer treated with pertuzumab and trastuzumab-containing neoadjuvant therapy compared to trastuzumab-containing 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 P6-17-04.

Background: BCS has been historically associated with a high re-excision rate, driven in part by lack of consensus on what constitutes an adequate negative margin. The SSO-ASTRO consensus guideline on invasive margins defined a negative margin as no ink on tumor based on evidence suggesting that more widely clear margins do not further decrease the risk of recurrence, potentially reducing the need for re-excision. In a large nationwide cohort of breast cancer patients undergoing BCS for invasive breast cancer we evaluate the rates of re-excision following BCS before and after the SSO-ASTRO consensus guidelines were disseminated. Methods: Breast cancer patients undergoing BCS for invasive breast cancer between January 2012 and December 2015 were identified among female beneficiaries in the MarketScan database. Patients receiving chemotherapy before surgery were excluded. Based upon presentation of the guideline recommendations in October 2013, the pre-guideline period was defined from January 2012 to September 2013. On-line publication of the guideline in February 2014 led to definition of the post-guideline period from March 2014 onwards. The peri-guideline period was defined as the time between the pre and post-guideline intervals. Any re-excision or mastectomy within 3 months of initial BCS was identified using ICD-9 or CPT codes. Overall re-excision rates and 95% CI were calculated; groups were compared using X2test. We used a regression model to evaluate the association between pre-peri-post guideline period and re-excision while adjusting for important covariates. Results are expressed as risk ratios (RRs) and 95%CI. Results: A total of 38,573 patients were included (20,159 in the pre-guideline, 4,607 peri-guideline and 13,807 post-guideline). The overall re-excision rate was 23.9% (95%CI 23.4-24.3). The pre-guideline re-excision rate was 25.3% (95%CI 24.7-29.9) compared to 21.6% (95%CI 20.9-22.3] in the post-guideline period. (p Conclusions: There has been a statistically significant decrease in the re-excision rate after BCS associated with the time of the dissemination of the SSO-ASTRO consensus guideline on invasive margins. The wide geographical variation observed suggests differences in the adoption rates. Our study confirms the impact that guidelines have modifying patterns of practice, reducing the frequency of unnecessary surgical interventions. Citation Format: Chavez-MacGregor M, Lei X, Morrow M, Giordano SH. Impact of the SSO-ASTRO consensus guidelines on invasive margins on the re-excision rate among patients undergoing breast conserving surgery (BCS) [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 P2-12-03.

BACKGROUND: The current American Joint Committee on Cancer (AJCC) breast cancer staging system provides important prognostic information, however its use is limited by the lack of data incorporating prognostic and predictive biological markers. In this study we sought to determine the relationship between stage, breast cancer subtype, grade and outcome in a large population-based cohort, and to develop a risk score point-based system incorporating biological factors to the current AJCC staging system. METHODS: Patients diagnosed with primary breast cancer stage I-IV, between 2005-2008 were identified in the California Cancer Registry. For patients with stage I-III disease, pathological stage was recorded. For those with stage IV, clinical stage was used. 5 year-breast cancer specific survival (BCSS) and overall survival (OS) rates were determined for each potential TNM combination according to breast cancer subtype. Cox proportional hazard models were used to identify independent predictors of outcome. A risk score point-based system (range 0-3 points) was created to complement the current anatomic AJCC staging system. One point was assigned for each one of the following tumor characteristics: hormone receptor (HR)-negative status, HER2-negative status and grade 3. Survival probabilities between groups were compared using log-rank test. Multivariable analysis models according to stage and risk score were performed for BCSS and OS. RESULTS: A total of 43,938 patients were included. The 5-year BCSS and OS for each TNM combination differed according to breast cancer subtype. The best outcomes were seen among HR-positive patients followed closely by those with HER2-positive and HR-positive tumors with the worst outcomes observed among patients with triple negative tumors. In a multivariable model, after adjusting for stage, treatment variables and other important confounders, ER negative status (OR 2.14; 95%CI 1.98-2.30), HER2-negative status (OR= 1.24; 95%CI1.14-1.34) and grade 3 (OR=2.03; 95% CI 1.88-2.20) were independent predictors of BCSS. Our risk score system separated patients into 4 risk groups within each stage category (all P Hazard ratios for BCSS according to stage and risk score.Stage/Risk ScoreHazard Ratio95%CII-0Reference I-10.630.42-0.97I-22.811.87-4.23I-34.902.79-8.61IIA-03.652.26-5.91IIA-12.241.50-3.33IIA-25.873.94-8.73IIA-39.356.24-13.99IIB-04.763.13-7.24IIB-15.043.37-7.53IIB-29.465.63-15.92IIB-314.599.78-21.79IIIA-09.136.12-13.62IIIA-17.384.92-11.06IIIA-212.017.14-20.19IIIA-332.5421.59-49.04IIIB-018.9712.62-28.52IIIB-119.0512.68-28.61IIIB-228.3418.91-42.47IIIB-335.6121.33-59.43IIIC-011.525.84-22.74IIIC-115.766.07-40.94IIIC-226.7716.74-42.83IIIC-356.6336.60-87.60IV-049.9330.64-81.36IV-167.4545.36-100.23IV-2107.6272.36-60.07IV-3164.04107.18-251.04 CONCLUSIONS: Incorporating biological factors to the current AJCC staging system provides more accurate prognostic information and reflects current treatment practice. The proposed risk score improves the AJCC breast cancer staging system and should be incorporated in the upcoming revision. Citation Format: Chavez-MacGregor M, Mittendorf EA, Clarke CA, Lichensztajn DY, Hunt KK, Giordano SH. Improving the AJCC breast cancer staging system by incorporating tumor biomarkers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-02.

