Search

Background: ER+, HER2- metastatic breast cancer (MBC) patients will receive sequential, endocrine based therapy, either as monotherapy or in combination with a targeted agent until endocrine resistance develops. OP-1250 is a small molecule Complete Estrogen Receptor Antagonist (CERAN) that completely inactivates ER by blocking the 2 activation functions of ER transcription (AF-1 & AF-2). While complete antagonism is believed to be the most critical mechanism of action, OP-1250 is also a strong degrader of the ER. OP-1250 demonstrates anti-cancer activity in preclinical models, including activity against brain metastases and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with favorable pharmacokinetics (PK) yielding high and steady drug levels in multiple species. The characteristics of OP-1250 including PK, ability to cross the blood brain barrier, and complete antagonism of the ER suggest that OP-1250 may have superior efficacy over standard of care and experimental agents, both as a monotherapy and in combination with other targeted therapies. Methods: OP-1250-001 is a phase I/II first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) and to characterize the safety, PK profile and preliminary efficacy in subjects with ER+, HER2- MBC. Eligible patients received prior endocrine therapy. OP-1250 was given orally, once a day continuously in 28-day cycles. Using a rolling 6 design, cohorts of 3 - 6 subjects were sequentially enrolled and monitored for DLTs. The study allows for expansion of 1 or 2 doses for further evaluation of safety and PK to best inform selection of the RP2D. The phase II portion will evaluate the preliminary activity of OP-1250 in 3 cohorts: 1) measurable disease; and 2 exploratory cohorts: 2) evaluable & non-measurable; and 3) central nervous system metastasis. Plasma is being collected for ctDNA sequencing to evaluate ESR1 and other relevant mutations. Results: Between August 5, 2020 and June 4, 2021, 28 subjects with a median age of 63 (range 37-82) have been enrolled. Of the 27 subjects for whom detailed data on prior therapy was reported, all subjects received > 1 prior endocrine therapy for MBC (74% received > 2 and 37% received > 3; range 1-6). All of the 27 subjects received a CDK4/6 inhibitor and 23 of 27 (85%) had received fulvestrant. 20 subjects of 28 (71%) subjects had visceral disease affecting the liver, lung, peritoneum, and/or pleura. OP-1250 was escalated through 5 dose cohorts (range 30 - 300 mg qd). 26 patients were evaluable for a DLT. As of the data cut-off date, no DLTs occurred. Most of the TEAE were grade 1 or 2. OP-1250 is orally bioavailable and extensively distributed with an effective half-life of approximately 2-3 days. Cmax and AUC show dose proportional increase. By cycle 2, exposure levels are at steady state with limited fluctuations and at all doses significantly higher than those seen with fulvestrant. Importantly, OP-1250 has now demonstrated clinical activity at doses that were well tolerated and within the predicted exposure windows where maximum efficacy was observed in preclinical models. Detailed response and safety data will be presented. Conclusion: OP-1250 is continuing evaluation in a phase I/II study. The population enrolled reflects the evolving standard of care in that all pts received prior CDK4/6 inhibitors and the majority also received fulvestrant. OP-1250 is well tolerated with a favorable PK across dose levels ensuring target coverage throughout the dosing interval. No MTD has been identified and selection of the RP2D will be based on consideration of long-term tolerability, efficacy, and the ability to combine with targeted agents. (NCT04505826) Citation Format: Manish Patel, Carlos Alemany, Zahi Mitri, Della Makower, Virginia Borges, Joseph Sparano, Trinh Le, Pamela Klein, Julia Lawrence, Peter Kushner, Demiana Faltaos, Cyrus Harmon, David Myles, JoAnne Zujewski, Erika Hamilton. Preliminary data from a phase I/II, multicenter, dose escalation study of OP-1250, an oral CERAN/SERD, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-12.

Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promote breast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NET utility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effective treatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67 (>15% vs ≤15%), and Ki67 (>10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient (pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primary ER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER 10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 and PgR ≥6). The ALTERNATE trial (NCT01953588) randomized postmenopausal women with clinical stage II or III, ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months, unless Ki67 was >10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy (NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar across the treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trial therefore provides a large independent data set to evaluate the NET appropriateness model. Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HR Allred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of the remaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-study Ki67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141 of 468), and Group 3 17% (104 of 607) (Table 1). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67 ≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 >10% at wk 4, compared to 231 of the 815 (28.3%) who had BL Ki67 >15% and subsequent Ki67 >10% at wk 4. 2% of pts who remained on NET due to on-treatment Ki67 Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be used for the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. When baseline ER Allred scores are >6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is >15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NET appropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67 was Table 1 Baseline levels of ER, PR, and Ki67 in Relation to Wk 4 Ki67 (N=1,085)BaselineWeek 4GroupNERAllred ScorePRAllred ScoreKi67Ki67 ≤10%N (%)Ki67 >10%N (%)1N=2615%1 (12.5%)7 (87.5%)2AN=647 or 815%148 (63%)87 (37%)2BN=466 or 7≥6≤15%42 (91.3%)4 (8.7%)51 (30.2)N=1236 or 7≥6>15%76 (61.8%)47 (38.2%)3N=1508≥6≤15%143 (95.3%)7 (4.7%)104 (17.1)N=4578≥6>15%360 (78.8%)97 (21.2%) Citation Format: Matthew J Ellis, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Mitch Dowsett, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Clifford Hudis, Eric P Winer, Kelly Hunt, Ann H Partridge, Cynthia X Ma, Lisa A Carey. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): An ALTERNATE trial analysis (Alliance A011106) [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 PD2-10.

PURPOSE Breast and cervical cancer are the most common cancers among women in East and Southern Africa, where mortality remains high because of late diagnosis and limited access to treatment. We explored local approaches to breast and cervical cancer advocacy to identify the most pressing issues and opportunities for increasing the impact of civil society activities in the region. METHODS Focus group discussions were conducted with participants of the 2016 Women’s Empowerment Cancer Advocacy Network (WE CAN) Summit in Nairobi, Kenya. Discussions were audio-recorded, transcribed, coded, and analyzed for emergent themes. Results were presented to participants of 2019 WE CAN summit for cross-validation. RESULTS Four focus group discussions were conducted with 50 participants. Thirty-six (70%) identified as advocates, 30 (59%) as cancer survivors, 14 (27%) as nongovernmental organization representatives, 13 (25%) as researchers, 4 (8%) as clinicians, and 6 (8%) as policymakers. Although most participants focused on cancer awareness and screening/early detection, some noted that treatment was often unavailable and advocated for a broader strategy to improving access to care. Challenges to designing and implementing such a strategy included knowledge gaps in addressing late diagnosis and access to care, difficulty collaborating with like-minded organizations, approaching policymakers, and addressing treatment financing. Cancer coalitions, although rare, were crucial to building collaborations with ministries of health, policymakers, and international organizations that advanced breast and cervical cancer care. CONCLUSION Participants indicated that they would benefit from additional training about resource-appropriate best practices for improving breast and cervical cancer care and outcomes. Coalition-building and collaborations, including with oncologists and other medical professionals involved in cancer care, were crucial to leveraging limited resources, sharing lessons learned, and developing local solutions to common challenges.

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

The 21-gene recurrence score (RS) assay (Oncotype DX™) predicts the likelihood of breast cancer recurrence and chemotherapy responsiveness. The aims of this study were to describe temporal trends in assay usage, to investigate factors associated with the receipt of the assay and to determine how the assay is associated with treatment decisions. Random samples of stage I-II female breast cancer patients diagnosed in 2004, 2005 and 2010 as reported to the National Cancer Institute's Surveillance Epidemiology and End Results program were included. Among women diagnosed in 2010 with estrogen receptor positive (ER+), lymph node-negative (LN-) tumors, factors associated with receipt of the assay were identified and the likelihood of chemotherapy by RS was estimated. Assay usage increased over time (ER+/LN-:8.0-27.0 %, p0.01; ER+/LN+: 2.0-15.7 %, p = 0.09; ER-: 0.2-1.7 %, p0.01) from 2005 to 2010. Receipt of the assay was associated with younger age, lower area income and tumor characteristics. Among women in the low (RS18) and high risk (RS30) categories, 3.3 and 95.9 % received chemotherapy, respectively. Within the intermediate risk group the receipt of chemotherapy varied: 12.8 % (RS: 18-19), 35.0 % (RS: 20-23) and 84.0 % (RS: 24-30). During the study years, assay usage increased among women for whom the assay is and is not guideline recommended. Factors such as insurance and race/ethnicity do not appear to be associated with the receipt of the assay. The RS, as determined broadly via three categories and within the intermediate risk group, does appear to influence chemotherapy decisions.

Background: Pathological complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as event-free survival (EFS) or overall survival (OS). The CTNeoBC meta-analysis did not validate the surrogacy of pCR for EFS or OS, and there is no precedent for its use as a regulatory endpoint in oncology. Use of the accelerated approval pathway has been proposed for neoadjuvant therapies that substantially improve pCR as a means to expedite widespread access to highly effective therapies for high-risk, early breast cancer. Potential risks of this approach include approving an agent that ultimately does not demonstrate clinical benefit and, in the interim, exposing curable patients to the toxicity of therapy without certainty of benefit. To mitigate the risks of this pathway, enrollment to neoadjuvant trials intended to support accelerated approval should be restricted to patients presenting with high-risk early-stage breast cancer. The 5-year EFS rate by breast cancer subtype in the CTNeoBC meta-analysis population is presented. Methods: We identified 12 neoadjuvant randomized trials (N = 12,993) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1-00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). The key objective of this analysis was to establish a definition of “high-risk” based on the Kaplan-Meier estimates of the 5-year EFS rate in the different clinical breast cancer subtypes (hormone receptor-positive, HER2-positive and triple-negative) analyzed by tumor stage and tumor grade at presentation. Results: The 5-year EFS rate was less than 65% in all the breast cancer subtypes with stage III disease. For patients with stage II disease, the impact of tumor grade varied by hormone receptor status. Patients with hormone receptor-negative breast cancer, regardless of HER2 status had a poor prognosis that was independent of tumor grade. For patients with hormone receptor-positive tumors, regardless of HER2 status, high grade histology was associated with an increased risk of recurrence. 5-year Event-Free Survival Rate (EFS) 5-year EFS Rate Estimate (95% confidence interval)TNMStage IIStage III Grade IIGrade IIIGrade IIGrade IIIHormone Receptor + HER2-83% (80%, 85%)71% (65%, 77%)63% (58%, 69%)51% (42%, 59%)HER2+ HR+81% (75%, 86%)69% (60%, 76%)50% (41%, 59%)48% (37%, 59%)HER2+ HR-61% (51%, 70%)66% (57%, 73%)58% (46%, 69%)46% (36%, 55%)Triple Negative66% (58%, 72%)72% (67%, 76%)38% (27%, 48%)37% (29%, 45%) Conclusions: This analysis estimated the 5-year EFS rate in the breast cancer subtypes from the CTNeoBC meta-analysis population. The HER2-positive population in the meta-analysis was at particularly high risk because most of the patients had locally advanced breast cancer and only 39% of these patients received trastuzumab therapy. We propose defining less than 75% 5-year EFS rate as “high-risk” for the purposes of designing neoadjuvant trials that intend to use pCR to support accelerated approval. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-17-01.

Background: Pathologic complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as disease-free survival (DFS), event-free survival (EFS), or overall survival (OS). A meta-analysis is needed to establish the magnitude of pCR improvement on a trial level that results in improved DFS, EFS, or OS. Methods: We identified 12 neoadjuvant randomized trials (N = 13,125) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1–00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), and NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). Key objectives of the meta-analysis were to determine: (1) the relationship of pCR to EFS and OS, (2) the definition of pCR that correlates best with long-term outcome, (3) the breast cancer subtypes in which pCR is best correlated with long-term outcome and (4) the magnitude of pCR effect needed to improve EFS and OS. We compared three pCR definitions: absence of invasive cancer and in situ cancer in the breast and axillary nodes (ypT0ypN0), absence of invasive cancer in the breast and axillary nodes with DCIS allowed (ypT0/isypN0), and absence of invasive cancer in the breast with DCIS allowed irrespective of nodal involvement (ypT0/is). Results: Overall 13%, 18% and 22% of patients achieved a pCR defined as ypT0ypN0, ypT0/isypN0, and ypT0/is, respectively. Eradication of tumor from both the breast and lymph nodes (ypT0ypN0 or ypT0/isypN0) was better associated with improved EFS and OS compared to eradication of tumor from the breast alone (ypT0/is). Patients who achieved a pCR (ypT0/isypN0) had an improved EFS (HR = 0.48) and OS (HR = 0.36) compared to those who did not. pCR was uncommon in patients with low-grade hormone receptor-positive (HR+) tumors (7%) and more common in the following tumor subtypes: high-grade HR+ (16%), triple negative (34%), HR+/HER2+ (30%), and hormone receptor-negative (HR−)/HER2+ (50%). Patients with more aggressive tumor subtypes who achieved pCR had greater EFS compared to patients who did not achieve pCR as follows: HR+ high grade (HR = 0.27), HR+/HER2+ (HR = 0.58), HR−/HER2+ (HR = 0.25), and triple negative (HR = 0.24). A trial level analysis on the relationship between pCR effect size and EFS did not show a correlation. Conclusions: Individual patients who attain a pCR, defined as either ypT0ypN0 or ypT0/isypN0, have a more favorable long-term outcome. The data show comparable EFS or OS regardless of the presence or absence of DCIS. For consistency, a standard pCR definition (ypT0ypN0 or ypT0/isypN0) should be used in future trials. Impact of pCR effect is limited to patients with HR+/grade 3, HR−/HER2−, and HER2+ tumors. This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS. This may be due to low pCR rates and the heterogeneity of the patient population included in this meta-analysis. The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials and may vary according to breast cancer subtype. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-11.