Background: The 7th edition AJCC staging system provides prognostic information based on the anatomic extent of disease determined by the tumor size (T), lymph node status (N), and presence or absence of metastatic disease (M). Tumor biology, including grade, estrogen receptor (ER) status and HER2 status, which are known to have prognostic and predictive value, are not incorporated. This study was undertaken to evaluate a risk score that takes into account the tumor grade and other biomarkers that can be added to the current anatomic TNM staging system to improve stratification of patients with respect to disease specific survival (DSS) and overall survival (OS). Methods: A prospectively maintained database was used to identify 3,327 patients with non-metastatic invasive breast cancer who underwent surgery as a first intervention from January 2007 through December 2013. Clinicopathologic data were recorded including: age, grade, ER status, HER2 status, and pathologic stage. Pathologic stage was determined according to the 7th edition of the AJCC staging guidelines. ER status was recorded as the percentage of cells staining positive by immunohistochemistry (IHC). Prior to 2010, tumors were classified as ER positive if there was >10% staining. A cut-off of 1% was used for patients treated after 2010, consistent with the change in American Society of Clinical Oncology (ASCO) guidelines. HER2 status was defined as positive if 3+ on immunohistochemistry or gene amplification was shown on fluorescence in situ hybridization. A risk score was calculated by assigning one point for each of the following tumor characteristics: ER-negative status, HER2 negative status and grade 3. Univariate survival analyses according to AJCC stage (I, IIA, IIB, IIIA and IIIC) and risk score (0-3) were performed for DSS and OS using the Kaplan Meier method. Results: Median follow-up time was 5.0 years (range, 0.1 to 8.8). Five year DSS for the entire cohort was 97.9% (95% CI: 97.3%-98.4%). The distribution in risk score in the entire cohort was: risk score 0=81 (2.4%), 1=2289 (68.8%), 2=683 (20.5%), and 3= (8.3%). As shown in the table, for all AJCC stages, the 5-yr DSS and 5-yr OS varied according to risk score (p StageRisk Scoren5-yr DSS (%)95% CI5-yr OS (%)95% CII (IA and IB)036100 9780.4-99.6 1117399.498.7-99.796.795.4-97.6 227498.896.4-00.694.691.0-06.8 311996.691.1-98.793.887.5-97.0IIA031100 96.879.2-99.5 163499.497.5-99.897.194.7-98.4 223697.593.2-99.194.188.7-97.0 39891.081.8-95.788.278.5-93.8IIB011100 100 130996.992.6-98.894.689.6-97.2 210792.983.6-97.189.380.1-94.4 34091.575.6-97.291.575.6-97.2IIIA03100 100 113498.388.2-99.891.582.6-96.0 25092.277.2-97.590.375.7-96.3 3768.621.3-91.268.621.3-91.2IIIC00 13992.272.1-98.084.463.7-93.9 21680.851.4-93.480.851.4-93.4 31033.36.3-64.633.36.2-64.6 Conclusion: The current study demonstrates that incorporating the risk score with current AJCC staging significantly improves the ability to stratify breast cancer patients with respect to DSS and OS. We recommend that the risk score be incorporated into the forthcoming revision of the AJCC staging system. Citation Format: Mittendorf EA, Vila J, Yi M, Chavez-MacGregor M, Chen RL, Giordano SH, Hunt KK. Evaluation of a risk score based on biologic factors to enhance prognostic stratification by the American Joint Committee on Cancer (AJCC) Staging System [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-17.

Background: Tumor biology is an important prognostic factor in breast cancer. The 8th edition AJCC pathologic prognostic stage incorporates biologic factors (grade, ER, PR, and HER2 status) along with anatomic staging to improve risk stratification. Additional staging models have been proposed including Bioscore and Risk Score. The Bioscore assigns a score of 0-7 based on anatomic stage, ER, HER2, and grade. The Risk Score assigns a score of 0-3 to each anatomic stage group, with 1 point assigned for ER-negative, HER2-negative, or grade 3 status. The objective of this study was to compare the performance of these models in a large, population-based cohort of breast cancer patients. Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was used to identify primary stage I-IV breast cancer patients diagnosed in 2010. Patients were excluded for inflammatory carcinoma, neoadjuvant therapy, and missing data on receptors or tumor grade. 5-year disease specific survival (DSS) estimates were calculated using Cox regression for each staging model: AJCC anatomic stage, AJCC pathologic prognostic stage, Bioscore and Risk Score. Harrell concordance index (C-index) and Akaike Information Criterion (AIC) were used to compare each model in predicting DSS, with higher C-index and lower AIC indicating better predictive value and model fit. Results: 21,901 patients were included with a median age was 60 years. Median follow up was 52 months. All four staging models stratified DSS survival, with stepwise increases in hazard ratios and decrease in DSS for each increase in risk category (Table). The C-index of each model with biologic factors was higher than for anatomic stage, with the Risk Score having the highest C-index (0.832 for the anatomic stage; 0.856 for pathologic prognostic stage; 0.855 for Bioscore; and 0.864 for Risk Score). AIC was lowest for Risk Score (27315 for anatomic stage; 26874 for prognostic stage; 27120 for Bioscore; and 26753 for Risk Score), suggesting the best model fit for staging. Discussion: Staging models incorporating biologic factors perform better than anatomic staging alone. The Risk Score has the lowest AIC and may be the easiest to use as it simply assigns 1 point each for ER-negative, HER2-negative, and grade 3 tumors to each anatomic stage. In addition, the Risk Score has the added benefit of being the only staging system to stratify stage IV disease. We advocate for consideration of the Risk Score as an alternative to the pathologic prognostic stage for ease of use, optimal communication with patients and providers, and to standardize future clinical trials. Table. 5-yr estimates of DSS in 21,464 breast cancer patients in 4 models of breast cancer stagingAnatomic Stage5-yr DSSPrognostic Stage5-yr DSSBioscore5-yr DSSRisk Score5-yr DSSIA98.6IA98.7098.9IA098.9IB96.3IB93.7199.1199.2IIA94.5IIA90.1297.5297.1IIB92IIB84.2393.2392.8IIIA83.3IIIA80.5488.3IIA096.7IIIB73.2IIIB72.3570.2197.7IIIC68.6IIIC53.3656.2291.0IV38.8IV38.8732.2386.8IIB096.6194.7290.4380.4IIIA092.8190.0274.9365.2IIIB096.0180.3269.6353.9IIIC063.3178.0268.2339.7IV061.7147.5230.3310.8 Citation Format: Olga Kantor, Jiangong Niu, Hui Zhao, Sharon H Giordano, Kelly K Hunt, Tari A King, Elizabeth A Mittendorf, Mariana Chavez-MacGregor. Comparative analysis of proposed strategies for incorporating biologic factors into breast cancer staging [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 P5-06-09.