Background: Aromatase inhibitors are effective for breast cancer prevention in postmenopausal women. In the recent MAP.3 study, exemestane significantly reduced invasive breast cancer in postmenopausal women with an elevated risk of developing breast cancer. At 35 months follow up there was no increase risk in cardiovascular events in this study; however, the effects of exemestane use on lipid profiles and cardiovascular health are still unclear. Methods: We conducted a single-arm phase II trial of exemestane in women at increased risk for breast cancer and examined the impact of exemestane on lipid profiles. Postmenopausal women at high risk for invasive breast cancer (e.g., Gail Model risk ≥ 1.7, a history of lobular neoplasia, atypical ductal hyperplasia, DCIS, or stage I/II breast cancer, or BRCA 1/2 mutation) were given exemestane (25 mg orally daily) for 2 years. Fasting serum total cholesterol, HDL, LDL, triglycerides, and homocysteine were collected at baseline, 3, 12, and 24 months after initiation of exemestane therapy. Apolipoprotein A and B were collected at baseline, 3 and 12 months. Wilcoxon sign ranked test was used to analyze if changes from baseline values differed from zero. The Hochberg p-value adjustment was used to account for multiple hypothesis tests. Results: Of the 42 women enrolled in the study, 6 dropped out prior to completing 1 year and 1 dropped out prior to completing 2 years of exemestane therapy. Thirty-one women have completed 2 years of exemestane therapy and the remaining 4 are expected to complete 2 years of therapy by January 2012. On average, participants were 58.5 years old, mostly Caucasian (n = 37; 84.1%), and had a BMI of 29.2 kg/m2. A majority (n = 19) of participants were on lipid-lowering medications (14 were taking a statin) or taking fish oil supplements (n =5) prior to starting on the trial and 1 was started on a statin approximately 10 months after starting the trial. There were no significant differences in mean lipid values for each of the 4 assessment points or in the mean change from baseline at 3, 12, and 24 months between patients who were taking lipid-lowering medications and those were not. In unadjusted analyses, change in HDL from baseline was significantly different from zero and decreased from baseline at 3, 12 and 24 months (−8.0 mg/dL, −8.5 mg/dL, and −9.9 mg/dL; All p-values ≤ .001 before and after applying the Hochberg adjustment). Total cholesterol also significantly decreased from baseline at 3 months (−13.6 mg/dL, p = .002) but was no longer significant at 12 and 24 months (−9.6 mg/dL and −11.4 mg/dL, respectively; p-values = .07). The rest of the lipid panel did not significantly change during follow-up. Discussion: In agreement with previous studies, we found that exemestane causes a significant decrease in HDL and total cholesterol, while leaving the rest of the lipid panel unchanged. Prior studies excluded patients on lipid-lowering medication; half of our participants were taking lipid-lowering medication. It is notable that both women off and on lipid-lowering medication had decreases in HDL. Additional studies are needed to elucidate long-term cardiovascular outcomes in this high risk but otherwise healthy population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-01.

Background: A reduction in mammographic density(MD) has been associated with the reduction in breast cancer risk among those taking tamoxifen. Aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. We are conducting a phase II trial of exemestane in women at increased risk for breast cancer. The primary endpoint for this study is change in MD. Methods: Subjects were screened and enrolled at two sites: Center for Cancer Research, National Cancer Institute and Lombardi Comprehensive Cancer Center, Georgetown University Hospital. Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk ≥1. 7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were excluded if AP spine T-score was Results:For the 22 subjects included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 3 by prior breast cancers. 18 had film screen mammograms at baseline and 12 months, 4 had film screen mammograms at baseline and digital mammogram at 12 months. Mammographic density declined 7% (p=0.0006, 95% CI −11% to −3%) at one year. The change in MD ranged from −26% to +14% and the standard deviation was 9%. In regard to the four subjects who had film screen mammograms at baseline and digital at follow up, the baseline percent dense areas were slightly higher than average but this did not reach statistical significance (p=0.32 by the Wilcoxon rank sum test). The 12 month MD comparison was similar to the 18 subjects with film images (p=0.90). Conclusions: Exemestane use was associated with a statistically significant decrease in MD at one year. Prior evaluations of AI therapy in high risk women have not shown a significant decline in MD, however time on treatment was shorter and other third generation AIs were used. Although the number of subjects is small, MD did not differ significantly between film screen and digital mammograms. We will further evaluate change in MD in the entire cohort at 1 and 2 years and between film screen and digital mammography. Phase III trials are on-going to evaluate the effect of exemestane on breast cancer prevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-03.

Sentinel lymph node biopsy (SLNB) has been adopted by some physicians in the evaluation of ductal carcinoma in situ (DCIS). In a review of the current literature, we found no convincing data that SLNB is warranted as standard of care in newly diagnosed DCIS. Although lymph node invasion is present in 2% of women with traditional axillary lymph node dissection (ALND), as a result of the excellent prognosis of DCIS, it is not recommended. However, the detailed evaluation of the lymph node(s) with SLNB raises the issue that perhaps patients at risk for recurrence can be identified early and be treated aggressively without the morbidity associated with ALND. Limited data suggest that, with the use of more sensitive methods for detection of cytokeratin-positive cells, the prevalence of positive lymph nodes in pure DCIS is approximately 2%-13%. In high-risk DCIS or DCIS with microinvasion, the prevalence is 8%-20%. Several limited retrospective studies with long-term follow-up have not demonstrated an adverse relapse-free or overall survival effect for women with immunohistochemically (IHC) positive cells in the lymph nodes compared with those with negative IHC results in the lymph nodes. Sentinel lymph node biopsy in DCIS is associated with known risks, and health care benefits, if any, have not been demonstrated. Sentinel lymph node biopsy is not recommended in patients with DCIS.