Background: Neoadjuvant chemotherapy (NACT) is an integral component for locally advanced and large operable breast cancer. The sequence of taxanes followed by anthracyclines has been the standard of care for almost 20 years. Eribulin (E) is a synthetic analogue of halichondrin B with distinct mechanism of action as microtubule dynamics inhibitor. The FDA approved E in 11/2010 for the treatment of patients (pts) with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Research Hypothesis: Sequential administration of eribulin followed by FAC/FEC-regimen, would have greater pathologic complete response (pCR) rate than sequential administration of paclitaxel followed by FAC/FEC-regimen as primary systemic therapy for woman with operable breast cancer. Methods: This is a phase II, randomized, single institution, open label study. Pts were randomized 1:1 to receive E (1.4 mg/m2 d1 and d8 q 21 days x 4) or paclitaxel (P) (80 mg/m2 weekly x12). Both arms received FAC/FEC regimen x 4 doses followed by surgery. Eligible pts were women age 18 or older, Karnosfky PS 80 – 100, histologically confirmed invasive breast cancer, clinical T2-T3, N0-3, M0, HER2-negative. Baseline LVEF of > 50% and normal hematology, liver and kidney laboratory function tests. Primary endpoint was pathologic complete response (pCR/RCB-0) assessed by residual cancer burden (RCB). [Symmans F, 2007]. This protocol (2012-0167) IRB of The University of Texas, MD Anderson Cancer Center. Results: A preplanned interim analysis aimed to validate trial assumption was conducted after treatment of 54 randomized pts. Between 8/2012 to 7/2014, 54 pts were randomized and 49 were evaluable for pCR(27 P arm and 22 E arm). Tumor response by RCB is shown in the table. pCR rates were 30% and 4.5% in the P and E arm, respectively. Table 1.ResponsePaclitaxel - FAC/FEC Arm (N=27)Eribulin - FAC/FEC Arm (N=22)RCB 0 (pCR)8 (30%)1 (4.5%)RCB I6 (22.2%)1 (4.5%)RCB II9 (33%)10 (45%)RCB III4 (14.8%)10 (45%) 53 pts were evaluable for toxicity. The combination was safe with mostly grade 1 and 2 toxicities in both arms. In the P arm grade 3 peripheral neuropathy and neutropenia was seen in 3% and 7%, respectively. In the E arm one patient died due to multiorgan failure during cycle 1. There was no other grade 3-5 toxicity. Biomarker analysis using CTCs by AdnaTest Breast were evaluated in 39 pts at baseline. 5/39 pts were positive for CTCs. 3 pts had transcripts for EpCAM, 1 for Muc-1 and another had both. 30 pts had an additional sample post therapy. 2 pts were positive for CTC at baseline as well as at follow up (FU) visit at 180 days. None of the samples showed CTC-EMT at baseline or at FU visits. Conclusions: The interim analysis demonstrated that E arm lead to significantly lower pCR/RCB1 rate compared to P arm. Ongoing biomarker analyses include TIL, hot spot mutation analysis (HSMA) and molecular inversion probes (MIP) will be presented at the time of the meeting. Clinical trial information: NCT01593020. Citation Format: Alvarez RH, Koenig KB, Ensor JE, Ibrahim NK, Chavez-MacGregor M, Litton JK, Schwartz Gomez JK, Cyriac A, Krishnamurty S, Caudle AS, Shaitelman SF, Whitman GJ, Booser DJ, Reuben JM, Valero V. A randomized phase II neoadjuvant (NACT) study of sequential eribulin followed by FAC/FEC-regimen compared to sequential paclitaxel followed by FAC/FEC-regimen in patients (pts) with operable breast cancer not overexpressing HER-2. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-04.

Background: Approximately 30% of TNBCs are characterized by microarray as claudin-low, mesenchymal or mesenchymal stem cell-like and, unlike basal TNBCs, these tumors frequently harbor aberrations in the PI3K/AKT/mTOR axis, raising the possibility of targeting this axis to enhance chemotherapy response. Assays to clinically identify mesenchymal TNBCs are under development, but published results confirm that up to 30% are metaplastic breast cancers (MpBCs), a chemo-refractory group of tumors that contain a mixture of epithelial and mesenchymal components, making them identifiable by microscopy. As such, MpBCs serve as surrogates of response for potential regimens to treat mesenchymal TNBC. Methods: Patients (pts) with advanced TNBC (N=64) were treated with liposomal doxorubicin (D), bevacizumab (A) and the mTOR inhibitors temsirolimus (T) or everolimus (E). D and A were administered IV on day 1 with T (IV on days 1, 8 and 15) or E (continuous daily oral administration) using 21 day cycles. Response was assessed every 6 weeks using RECIST. When available, archived tissue was evaluated for aberrations in the PI3K pathway using standard assays. Results: Fifty-two MpBC pts were treated with DAT (N=39) or DAE (N=13). Median age was 58 (range 37-79); median # of prior regimens for metastatic disease was 1 (range 0-5). The objective response rate (ORR) was 21% [complete response (CR)=4 (8%); partial response (PR)=7 (13%)] and 10 (19%) pts had stable disease (SD)≥6 months for a clinical benefit rate (CBR) of 40%. Tissue was available for testing in 43 pts and 32 (74%) had a PI3K pathway activating aberration (Table 1). Response According to PI3K Pathway AberrationPI3K Pathway AberrationN (%)CRPRSD≥6monthsCBRORRAny PI3K Pathway Aberration*32 (74)46444%31%PIK3CA Mutation19 (59)23447%26%p.H1047R12 (38)21350%25%p.E545K6 (19)02150%33%p.G1007R1 (3)010100%100%p.E545A1 (3)0000%0%p.H1047Y1 (3)0000%0%p.K111E1 (3)0000%0%p.E542K1 (3)0000%0%PIK3CA Amplification1 (3)010100%100%PTEN Mutation5 (16)0000%0%PTEN Loss5 (16)02040%40%AKT1 p.E17K Mutation2 (6)0000%0%AKT2 Amplification1 (3)100100%100%PIK3R1 Mutation2 (6)01050%50%NF2 Mutation1 (3)100100%100%No PI3K Pathway Aberration11 (26)00545%0%*Some tumors had >1 aberration detected PI3K pathway activation was associated with a significant improvement in ORR (31 vs 0%; P=0.043) but not CBR (44 vs 45%; P=1.000) or progression-free survival (median 5.1 vs 2.9 months; P=0.352). A pt with 5 year+ durable CR (on maintenance everolimus) had a mutation in NF2. To emphasize the importance of pt selection, it is notable that 12 pts with non-metaplastic TNBC were also treated with DAT, and only 1 pt had a response (CR/PR=1; SD≥6 months=0), for a CBR that was significantly worse than pts with MpBC (8 vs 40%; P=0.045). Conclusions: Using MpBC as a surrogate of response, DAT/DAE has significantly better activity in mesenchymal compared to non-selected TNBC. Response is enhanced in pts with PI3K pathway activation. DAT/DAE should be tested in non-metaplastic, mesenchymal TNBC once a diagnostic assay is available. Citation Format: Basho RK, Gilcrease M, Murthy RK, Helgason T, Booser DJ, Karp DD, Meric-Bernstam F, Wheler JJ, Valero V, Albarracin C, Litton J, Chavez-MacGregor M, Ibrahim NK, Murray JL, Koenig KB, Hong D, Subbiah V, Kurzrock R, Janku F, Moulder S. Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer (TNBC): Evidence of efficacy and proof of concept from a phase I trial with dose expansion of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-02.