Purpose: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer. Experimental Design: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m2 i.v. day 1) and capecitabine (1000 mg/m2 orally twice daily days 2–15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m2 i.v. day 1) and capecitabine (937.5 mg/m2 orally twice daily days 2–15). Results: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m2 at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m2/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine. Conclusions: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m2 docetaxel and 1600 mg/m2/day days 2–15 is recommended.

Genetic syndromes that convey a significant risk of breast cancer are responsible for a small but significant percentage of these cancers. However, the vast majority of breast cancers occur in women with no family history of the disease. Nongenetic risk factors include age, previous breast disease, breast tissue density, radiation exposure, and lifestyle factors, such as weight, exercise, and alcohol consumption. In this article, the authors outline genetic and other risk factors for breast cancer, explore risk-reduction strategies, and encourage primary care physicians to assess breast cancer risk in all their patients.

Background Apheresis catheters have simplified collection of peripheral blood stem cells (PBSC), but may be associated with thrombosis of the instrumented vessels. We performed a retrospective analysis to study the prevalence of thromboembolism associated with the use of femoral apheresis catheters in patients with breast cancer. Patients and methods Patients were participants in clinical trials of high-dose chemotherapy with autologous PBSC rescue. They underwent mobilization with either high-dose cyclophosphamide (n=21) or cyclophosphamide/paclitaxel (n=64), followed by filgrastim. Double lumen catheters (12 or 13 Fr) were placed in the femoral vein and removed within 12 h of the last apheresis procedure. Apheresis was performed using a continuous flow cell separator and ACD-A anticoagulant. Thromboembolism was diagnosed by either venous ultrasonography or ventilation-perfusion scan. Results Nine of 85 patients (10.6%) undergoing large volume apheresis with use of a femoral catheter developed thromboembolic complications. Pulmonary embolus (PE) was diagnosed in five and femoral vein thrombosis in four patients. Four of the five patients who developed PE were symptomatic; one asymptomatic patient had a pleural-based, wedge-shaped lesion detected on a staging computed tomography scan. The mean number of apheresis procedures was 2.4 (range one to four) and the mean interval between removal of the apheresis catheter and diagnosis of thrombosis was 17.6 days. In contrast, none of 18 patients undergoing apheresis using jugular venous access and none of 54 healthy allogeneic donors undergoing concurrent filgrastim-mobilized PBSC donation (mean 1.7 procedures/donor) using femoral access experienced thromboembolic complications. Conclusions Thromboembolism following femoral venous catheter placement for PBSC collection in patients with breast cancer may be more common than previously recognized. Healthy PBSC donors are not at the same risk. Onset of symptoms related to thrombosis tended to occur several weeks after catheter removal. This suggests that the physicians not only need to be vigilant during the period of apheresis, but also need to observe patients for thromboembolic complications after the catheter is removed. The long interval between the removal of apheresis catheter and the development of thromboembolism may have a potential impact on prophylactic strategies developed in future, such as the duration of prophylactic anticoagulation. Avoidance of the femoral site in breast cancer patients, and close prospective monitoring after catheter removal, are indicated.

Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.

Identification of HER2 as an important cellular marker in the biology and treatment of breast cancer has highlighted the importance of reliable testing methodology. Controversy exists regarding type of test, reliability, definition of positivity, and which test may best predict for patient (pt) efficacy to anti-HER2 therapies. Purpose: To determine the concordance between HER2 results by 3 central laboratories, impact of round-robin adjudication of discordant cases, and heterogeneity in HER2 results using specimens from 3 adjuvant trials where HER2 testing was performed by local and central laboratories for enrollment. Methods: We performed a blinded round-robin exchange of randomly sampled, HER2-normal (IHC-& FISH-) and HER2-positive breast tumors among 3 central laboratories (NCCTG, BCIRG and NSABP) for confirmatory HER2 testing. The 3 laboratories performed immunohistochemistry (IHC) for HER2 using the HercepTest kit (Dako, Carpenteria, CA) and fluorescence in situ hybridization (FISH) for HER2 using the PathVysion HER2 DNA probe kit/HER2/CEN17 probe mixture (Abbott Molecular, Des Plaines, IL) on 389 tumor specimens obtained from N9831/BCIRG006 (37 IHC+/FISH+, 33 IHC+/FISH-, 36 IHC-/FISH+, 62 IHC-& FISH-) and BCIRG005 (96 IHC-& FISH-); 123 cases had ≥2 blocks examined from the same pt. HER2 positivity was defined according to FDA-approved guidelines used in the clinical trials (IHC+: 3+ complete membrane staining in >10% cells; FISH+: HER2/CEN17 ratio ≥2.0). The HER2 status (IHC: 3+ vs 0-2+; FISH: amplified vs not) for each block was independently determined at each site; discordant IHC and FISH cases were adjudicated at a face-to-face meeting. Results: Independent reads were concordant across pathologists in IHC status in 351/381 (92%) cases and in FISH status in 343/373 (92%) cases. Upon adjudication, a consensus was reached on 16 and 18 of the discordant IHC and FISH cases, respectively. Among 96 BCIRG005 cases, IHC-and FISH-were confirmed in the primary block in all 96 cases. Among 59 evaluable N9831 HER2-normal cases, IHC-and FISH-were confirmed in the primary block in 57 (97%) cases (but another block tested HER2+ for 4 cases). Among 102 N9831/BCIRG006 HER2+ cases, HER2 positivity was confirmed in the primary block in 73 (72%) cases. Among 118 cases with IHC results for > 1 block, the adjudicated IHC result agreed across blocks in 106 (90%) cases. Among 113 cases with FISH results for >1 block, the adjudicated FISH result agreed in 107 (95%) cases. Among 53 N9831 HER2-normal cases adjudicated as IHC-& FISH-(although they all had a previous local HER2+ test), there was significant improvement in disease-free survival associated with trastuzumab given concurrently with paclitaxel after doxorubicin and cyclophosphamide compared to chemotherapy alone (HR=0.31, 95% CI 0.11-0.91; A 23 pts, 10 events; C 30 pts, 5 events). Conclusions: Excellent agreement (96%) was observed among the pathologists at adjudication, suggesting that standardized methods improve assay proficiency. HER2 heterogeneity across blocks was observed more at the protein than at the gene level. In the small subset of N9831 pts adjudicated as HER2-normal trastuzumab benefit was observed. This work was supported by NCI and Genentech. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD10-02.

Marrow stromal layers were used to investigate the potential role of negative regulators produced by the marrow microenvironment as one potential cause of hematopoietic suppression after chemotherapy and cytokines. Stromal layers were established from marrow of normal or prechemotherapy donors and breast cancer patients after hematological recovery from one cycle of 5-fluorouracil, leucovorin, doxorubicin, and cyclophosphamide and GM-CSF or PIXY321 (GM-CSF/IL-3 fusion protein). Normal donor CD34+ cells were placed in contact with stromal layers, and the number of colony-forming units for granulocytes and macrophages (CFU-GM) was determined. There were 25-79% fewer CFU-GM in post-chemotherapy stromal layer cocultures than in no chemotherapy cocultures. With neutralizing antibody to TNF-alpha the number of CFU-GM in no chemotherapy and post-chemotherapy stromal cocultures was, respectively, 96 +/- 7% (n = 5) and 142 +/- 8% (n = 5) of the number with no antibody treatment. PIXY321 and GM-CSF pretreated stromal layers also suppressed production of CFU-GM. Anti-TNF-alpha promoted an increase in CFU-GM numbers from GM-CSF, but not PIXY321, pretreated stromal cocultures. The results demonstrate that post-chemotherapy marrow stromal layers were deficient in supporting in vitro hematopoiesis and suggest that negative regulators induced by chemotherapy and cytokines may be one cause for this defect.

Our previous work in patients undergoing autologous transplant for multiple myeloma (MM) or breast cancer (BC) has shown that retroviral transduction of adult CD34+ cells for 72 hours in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor (SCF ) resulted in .01% to 1% long-term marking of peripheral blood and marrow cells (Blood 85:3948, 1995). In this study we compare these previous studies to transduction with no added growth factors, previously shown to result in higher levels of marking in children (Lancet 342:1134, 1993) or transduction in the presence of an autologous stromal layer. Peripheral blood (PB) mononuclear cells were collected via apheresis after high-dose cyclophosphamide and granulocyte colony-stimulating factor. Bone marrow (BM) was also harvested in all patients. One third of both BM and PB collections were enriched for CD34+ cells and transduced with one of two marking vectors containing the neomycin-resistance gene to distinguish cells originating from BM and PB posttransplantation. Cells from 3 MM and 2 BC patients were transduced without growth factors for 6 hours and cells from 2 MM and 2 BC patients were transduced in the presence of autologous marrow stroma. Immediately posttransduction, the percentage of Neo-resistant PB and BM progenitors (colony-forming units) were: 0% to 19% in the 6-hour no growth factor group and 0% to 36% in the autologous stroma group. After conditioning therapy, both transduced and untransduced PB and BM fractions were infused into the patients. Semi-quantitative nested DNA polymerase chain reaction was performed on total, mononuclear, and granulocyte fractions of PB and BM at 1, 3, 6, 9, 12, and 18 months. Poor marking has been observed in both groups, with no consistently positive patients. These results compare unfavorably with our prior experience using growth factors during transduction. Further optimization of transduction conditions and vectors needs to be developed to improve transduction efficiency of adult human repopulating hematopoietic cells.

New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. Clin Cancer Res; 19(11); 2817–23. ©2013 AACR.

These studies investigated the effectiveness of in vivo administration of cytokines in ameliorating potential marrow damage induced by chemotherapy. Breast cancer patients received 5-fluorouracil, leucovorin, doxorubicin and cyclophosphamide (FLAC) followed by either GM-CSF, PIXY321, or no cytokine. Marrow was obtained before and after one or two cycles of FLAC once blood cell counts had recovered. Colony-forming units for granulocytes and macrophages (CFU-GM) were used to indicate the effect of therapy on recovery of committed progenitor cells responsible for early blood cell recovery. The frequency and number of CFU-GM in marrow obtained after FLAC + PIXY321 were significantly lower than in marrow obtained after FLAC+GM-CSF or FLAC without cytokine. CD34+ cell numbers were also reduced after FLAC + PIXY321. CFU-GM production in marrow long-term cultures (LTC) was used to assess the effect of therapy on primitive progenitors. After 5 weeks the number of CFU-GM in LTC of post-therapy marrow from all three treatment arms was < 15% of the number in pre-therapy LTC. Suppressive effects of FLAC on primitive progenitors were observed even when committed progenitors and CD34+ cells had recovered to pre-therapy levels. These results demonstrate that cytokine treatment did not ameliorate suppressive or toxic effects of FLAC on the functional integrity of the marrow.

This study utilized a recently developed culture and quantitation system to detect megakaryocyte precursors in CD34' bone marrow cells from normal donors and breast cancer patients treated with 5-fluorouracil, leucovorin, adriamycin and cyclophosphamide (FLAC). Bone marrow was obtained from patients before and then after their first cycle of FLAC once blood cell counts had reeovered. CD34+ cells were isolated and placed in liquid culture with growth factors to stimulate pro- liferation and lineage commitment. Absorbance values from an enzyme-linked immunosorbent assay were used to quantitate expression of platelet glycoprotein GPIIbDIIa. There was an increase in absorbance with increasing numbers of cells seeded per culture that was associated with an increase in the number of megakaryocyte lineage cells pro- duced. After 10 days in liquid culture, absorbance values for expression of GPIIbDIIa from 2,000 nor- mal donor and pre-chemotherapy CD34+ marrow cells were 2 1.0. Absorbance values from cultures of post-chemotherapy CD34+ cells from four patients were similar to values from pre-chemotherapy CD34' cells. In contrast, absorbance values from cultures of post-chemotherapy CD34' cells from two other patients were low (absorbance ~0.5). Low absorbance values for GPIIbDIIa expression indi- cate that megakaryocyte production from those CD34+ cells was reduced. Both of those patients developed prolonged thrombocytopenia and platelet nadirs of less than 20,0OO/pl during FLAC chemotherapy. In contrast, only one out of four patients whose cultures of post-chemotherapy CD34+ cells had absorbance values 2 1.0 developed platelet nadirs less than 20,OOO/pl. These results suggest that low platelet nadirs and delayed platelet recovery may be associated with suppressive effects of chemotherapy on recovery of megakaryocyte precursors. Stern Cells 1996;14(suppl1):31-37