Background: We previously described a novel breast cancer staging system, the CPS+EG score, which incorporates pretreatment clinical stage, post-treatment pathologic stage, estrogen receptor (ER) status and nuclear grade to create an ordinal scale that is predictive of disease-specific survival (DSS) after receipt of neoadjuvant chemotherapy. The prior work predated (1997-2005) routine use of trastuzumab for patients with HER2+ disease. The current study was undertaken to update the staging system with a more contemporary cohort of patients to include patients with HER2+ disease receiving trastuzumab. The impact of using 1% as the cutoff for ER-positivity was also assessed. Methods: A cohort of 2377 patients treated with neoadjuvant chemotherapy from 2005-2012 was identified. Clinicopathologic characteristics, treatment regimens and patient outcomes were recorded. Patient scores were computed using two versions of the CPS+EG staging system with ER status categorized as positive if >10% or if >1%. Fits of the Cox proportional hazards (PH) model for the two sets of prognostic scores were compared using the Akaike Information Criterion (AIC). HER2 status was then added to the model and the likelihood ratio test was used to determine the improvement in fit. Results: Median follow-up time was 4.2 years (range, 0.5 to 11.7). Five year DSS was 89% (95% CI: 87%-90%). This cohort validated our previous finding that the CPS+EG score facilitates more refined categorization into prognostic subgroups than initial clinical or final pathologic stage alone (table). The AIC demonstrated that the CPS+EG model fits were nearly identical for ER status categorized using either cutoff, though the fit was slightly better for the >1% cutoff. There were 591 HER2+ patients included; all of them received trastuzumab-based chemotherapy. The improvement in the fit of the model when HER2 status was added was highly significant (p=0.00005) and incorporation of HER2 into the CPS+EG staging system by adding one additional point for HER2-negative status defined the bioscore (table) which again stratified patients with respect to prognosis. Conclusion: The current study demonstrates a novel bioscore that significantly improves a previously validated prognostic score in patients receiving neoadjuvant chemotherapy and allows the staging system to be applied to patients with HER2+ disease. We recommend that biologic markers and response to treatment be incorporated into the forthcoming revision of the AJCC staging system. Clinical Stage5-yr DSS (95%CI)Pathologic Stage5-yr DSS (95%CI)CPS+EG Score (1% cutoff for ER+)5-yr DSS (95%CI)Bioscore5-yr DSS (95%CI)0 097% (95-98%)098% (92-100%)097% (78-10)%)IA96% (75-99%)IA95% (92-97%)198% (96-99%)199% (95-100%)IIA96% (94-97%)IB90% (76-98%)294% (91-95%)297% (95-98%)IIB90% (87-92%)IIA91% (87-94%)387% (84-90%)393% (90-95%)IIIA85% (80-89%)IIB86% (81-90%)475% (69-80%)486% (82-89%)IIIB78% (70-85%)IIIA80% (75-84%)552% (40-63%)571% (64-77%)IIIC76% (70-81%)IIIB64% (42-80%)60648% (35-60%) IIIC64% (55-72%) 70 Citation Format: Mittendorf EA, Vila J, Tucker SL, Chavez-MacGregor M, Smith BD, Symmans WF, Sahin AA, Hortobagyi GN, Hunt KK. Bioscore: A novel staging system for breast cancer patients receiving neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-04.

Background: Everolimus (EVE; 10 mg) and exemestane (EXE; 25 mg) doublet therapy improved progression-free survival in women with hormone receptor-positive (HR+)/ HER2– advanced breast cancer (aBC; BOLERO-2), but was associated with significant mucositis as well as eventual disease progression. Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown clinical activity in combination with endocrine therapy and could potentially overcome phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor resistance by acting downstream of the PI3K pathway. Methods: In this ongoing Phase Ib/II study (NCT01857193), postmenopausal women with anastrozole- or letrozole-resistant HR+/HER2– aBC received escalating doses of the CDK4/6 inhibitor ribociclib (LEE011 [LEE]; once daily [QD], days 1–21 of 28-day cycles) with EVE (1–5 mg QD) and EXE (25 mg QD). Dose escalation was guided by a Bayesian logic regression model with overdose control principle and real-time pharmacokinetics. Pre-treatment tumor samples were sequenced by the Foundation Medicine platform. Here we report on the safety and efficacy of triplet therapy, and explore potential predictive biomarkers of response. Results: At the cut-off date March 2, 2015, 84 patients (pts) had been treated; here we present results from the 70 pts in the triplet arm treated with LEE (200–350 mg), EVE (most at 2.5 mg), and EXE. The median number of prior regimens was 5, and 18 (25.7%) pts had received prior PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. Grade 3/4 treatment-related adverse events (AEs; ≥5% pts) were neutropenia (45.7%), leukopenia (8.6%), and thrombocytopenia (5.7%). Two (2.9%) pts discontinued due to AEs. Grade 3 dose-limiting toxicities were reported in 6 pts treated with LEE (300 mg) and EVE (2.5 mg): increased alanine aminotransferase/aspartate aminotransferase (2 pts), febrile neutropenia and hypophosphatemia (1 pt), oral mucositis (1 pt), rash and thrombocytopenia (1 pt), and thrombocytopenia with bleeding (1 pt). The recommended Phase II dose will be reported at the meeting. Among 55 pts evaluable for best overall response, there was 1 (1.8%) complete response (CR), 2 (3.6%) confirmed and 3 (5.5%) unconfirmed partial responses (PR), 7 (12.7%) non-CR, non-progressive disease (NCRNPD), and 26 (47.3%) stable disease (SD). Disease control rate (CR+PR+SD+NCRNPD) was 70.9%. One pt received treatment for ≥14 months, and 23 (32.9%) pts for ≥4 months. There was a trend towards longer duration of treatment in the CCND1 amplified group (n=10; median 166 days) than in the non-amplified group (n=22; median 60 days). A retrospective analysis of BOLERO-2 showed no differential effect of CCND1 amplification on PFS. Conclusions: Triplet combination of endocrine therapy with mTOR and CDK4/6 inhibition is feasible, permits lower dosing of EVE (resulting in better tolerability), and shows encouraging signs of clinical activity, including in some pts with prior exposure to PI3K/AKT/mTOR or CDK4/6 inhibitors. Duration of treatment was longer in pts with cyclin D amplification, possibly due to inclusion of a CDK4/6 inhibitor. These results suggest that that triplet therapy might be beneficial for pts who progress on doublets or who have cyclin D amplification. Citation Format: Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, Weise A, Nardi L, Zhang V, Bhansali SG, Hewes B, Chavez-MacGregor M. Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2– advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-01.

Background: Adjuvant chemotherapy for early breast cancer is associated with a small risk of developing MDS and AML. The aim of this study is to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. Methods: Patients diagnosed with stage I-III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Development of AML or MDS, chemotherapy use, and comorbidities were identified using ICD-9 and HCPCS codes. A single inpatient or 2 outpatient codes 30 days apart were required for identification of AML or MDS. Analyses included descriptive statistics, Kaplan-Meier method for 5-year AML/MDS rates and Cox proportional hazards models to estimate the hazard of AML and MDS after adjusting for clinically relevant covariates. Results: 68,702 patients were included, of them 166 (0.24%) developed AML and 385 (0.56%) developed MDS. The median time from breast cancer diagnosis to AML or MDS was 924 and 943 days respectively. The 5-year AML rates were 0.23% for the no chemotherapy group, 0.53% for anthracycline (A)-based regimens, 0.48% for anthracycline and taxane (AT)-based regimens, 0.39% for other (O) regimens and 0.09% for those who received docetaxel and cyclophosphamide (TC). 5-year MDS estimates were 0.62%, 1.07%, 0.72%, 1.08 and 0.38% respectively. In the multivariable model using no chemotherapy as the reference category, A (HR 3.03; 95%CI 1.75-5.24) and AT (HR 3.06; 95%CI 1.70-5.52) were the chemotherapy regimens associated with the highest risk for developing AML, followed by O (HR 2.05; 95%CI, 1.13-3.69). No significant increase in risk was observed in patients who received TC (HR 0.91; 95%CI 0.26-4.60). Similar results were observed when evaluating risk of MDS among patients treated with A (HR 2.25; 95%CI, 1.50-3.37), AT (HR 1.67; 95%CI 1.06-2.65), O (HR 2.30; 95%CI 1.61-3.29) and TC (HR 1.22; 95%CI 0.60-2.66). Conclusion: In this large cohort of patients we observed a small but significant increase in risk for AML and MDS with adjuvant chemotherapy. The highest risk was associated with A and AT-based chemotherapy. TC was the only regimen that was not significantly associated with an increased risk. Because of relative recent adoption of TC, longer follow-up is needed to better estimate the risk of MDS and AML in this group of patients. Citation Format: Aron S Rosenstock, Sharon H Giordano, Jiangong Niu, Hui Zhao, Antonio C Wolff, Thomas A Buchholz, Mariana Chavez-MacGregor. AML and MDS after adjuvant chemotherapy: A population based study among older breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-04.