PURPOSE In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

Introduction: Preliminary data show that up to 10% of patients on early clinical trials have complete (CR) or partial (PR) responses. Exceptional responses (ER) are also observed in certain clinical cases using standard chemotherapy. The ERI Pilot study is evaluating the molecular alterations found in tumors from cancer patients who respond to a systemic treatment (standard or investigational) that is ineffective in at least 90% of patients. The study is available through the Cancer Trials Support Unit (www.ctsu.org). Experimental Procedures Cases of patients who achieve a CR or PR > 6 months are proposed by email at NCIExceptionalResponders@mail.nih.gov. Once provisionally approved, the proposer sends tissue to a central repository, where the tissue is evaluated for percent tumor &necrosis; nucleic acids are isolated & sent for whole exome, mRNA & deep targeted sequencing. Tissue may be frozen or formalin fixed paraffin embedded but must be at least an entire core biopsy. Data will be correlated with mechanism of action of the treatment given. The ERI pilot study will characterize > 100 ERs. If sufficient tissue is available, whole genome sequencing &other molecular analysis may be done. We anticipate that some specimens will not be of sufficient quality/quantity; thus many more tumors will need to be submitted to obtain these results. Six months after the genomic data are generated they will be released to a publicly available, controlled access database to facilitate research by qualified investigators. The ERI study accepts all types of malignant disease in adults or children if adequate tissue obtained prior to the ER exists. The ER could have been to an approved or investigational, targeted, or non-targeted systemic treatment. The feasibility of retrospectively collecting tumor tissue & clinical data for genomic analysis is a goal of the ERI study. Results: The ER study was activated on September 24, 2014. As of December 2, > 80 cases have been proposed, 46 are provisionally approved & 26 cases were not ERs or were withdrawn. Accepted Cases: solid & hematologic tumors (2 brain, 4 breast, 2 colon, 6 gastric, 1 hepatocellular, 7 head/neck, 2 renal, 2 lung cancer, 1 melanoma, 2 ovarian, 6 pancreatic, 2 prostate and 4 sarcomas; 2 acute leukemia, 2 lymphoma, 1 myeloma). Approximately 75% involved standard & 25% involved targeted drugs or combinations. Tissue analysis is ongoing & results will be presented. Conclusions: Collection of archived tissue from ERs for genomic evaluation is feasible. Efficient ER case identification occurs through expert review and consensus-based case selection. Citation Format: Barbara A. Conley, S Percy Ivy, James V. Tricoli, Jean-Claude Zenklusen, Roy Tarnuzzer, Irina Lubensky, Naoko Takebe, Paul M. Williams, JoAnne Zujewski, Richard Little, Jeffrey White, Elise Kohn, Shakun Malik, Ben Kim, Erin Souhan, Lou Staudt. The NCI exceptional responders initiatives: Initial feasibility result. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 612. doi:10.1158/1538-7445.AM2015-612

Background: Preoperative chemotherapy for stage II breast cancer may reduce locoregional tumors and provides initial treatment for systemic micrometastases. We conducted a prospective, randomized trial to evaluate the ability of intensive preoperative chemotherapy to enhance the outcome of this approach. Methods: Patients with clinical stage II breast cancer (T2N0, T1N1, and T2N1) were prospectively randomized to receive either preoperative or postoperative chemotherapy with five 21-day cycles of fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC)/granulocyte-colony-stimulating factor. Local therapy consisted of modified radical mastectomy or segmentectomy/axillary dissection/breast radiotherapy, according to patient preference. Results: Fifty-three women were randomized (26 preoperative chemotherapy and 27 postoperative chemotherapy). The objective clinical response rate of the primary tumor to preoperative chemotherapy was 80%, and the pathologic complete response rate was 20%. Preoperative chemotherapy reduced the overall incidence and number of axillary lymph node metastases. There was no difference in the use of breast-conserving local therapy between the two treatment arms. There were 20 local/regional or distant recurrences (9 preoperative and 11 postoperative). There was no difference in the overall or disease-free survival between the preoperative and postoperative chemotherapy arms. Conclusions: Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy was effective against local/regional tumors in stage II breast cancer but was otherwise comparable to postoperative chemotherapy.

Farnesyl transferase inhibitors (FTIs) serve to specifically inhibit farnesyl isoprenoid lipid modification of proteins. Although originally developed as anti-Ras oncoprotein drugs, it now appears that these compounds function independently of Ras. FTIs have been shown to inhibit transformation by a variety of mechanisms, including apoptosis involving cytochrome c release from mitochondria. Tamoxifen exhibits both anti-estrogenic and estrogenic properties and is widely used as an estrogen antagonist for the treatment of estrogen receptor (ER) positive human breast tumors. Tamoxifen can induce ER-dependent apoptosis in human breast tumor cells by a mechanism involving the Bcl2/mitochondrial arm of the apoptotic machinery. Since tamoxifen and FTIs may stimulate distinct components of the mitochondrial-based apoptotic machinery, we reasoned that their effects might be synergistic. Here we show that anti-estrogens and an FTI (FTI-277) synergize to inhibit cell growth and enhance cell death in ER positive, human breast tumor cell lines. However, the drugs exhibited only additive effects on an ER negative cell line. Analysis of treated ER positive T-47D cells demonstrated that a synergistic increase in apoptosis was induced, as measured by increased caspase 3 activity. Thus, tamoxifen and FTIs may synergize to promote apoptotic cell death in ER positive human breast tumor cells.

Background: PARPi O demonstrates single agent activity in breast and ovarian cancer (Br/OvCa) pts with germline BRCA1/2 mutation (gBRCAm), and with BRCA-like phenotype. Subsets of TNBC are known to respond to therapies targeting DNA repair mechanisms. We hypothesize that O and C combination can be safely tolerated in TNBC pts and may result in benefit. Methods: Pts with recurrent or unresectable TNBC, BRCAPro score Results: 25 women (median age 52 [39-76]) were treated. All pts except one received prior therapy (median 5 [0-12]; prior platinum in 3pts). DLT was thrombocytopenia (DL 2: O 400mg/C AUC4 [1/6pts] and DL3: O 400mg/C AUC 5 [2/3pts]). MTD was reached at DL3 (C/AUC 5 with O 400mg capsule q12h d1-7 q21d). The expansion dose was O 400mg q12h d1-7, C/AUC 4. Gr 3/4 AEs included neutropenia (36%), thrombocytopenia (12%), and anemia (12%). 2 pts required C dose reduction and early discontinuation due to delayed marrow recovery. 13 pts (52%) needed peg-filgrastim, 6 (24%) blood transfusion, and 3 (12%) erythropoietin on at least one cycle. Responses (N=22 evaluable) included 1 CR (46+ mo), 2 PR (3, 5 mo), and 8 with SD ≥4 mo (36%; median 5 [4-7]), for a disease control rate of 50%. The pt who achieved CR had a strong family history of Br/OvCa. Peripheral blood mononuclear cells preC1, d3 or d7, and prior to C2 were collected for PAR incorporation ELISA. Paired tumor biopsies (pre/post-cycle1) were obtained from expansion cohort patients for biomarker proteomics and apoptosis endpoints; results will be presented. Conclusions: RP2D O capsule formulation 400 mg q12h d1-7 with C AUC4 q21d is tolerable in heavily pretreated TNBC pts. Interactive marrow suppression was observed. Citation Format: Victoria L. Chiou, Elise C. Kohn, Christina M. Annunziata, Lori Minasian, JoAnne Zujewski, Minshu Yu, Jay Ji, James Doroshow, Nicolas Gordon, Nicole Houston, Jung-Min Lee. Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT337. doi:10.1158/1538-7445.AM2014-CT337