Background: Oncotype Dx is a 21-gene assay performed in paraffin-embedded tumor tissue. This test is used to assist in estimating the likelihood of recurrence and the benefit from chemotherapy in patients with hormone receptor (HR)-positive, node-negative breast cancer. One of he purported benefits of this assay is that by identifying low risk patients, Oncotype Dx use will be associated with a decrease in chemotherapy use among those patients less likely to benefit from it. In this study we sought to describe the utilization patterns of Oncotype Dx and its relationship with the use of adjuvant chemotherapy in a large population-based study. Methods: We identified 112,522 patients younger than 65 years old diagnosed with early stage breast cancer between 2004-2012 in the MarketScan database. Standard algorithms were used to identify our cohort and HR-positivity was defined according to prescription information. A total of 34,245 patients older that 66 and diagnosed with early stage breast cancer between 2006-2009 were identified in the SEER-Medicare database. Descriptive statistics were used as well as logistic regression models to estimate the impact of Oncotype Dx testing on adjuvant chemotherapy administration. Results: In the cohort of young patients ( Among the older patients (≥66 years old), 11.35% (n=3,017) underwent Oncotype Dx testing. Utilization was associated with younger age, histological grade, educational level, marital status, geographic location and comorbidities (p Conclusions: The use of Oncotype Dx in clinical practice is common, with an increase use in more recent years. Utilization was determined by patient-related characteristics. Among younger patients Oncotype Dx testing was associated with a reduction in the use of adjuvant chemotherapy, but this decrease was not observed among those ≥66 years old. It is possible that this discordance is related to comorbidities and the fact that older patients are less likely to be considered candidates for chemotherapy. Citation Format: Mariana Chavez-MacGregor, Jiangong Niu, Benjamin Smith, Hui Zhao, Thomas A Buchholz, Sharon H Giordano. Oncotype Dx use and its relationship with chemotherapy administration in the general population [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-05.

Background: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in BC. This pathway is associated with resistance to endocrine therapies among HR+ tumors. Everolimus, an mTOR-inhibitor, increases the biological activity of endocrine therapy. S1207 evaluates the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: Specific aims/ design: Randomized phase III double-blinded, placebo-controlled trial. Primary objective is to assess whether the addition of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk, HR+ BC. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and QoL. Patients are randomized to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or placebo. Submission of tissue specimens/blood samples is required for translational studies Eligibility criteria: Patients with histologically confirmed HER2-negative and HR+ invasive BC treated with surgery, adjuvant chemotherapy and radiation therapy (if indicated) are eligible if they have: node-negative disease and tumors >2cm and a recurrence score (RS) >25; 1-3 positive nodes and RS >25 or grade 3 in the absence of RS; >4 positive lymph nodes regardless of RS. Patients >1 positive lymph node after completing neoadjuvant chemotherapy are eligible. Statistics/Target accrual:Parallel randomization design with equal allocation to the two treatment groups, the study will randomize 3,500 patients. All analyses are intent-to-treat with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years. Support: NIH/NCI NCTN Grants CA180888, 180819, 180868, 180821,180822 189867, and in part by Novartis Clinical trial information: NCT01674140. Citation Format: Chavez-MacGregor M, Barlow WE, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Gralow J, Lew DL, Hortobagyi GN. Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-11.

Background: Differences in gene or protein expression patterns between breast cancers according to race/ethnicity and cancer subtype. Methods: Transcriptional profiling was performed using Affymetrix HG-U133A platform in 376 patients and reverse phase protein array analysis (RPPA) was done for 177 proteins in 255 patients from a separate cohort. Unsupervised clustering was conducted, as well as supervised comparison by race and tumor subtype. Standard statistical methods, BRB-Array tools, and Ingenuity Pathways software packages were used to analyze the data. Results: Median age was 50 years in both the cohorts. In the RPPA cohort, 54.5% of the tumors were hormone receptor–positive (HR-positive), 20.7% HER2-positive, and 24.71% triple-negative (TNBC). One hundred and forty-seven (57.6%), 47 (18.43%), and 46 (18.1%) of the patients were White, Hispanic, and Black, respectively. Unsupervised hierarchical clustering of the protein expression data showed no distinct clusters by race (P values were 0.492, 0.489, and 0.494 for the HR-positive, HER2-positive, and TNBC tumors respectively). In the gene expression cohort, 54.2% of the tumors were HR-positive, 16.5% HER2-positive, and 29.3% TNBC. Two hundred and sixteen (57.5%), 111 (29.52%), and 32 (8.52%) patients were White, Hispanic, and Black, respectively. No probe set with a false discovery rate (FDR) of Conclusions: We did not detect a significant variation in RNA or protein expression comparing different race/ethnicity groups of women with breast cancer. Impact: More research on the complex network of factors that result in outcomes differences among race/ethnicities is needed. Cancer Epidemiol Biomarkers Prev; 23(2); 316–23. ©2013 AACR.

Background: Very little is known about the survival of patients with inflammatory breast cancer (IBC) and distant metastasis. Furthermore, the American Joint Committee on Cancer classification of breast cancer does not recognize metastatic IBC as a distinct entity within stage IV. We hypothesized that the survival of patients with IBC and distant metastasis is worse than the survival of patients with stage-matched non-IBC. Patients and Methods: We retrospectively reviewed 5314 consecutive patients with stage III or IV breast cancer (IBC or non-IBC) who were treated at our institution between 1986 and 2012. A total of 1079 patients presented with IBC (stage III: 861; stage IV: 218) and 4235 non-IBC (stage III: 2781; stage IV: 1454). We compared the time to distant metastasis from initial diagnosis, distant metastasis–free survival (DMFS), and overall survival (OS) in stage-matched patients with IBC or non-IBC. Results: The median follow-up periods were 3.3 years for patients with stage III disease (range, 0-32.2 years) and 1.8 years for patients with stage IV disease (range, 0-19.9 years). The total number of recorded events (metastasis/death) was 1657 for stage III, while the numbers of deaths for stage III and IV were 1337 and 973, respectively. In patients with stage III, the time to distant metastasis was shorter in IBC than in non-IBC (median 1.3 vs. 1.7 years, P < .001). DMFS and OS were shorter in patients with stage III IBC than in those with stage III non-IBC (2.5 vs. 6.9 years, P < .001; and 4.7 vs. 8.9 years, P < .001; respectively). However, there was no significant difference in OS after development of distant metastasis between stage III IBC and non-IBC (median for both 1.3 years, P = .83). In multivariate analysis, the diagnosis of IBC remained significantly associated with mortality after adjusting for potential confounders. De novo stage IV IBC presented more frequently with multiple sites of metastasis than de novo stage IV non-IBC (P = .02). In patients with de novo stage IV disease, OS was shorter in IBC than in non-IBC (2.3 vs. 3.4 years, P = .004). In the multicovariate Cox model, while ethnicity, tumor grade, hormone receptor status and HER2 status, site of metastasis, number of sites of metastasis, and definitive breast surgery by 1 year were all significant factors in OS for stage IV breast cancer, the diagnosis of IBC conferred a hazard ratio of 1.33 (95% confidence interval: 1.05 - 1.69) in multivariate analysis. Conclusion: Our findings suggest that IBC patients with metastasis at diagnosis have worse outcomes than stage-matched non-IBC patients. IBC patients presenting with de novo stage IV disease should be considered as a separate subcategory of stage IV in the tumor-node-metastasis classification because their clinical course and prognosis are different from those of patients with stage IV non-IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-02.

Background Breast cancer in men is a rare disease and accounts for 0.6% of all breast cancer cases. Prior reports suggest that male breast cancer typically has a ductal histology and is more likely than cancers of the female breast to express estrogen and progesterone receptors (ER and PR). To our knowledge, there are no population-based estimates of the rates of Her-2 positive breast cancer or of the distribution of breast cancer subtypes in male patients. The categorization of breast cancers according to tumor subtype has important implications in the prognosis and in the management of breast cancer patients. We explored the tumor subtype distribution by race/ethnicity in the large, ethnically diverse population of California. Methods: Retrospective study using the CCR. Participants included all male breast cancer patients diagnosed with invasive breast cancer between 2005–2009 with known ER, PR and Her2neu status. Among the patients with hormone receptor positive (HR+) tumors, survival analysis using Kaplan-Meier method was used. Differences in probability of survival between groups were compared using logrank test. Results: Six-hundred and seven patients were included. Median age at diagnosis was 68 years. Ductal histology was present in 84.7% (n=514) of the cases, 51.6% (n=313) of all the tumors were classified as grade II. Four hundred and ninety four (81.4%) patients had HR+ tumors, defined as ER+ and/or PR+ and Her2neu negative. Ninety (14.8%) had Her2neu positive, and 23 (3.8%) had triple receptor negative tumors (TN). The majority of patients were white (71%), 11% were Hispanic, 7.6% black and 10.4% were Asian/Pacific Islander/other. The breast cancer tumor subtype varied significantly across races/ethnicities (p Conclusions: In this large cohort of male breast cancer patients, the distribution of tumor subtype was different than what has been reported in females. Among males, differences in tumor subtype exist among different racial/ethnic groups. Blacks were more likely to have triple receptor negative tumors and more likely to have ER+/PR- tumors than white patients. Among HR+ patients, blacks experience the worse survival. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-19-01.

Background: Preclinical data suggest that combination of endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and mammalian target of rapamycin inhibitor (mTORi) may overcome prior treatment resistance in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The Phase Ib CLEE011X2106 study (NCT01857193) is investigating ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in patients with HR+, HER2- ABC resistant to letrozole or anastrozole. The objective of this analysis is to characterize baseline gene expression patterns in the CDK4/6i-naïve and -refractory groups, and assess the potential correlation with clinical activities. Methods: Postmenopausal women with HR+, HER2- ABC resistant to letrozole or anastrozole, and who had received no prior CDK4/6i or whose disease had progressed on or within 1 month of CDK4/6i therapy, were enrolled in the CDK4/6i-naïve and -refractory dose expansion groups, respectively. More than 1 line of chemotherapy for ABC or prior treatment with EXE or an mTORi was not permitted. Patients received RIB (300 mg, 3-weeks on/1-week off) + EVE (2.5 mg, continuous) + EXE (25 mg, continuous) until disease progression or study discontinuation. Baseline tumor samples (collected after CDK4/6i therapy in the CDK4/6i-refractory group) were assessed for mRNA expression using the NanoString 230-gene nCounter® GX Human Cancer Reference panel. Results: As of May 15, 2017, the 24-week clinical benefit rate was 56% (9/16) in the CDK4/6i-naïve group and 24% (4/17) in the -refractory group. Baseline tumor mRNA expression was evaluable in 14 patients: CDK4/6i naïve, n=8 (best response: 7 stable disease [SD], 1 progressive disease [PD]); CDK4/6i refractory, n=6 (2 SD, 4 PD). Across all patients (both groups), those with SD tended to have higher ESR1 expression compared with those experiencing PD, with a trend for higher baseline ESR1 expression in the CDK4/6i-naïve group compared with the -refractory group. Also across all patients, higher overall baseline expression of cell cycle control genes and mitogen-activated protein kinase (MAPK) pathway genes appeared to trend with PD. Additionally, in the CDK4/6i-refractory group, there was a trend for higher CDK2 and/or CCNE1 expression in patients with PD compared with SD. A heat map of 24 genes indicated differences in gene expression patterns between the CDK4/6i-naïve and -refractory groups. Conclusions: Gene expression patterns differ between CDK4/6i-naïve and -refractory tumors. Higher expression of cell cycle control genes (particularly CDK2 and CCNE1) and MAPK pathway genes appears to trend with resistance to the RIB + EVE + EXE combination after progression on prior CDK4/6i. Due to the small number of samples, further investigation is needed. Citation Format: Aditya Bardia, Shanu Modi, Javier Cortes, Mario Campone, Luc Dirix, Brigette Ma, J Thaddeus Beck, Jorge Chaves, Amy Weise, Jacqueline Vuky, Gilberto Lopes, Miguel Gil-Gil, Xiaochun Liu, Wei He, Faye Su, Michelle Miller, Mariana Chavez-MacGregor. Baseline gene expression patterns of CDK4/6 inhibitor-naïve or -refractory HR+, HER2- advanced breast cancer in the phase Ib study of ribociclib plus everolimus plus exemestane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT069.

Background: The rate of pathologic complete response (pCR) to neoadjuvant systemic treatment (NST) of patients with a body mass index (BMI) of ≥25 has been reported to be significantly lower than that of patients with a BMI Material and Methods: We retrospectively reviewed the medical records of 263 patients with primary IBC and 865 patients with stage III non-IBC who underwent standard NST consisting of anthracyclines and/or taxanes with or without concurrent trastuzumab followed by definitive surgery at our institution between November 1, 2006, and December 31, 2012. Results: The median follow-up time for survivors was 19.8 months (0.1-69.9 months). One hundred forty-five (55.1%) IBC and 566 (65.7%) non-IBC were hormone receptor-positive and 91 (34.6%) IBC and 198 (22.9%) non-IBC were human epidermal growth factor receptors (HER2)-positive. One hundred forty-four (54.8%) IBC and 446 (51.9%) non-IBC were postmenopausal. Of the 1128 patients included in the study, 223 (19.8%) achieved pCR, including 42 (16.0%) IBC and 181 (20.9%) non-IBC. The median change in BMI during NST of the patients who achieved pCR (0.1) was significantly higher than that of the patients who did not achieve pCR (-0.1; p = 0.04). The pCR rate of the patients whose BMIs had positive change post NST (23.2%) was higher than that of the patients whose BMIs were lower after NST (18.2%), but this difference was not significant (p = 0.054). Multivariate analysis did not reveal positive change in BMI post NST to be a significant predictor of pCR. Univariate analysis with the log-rank test revealed that higher BMI change from pre NST as a categorical variable (BMI change >0 vs. ≤0) predicted increased OS in all patients (p = 0.005) and in IBC patients (p Conclusion: In patients with stage III breast cancer, a higher BMI after NST than at baseline does not predict lower pCR rate or decreased survival after adjust for other clinical variables. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD2-4.