Aim: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised phase III adjuvant breast cancer trial comparing 3 oral lapatinib (L)-containing regimens with trastuzumab (T), each given for 1 year. DFS results of L + T and T—> L compared to T, presented at ASCO 2014, showed a non-significant DFS benefit. Results of L vs T and key secondary analyses are presented for the first time. Methods: 8381 patients (pts) were randomised to receive either T (N = 2097), L (N = 2100), T —> L (N = 2091), or L + T (N = 2093) from 2007-2011. Primary comparison of L vs T evaluated non-inferiority at a margin of 1.11 and the futility boundary for this arm was crossed resulting in premature arm closure (Aug 2011). Pts in the L arm who were free of disease recurrence at that time were offered T as adjuvant treatment. Key secondary analyses including DFS by hormone receptor status and CNS endpoints are now presented. Results: In 4197 pts and at a median follow-up of 4.5 years, 366 (17%) DFS events in the L and 301 (14%) DFS events in the T arms were observed. 1090 (52%) pts in the L arm received at least one T dose. In post-hoc analysis, there was evidence that these pts benefitted from receiving T [hazard ratio (HR) = 0.67; 95% CI 0.49-0.91 from a time-dependent Cox model of DFS]. The non-inferiority HR was 1.34 (95% CI 1.15-1.56) in the ITT population; 1.45 for hormone receptor negative, 1.23 for hormone receptor positive. CNS as first site of metastases occurred in 2% of cases in all arms. AEs of any grade were more common with L than T: diarrhoea (64% vs 20%), rash or erythema (54% vs 20%) and hepatobiliary (25% vs 16%). Any cardiac events were infrequent in both arms, but more common in T compared to L (4.5% vs 1.9%; p Conclusions: Overall, L added to T did not statistically improve DFS. L did not appear to decrease the rate of CNS as first site of metastases. T confers a better outcome compared to L in pts with HER2-positive EBC and remains the standard of care. There is evidence of T benefit even when initiated later in the course of follow-up. Disclosure: E. De Azambuja: Disclosed an advisory role with GSK; honoraria from Roche; research funding from GSK; and travel grants from GSK/Roche; G. Viale: disclosed an advisory role with Roche and Dako; and honoraria from GSK, Roche, and Dako; R. Crescenzo: disclosed compensated employment with GlaxoSmithKline; and stock ownership with Glaxo SmithKline; K. Pritchard: disclosed an advisory role with Roche; honoraria from Roche; research funding from Roche; and expert testimony on behalf of Roche; C. Jackisch: disclosed honoraria from Roche and GSK; F. Boyle: disclosed honoraria from GlaxoSmithKline; and research funding from GlaxoSmithKline; R.D. Gelber: disclosed research funding from GSK and Roche; M. Piccart: disclosed consultancy with PharmaMar; honoraria from Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, Sanofi Aventis, Symphogen, Synthon, and Verastem; research grants from most companies. All other authors have declared no conflicts of interest.

508 Background: Adjuvant T plus chemotherapy improves disease-free survival (DFS) and overall survival (OS) vs. chemotherapy alone for pts with early stage HER2-positive breast cancer. We conducted a meta-analysis to estimate DFS and OS for pts with small tumors (≤2cm) in the T arms from 5 of the 6 randomized adjuvant trastuzumab trials. Pts with tumors ≤2cm, with 0 or 1 positive lymph nodes, and hormone receptor (HR) positive disease had a 5-year DFS of 91% and a 5-year OS of 97% (O’Sullivan, SABCS 2013; abstract:1327). We now plan to conduct an additional meta-analysis to assess the efficacy of T compared with no T for pts with small tumors (≤2cm). Methods: Six randomized controlled trials (RCT) were identified by a Medline search from 2004-2013. Trial groups from 5 phase III RCTs provided data (HERA, NCCTG N9831, NSABP B31, PACS 04, and FinHER).In total, 11,200 pts were randomized in these 5 trials;4,220 of whom had ≤2cm tumors, and known number of positive axillary lymph nodes and HR status(2,588 rand...

Background Trastuzumab (T) combined with chemotherapy improves survival of women with HER2-positive breast cancer. Dual therapy with T and other HER-2 targeted agents (lapatinib/pertuzumab) has demonstrated improved efficacy compared to T alone in advanced breast cancer, and is in clinical trials in early stage disease. We hypothesize that subgroups of patients with HER2-positive tumors and limited tumor burden (tumor size and no or few positive lymph nodes) have a favorable outcome and would not be candidates for dual therapy. This study will analyze the disease-free survival (DFS)and overall survival (OS) of patients with early stage breast cancer treated with chemotherapy and T in the seminal randomized studies (RCTs). Methods RCTs were identified by a Medline search from 2004-2013. Trial groups from five phase III RCTs agreed to provide data. TrialNumberEligibilityRegimenNSABP B312130T1-3; pN1, pN2a, or pN3a; M0ACx4 then Tx4 VSACx4 then THx4 then Hx40wkNCCTG N98313505T1-3; pN1-2; M0ACx4 then Tx12wk VS ACTx4 then Hx52wk VS ACx4 then Tx12wk then Hx40wkHERA5102T1-3; pN1-2; M0Any (neo)adjuvant regimen, then H q3wk x1yr VS H q3wk x 2yr VS observationFinHER232T1-4; N0-3; M0Vx3 or T*x3 then FECx3 VS Vx3 or T*x3 with Hx9wk then FECx3PACS043010(528 HER2+)T1-3; pN1-2; M0FE(100)Cx6 VSFE(100)Cx6 then Hx1yr VS T*E(75) x6 VS T*E(75) x6 then Hx1yrA, adriamycin; C, cyclophosphamide; T, paclitaxel; T*, docetaxel; H, trastuzumab; P, carboplatin; F, 5-fluorouracil; E, epirubicin; Treatment regimen also included 5 years of hormonal therapy for ER positive patients. The ER+/HER2+ and the ER-/HER2+ cohorts will be analyzed separately. Patients with tumors 3 cm or smaller (T1a, T1b, T1c and >2 cm- 3cm) and 0, 1, 2 and 3 positive lymph nodes will be included. Initially a log rank test will be used to determine if the survival results are different by study. If there is no difference across studies, Kaplan-Meier survival curves with confidence intervals will be estimated. If there is a difference between studies, individual Kaplan-Meier curves will be estimated and the mean of the curves will be estimated along with confidence intervals using the adjusted standard deviation. Estimates at 3, 5 and 8 years will be presented as well as estimates of the event rates within each subpopulation defined by tumor size, number of positive lymph nodes, and ER status. Survival endpoints of DFS, and OS as defined in the original studies will be analyzed. Results and Conclusion Data from the five trials will be analyzed and an abstract provided prior to the meeting. Subgroups of patients with a very favorable outcome when treated with adjuvant chemotherapy and T will be identified. Our survival estimates might serve as benchmarks for future trials evaluating therapy reduction. Our results will complement those of the Dana Farber single arm multicenter trial in patients with “low risk” HER2-positive disease (APT trial; NCT00542451), being submitted to SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-03.