Background: ET is the standard of care for HR+ ABC; however, disease progression eventually occurs. Breast cancer driver mutations can include alterations in the cyclin D–cyclin-dependent kinase (CDK)4/6–inhibitor of CDK4 (INK4; p16)–retinoblastoma pathway and in upstream pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway. Doublet combination strategies with selective CDK4/6 inhibitors such as ribociclib (RIB) have demonstrated increased progression-free survival (PFS) in Phase III studies of HR+ ABC. Here, we evaluate the clinical activity of RIB-based ET combinations in Phase I clinical trials, including in tumors with various molecular alterations. Methods: Postmenopausal women with HR+, HER2– ABC received RIB with letrozole (LET; 2.5 mg continuous; NCT01872260; previously untreated or first-line patients [pts]), exemestane (EXE; 25 mg continuous; NCT01857193; aromatase inhibitor [AI]-refractory disease), or fulvestrant (FUL; 500 mg; NCT02088684; AI-refractory disease). RIB was administered at 600 mg/day 3 weeks on/1 week off (all combinations) or 400 mg/day continuously (additional subgroup in the RIB + FUL study). Fresh or archival tumor tissue was collected from all pts. Clinical activity and next-generation sequencing (NGS) data from pretreatment tumor samples were assessed. Results: Preliminary clinical activity was observed with all 3 combinations, with clinical benefit rates (CBR; including stable disease for ≥24 weeks) of: RIB + LET (N=47 pretreated or first-line pts) 60%, RIB + EXE (N=14 pretreated pts) 50%, and RIB + FUL (N=28 pretreated pts; n=13 at 600 mg/day RIB, n=15 at 400 mg/day RIB) 52%. Best overall responses of complete response [CR] or partial response [PR] were observed in 14 pts (RIB + LET), 4 pts (RIB + EXE), and 5 pts (RIB + FUL). In a first-line subset of pts (N=28), RIB + LET had a median PFS of 25.3 months. Most common Grade 3/4 adverse events for all 3 combinations were neutropenia and leukopenia. NGS data were available for 33, 6, and 16 pts treated with RIB + LET, RIB + EXE, and RIB + FUL, respectively. CR and/or PR were observed in pts with PIK3CA and/or CCND1 (cyclin D) alterations treated with RIB + LET (9/19 pts and 4/9 pts, respectively); and RIB + FUL (1/10 pts and 2/5 pts, respectively). Integrated biomarker analyses from all 3 trials will be provided at the time of the meeting. Conclusions: RIB + ET doublet combinations are well tolerated, with encouraging clinical activity that includes responses and durable PFS in heavily pretreated pts, and are consistent with previously reported first-line data (NCT01958021). Preliminary biomarker analyses suggest pts with PIK3CA and/or CCND1 alterations derive treatment benefit from RIB + ET combinations. Other genetic alterations are being evaluated. Citation Format: Dejan Juric, Mario Campone, Pamela Munster, Roohi Ismail-Khan, Laura Garcia Estévez, Mariana Chavez-MacGregor, Antonio Frassoldati, Rina Hui, Ingrid A. Mayer, Javier Cortés, Anthony Gonçalves, Richard H. De Boer, Luc Dirix, Sara M. Tolaney, Soo Chin Lee, Michela Maur, Yingbo Wang, Faye Su, Jason R. Dobson, Caroline Germa, Becker Hewes, Aditya Bardia. Ribociclib + endocrine therapy (ET) doublet combinations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): Phase I clinical activity and impact of molecular alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT087. doi:10.1158/1538-7445.AM2017-CT087

Background: Metaplastic breast cancers (MpBCs) are a chemo-refractory group of tumors that contain a component of squamous and/or mesenchymal differentiation identifiable by light microscopy. MpBCs contain a high frequency of aberrations in the PI3K/AKT/mTOR pathway, making this pathway a potential target for therapy. Methods: Patients with advanced MpBC (N = 52) were treated with liposomal doxorubicin (D), bevacizumab (A) and the mTOR inhibitors temsirolimus (T) or everolimus (E). D and A were administered IV on day 1 with T (IV on days 1, 8 and 15) or E (continuous daily oral administration) using 21 day cycles. All tumors were evaluated to assess histology of metaplasia (spindle, mixed spindle vs non-spindle cell). Response was assessed every 6 weeks using RECIST. When available, archived tissue was evaluated for aberrations in the PI3K pathway using standard assays. Results: Fifty-two MpBC patients were treated with DAT (N = 39) or DAE (N = 13). Median age was 58 (range 37-79); median number of prior regimens for metastatic disease was 1 (range 0-5). The objective response rate (ORR) was 21% [complete response (CR) = 4 (8%); partial response (PR) = 7 (13%)] and 10 (19%) pts had stable disease (SD)≥6 months for a clinical benefit rate (CBR) of 40%. Tissue was available in 43 pts and 32 (74%) had a PI3K pathway activating aberrations. PI3K pathway aberration was associated with a significant improvement in ORR (31 vs 0%; P = 0.04) but not CBR (44 vs 45%; P = 1.00) or progression-free survival (median 5 vs 3 months; P = 0.35). The most frequent PI3K pathway aberration was mutation in PIK3CA, occurring in 19 patients. Outcomes were similar if mutations of PIK3CA were located in the helical or kinase domain (ORR 25% vs 27%; P = 1.00 and CBR 38% vs 47%; P = 1.00, respectively). Spindle cell was the most frequent metaplastic histology seen, occurring in 18 tumors and mixed with other metaplastic histologies including squamous, chondroid and osseous in 14 additional tumors, while 20 tumors had non-spindle cell morphologies. The incidence of PI3K pathway aberration was similar across histologies (61% in spindle vs 67% in mixed spindle vs 60% in non-spindle cell). Tumors with mixed histology had lower ORR, CBR and PFS, but this was not statistically significant, likely due to small numbers in each cohort: ORR 22% in spindle vs 7% in mixed spindle vs 30% in non-spindle cell, P = 0.27; CBR 50% in spindle vs 21% in mixed spindle vs 40% in non-spindle cell, P = 0.25; and PFS median 4 months in spindle vs 2 months in mixed spindle vs 5 months in non-spindle cell, P = 0.68. Conclusions: Response to mTOR inhibition is enhanced in MpBCs with PI3K pathway aberrations. However, specific aberrations in PIK3CA do not lead to differential response to mTOR inhibition. PI3K pathway aberrations and response to mTOR inhibition are seen across all histologies of MpBC, and the response is not enhanced in particular histologies. Citation Format: Reva K. Basho, Michael Gilcrease, Rashmi K. Murthy, Thorunn Helgason, Daniel J. Booser, Daniel D. Karp, Funda Meric-Bernstam, Kenneth R. Hess, Shelley M. Herbrich, Vicente Valero, Constance Albarracin, Jennifer Litton, Mariana Chavez-MacGregor, Nuhad K. Ibrahim, James L. Murray, Kimberly B. Koenig, David Hong, Vivek Subbiah, Razelle Kurzrock, Filip Janku, Stacy Moulder. Targeting the PI3K/AKT/mTOR pathway for the treatment of metaplastic breast cancer: Does location of PIK3CA mutation or histology affect response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2273.

Background: Tumor cells with a mesenchymal phenotype include cancer stem-like cells (CSCs), which are known to contribute to metastasis. Circulating tumor cells (CTCs) are epithelial cells in peripheral blood that are detected using an anti-EpCAM antibody; however, CTCs undergoing epithelial-mesenchymal transition (EMT) may not be detected using this method. We have developed an antibody-independent CTC enrichment platform, Apostream®, which does not rely on EpCAM-based capture. We used this instrument to determine the clinical relevancy and feasibility of measuring EMT-CTCs in breast cancer patients. Methods: Blood samples from newly diagnosed breast cancer patients were prospectively collected at baseline (T0), after primary systemic therapy (T1), and after definitive surgery (T2) and processed using the Apostream® system. Isolated cells were stained with antibodies to cytokeratin (anti-CK), leukocytes (anti-CD45), and the nuclear stain, 4,6-diamidino-2-phenylindole (DAPI), to identify CTCs. These CTCs were also stained with additional markers and examined on a laser scanning cytometer to measure protein expression levels of epithelial (EpCAM, E-cadherin), mesenchymal (β-catenin, vimentin) and CSC-markers (CD44, CD24). Pathological complete response (pCR) and residual cancer burden (RCB) statuses after preoperative treatment were obtained to correlate baseline CTCs and marker expression with treatment response. Results: The study enrolled 33 patients (10 with early-stage, 19 with locally advanced, and 4 with metastatic breast cancer); 32, 12, and 10 patients provided samples at T0, T1, and T2, respectively. Of the 20 patients who underwent surgery, 6 patients achieved pCR. CTCs were detected (≥ 1 cell in at least one of the three samples) in 47%, 75%, and 80% of the T0, T1, and T2 samples, respectively. EMT markers (either vimentin or β-catenin) were detected in 67%, 11%, and 38% of these CTCs, respectively. The mean number of CTCs per mL detected at T0 was 0.43 (range, 0-3.7). CTC detection was correlated with a high histological Nottingham index (P=0.039). Conversely, vimentin-positive CTC detection was inversely correlated with clinical stage at T0 (P=0.034). No significant correlation was observed between CTCs detected at baseline and breast cancer subtypes. However, there was a trend for CTCs detected at T0 to be predictive of chemotherapy response, as 62% of patients with CTCs at T0 achieved a pCR, whereas only 11% of patients without CTCs at T0 had a pCR (P=0.057). The other EMT and CSC markers we tested did not predict response. Conclusions: Apostream® was successful in detecting EMT-CTCs in this prospective study. There was a trend for the presence of CTCs at baseline to predict pCR. We will present our final data analysis of 50 patients. pCR (n=6)†RCB-I (n=2)RCB-II (n=5)RCB-III (n=4)P-valueCK+CD45- CTCsNegative (n=9)1(11)2(22)3(33)3(33)0.146 0.057*Positive (n=8)5(62)0(0)2(25)1(13)† All data are no. of patients (%) Two did not have an RCB status available, and 1 did not have a T0 sample. * Comparing pCR status (pCR vs no-pCR) between CTCs negative and positive. Citation Format: Fanny Le Du, Dzifa Y Duose, Elisha J Dettman, Jackson A Summer, Mariana Chavez-MacGregor, Carlos H Barcenas, Abenaa M Brewster, Alvarez H Ricardo, Vincente Valero, Ana M Gonzalez-Angulo, James M Reuben, Naoto T Ueno. Predictive impact of circulating tumor cells with an epithelial-to-mesenchymal transition phenotype in patients with primary breast cancer treated with primary systemic therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-10.

Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that accounts for 3 to 5% of all invasive breast tumors in the United States. IBC possesses an increase of proangiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) as compared with non-IBC. In particular, FGF family receptors play a critical role in tumorigenesis, morphogenesis, and inducers of angiogenesis. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor with in vitro IC50 values of approximately 10 nmol/L against FGFR1-3, VEGFR1-3, and PDGFR. These structurally related receptors are important for the growth and survival of endothelial cells during tumor angiogenesis. Trial Design: This is a single institution, single arm phase II study. Patients receive a single daily oral dose of dovitinib 500 mg for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule). Eligibility: Patients have histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d’orange). Pathological evidence of dermal lymphatic invasion should be noted but is not required for diagnosis. HER2-negative. ECOG PS 0-2. Baseline MUGA or echocardiogram scans with LVEF of > 50%. Normal hematology, liver and kidney function laboratory studies. Patients must have received at least 2 chemotherapy lines for metastatic disease and have relapsed. Research Hypothesis: Dovitinib has antitumor activity in patients with HER2-negative advanced IBC. Specific Aims: Primary objective: to determine the disease control rate (CR, PR, and SD). Secondary objective: to evaluate safety profile. Exploratory biomarkers: circulating tumor cells (CTC), CTC undergoing EMT, and cancer stem cells Statistical Methods: The primary endpoint is the six-month disease control rate (ORR) as defined by RECIST 1.1. A response is anyone who experiences SD, CR or PR in the first 6 months. We will conduct this study with Simon’s two-stage design using the mini-max criterion and the response rate will be estimated accordingly. It is assumed that dovitinib will have a target ORR of 30%. An ORR of 10% or lower is considered a failure based on the typical ORR with a second line regimen for IBC and the new regimen will be rejected under this circumstance. When the probability of accepting a "bad" regimen (i.e. response rate < 10%) is 0.05 and the probability of rejecting a "good" regimen (i.e. response rate > 30%) is also 0.10, Simon’s design to minimize the maximum sample size requires 22 patients in the first stage. If two or less patients respond to the treatment, the trial will be stopped and the regimen will be declared as ineffective. If at least three of the first 22 patients respond to the treatment, 11 additional patients will be entered in the study to reach a total of 33 patients. By the end of the study, the new regimen will be rejected if response rate is less than or equal to 6 out of 33 patients and will be accepted otherwise. Present Accrual and Target Accrual: A total of 22 patients were accrued. Target accrual is 33 patients. Citation Format: Ricardo H Alvarez, Mariana Chavez-MacGregor, Joe Ensor, James L Murray, Kimberly Koenig, Savitri Krishnamurty, Antony Lucci, Gildy V Babiera, Wendy Woodward, Gary J Whitman, Summer A Jackson, Michael Shi, Kenneth Culver, James L Reuben, Naoto T Ueno, Vicente Valero. A phase II study of dovitinib as salvage therapy in patients with stage IV inflammatory breast cancer HER2-negative with local or distant relapse [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-15.