Background: Tamoxifen and fenretinide combination therapy has been shown to be an active treatment regimen in metastatic breast cancer patients. This pilot study sought to determine whether the addition of fenretinide to tamoxifen would be associated with antitumor activity in metastatic breast cancer patients who had been previously treated with tamoxifen or who had hormone receptor negative disease. The effect of this therapy on circulating plasma transforming growth factor‐beta (TGF‐β) levels and serum lipids was also examined. Patientsand Methods: Thirty‐one patients were treated with tamoxifen (20mg po daily), and fenretinide (400mg po daily with a 3‐day drug holiday each month). Plasma TGF‐β testing was performed using isoform specific sandwich ELISA. Results: Twenty four of the 31 patients were evaluable for an antitumor response including 14 estrogen receptor (ER) positive patients who had failed prior tamoxifen therapy, seven ER‐negative patients, and three hormone therapy naive ER‐positive patients. There were no objective antitumor responses; three patients had stable disease for 8, 8, and 24 months. Five patients (16%) discontinued therapy for toxicity (one for grade 3 skin rash and four for abnormal dark adaptation). There was a statistically significant decrease in total cholesterol (median change per patient of −13.5 mg/dl; p=0.049, a 6.5% decrease), and an increase in HDL levels (median change per patient of +18 mg/dl, p=0.0001, a 35% increase) with tamoxifen and fenretinide therapy. TGF-β1 plasma levels were normal in 26 of 28 patients, and no changes in these levels post-treatment were demonstrated. Conclusions: Tamoxifen and fenretinide therapy is not an active combination in ER negative metastatic breast cancer or in patients whose disease has progressed on tamoxifen. This combination had a beneficial effect on total serum cholesterol and HDL levels with no associated rise in serum triglyceride levels. The 400 mg dose of fenretinide was associated with symptomatic nyctalopia in one-third of patients making it an unsuitable dose for use in breast cancer prevention studies.

High-dose chemotherapy with autologous bone marrow or stem cell rescue (HDC/ASCR) has been proposed as a promising treatment strategy for breast cancer. Despite the frequency with which this procedure is performed, the role of HDC/ASCR in the treatment of breast cancer remains undefined. The purpose of this review is to examine the rationale for the procedure, the research progress to date, and the limitations of available data. A literature search of Medline from January 1966 through May 1997, CancerLit from January 1983 through May 1997, and Current Contents through May 1997 identified more than 600 English language papers or abstracts on this topic. Our review focuses on the preclinical and clinical data that explore the concept of chemotherapy dose intensity and the role of dose intensity in treating breast cancer. HDC/ASCR is based on the hypothesis that high-dose chemotherapy will overcome drug resistance, eradicate metastatic disease, and increase the proportion of women with breast cancer who are "cured." To date, results from only one phase 3 trial of HDC/ASCR compared with more conventional therapy have been published. Phase 2 and some phase 3 data on HDC/ASCR in the treatment of high-risk primary breast cancer and metastatic breast cancer are discussed. However, the results are inconclusive. The completion of national and international randomized trials is urgently needed to establish definitively the role of HDC/ASCR in the treatment of breast cancer.

Primitive hematopoietic progenitor and stem cells have been pursued as highly desirable targets for genetic therapy. Retroviral vectors have been used for the majority of preclinical and clinical studies directed at these cells; however, both preclinical and early clinical studies indicate that the gene transfer efficiency of the current generation of vectors using known transduction conditions into primate and human repopulating stem cells is too low to be of clinical utility in most situations. In this presentation I will summarize the status of our completed and ongoing clinical genetic marking trials, and describe our efforts in the laboratory and use of primate transplantation models to improve on these results.

2514 Background: O capsules have single agent activity against Br/OvCa in BRCA1/2mut+carriers. Our goals were to define safety and explore predictive biomarkers for an OC regimen in these pts. Methods: 3x3 dose escalation optimized daily oral O (100 or 200mg q12h; DL1&2) with IV C/AUC3 on d8 and q21d, and on DL3-6, O d1-7 at 200 then 400mg q12h with C/AUC3-5 on d2. ≤ 8 OC cycles were given, followed by daily O until progression. Safety was assessed q cycle and response q2 cycles. PBMCs were collected for polymorphism analysis (PARP1; XRCC1), and serially for PAR incorporation by ELISA. Paired tumor biopsies (pre/postC1) were collected in phase Ib pts for protein microarray (RPPA) and TUNEL endpoints. Results: 45 women (37Ov/8Br) with BRCA1 (32), BRCA2 (11), 1 each BRCA1&2 and BRCApro 68% received OC. All OvCa pts previously received C (6-55mo prior, median 14). DLT was thrombocytopenia (O 200mg q12h, C/AUC3 2/5 pts). MTD was not reached on the intermittent schedule. RP2D is O 400mg q12hx14, C/AUC5 (1/6: g4 thrombocytopenia). Gr 3/4 AEs included neutropenia (42%), thrombocytopenia (20%), anemia (13%), C hypersensitivity (9%), and fatigue (7%). 7 pts discontinued C early for hypersensitivity reaction (4) or myelosuppression (3). Responses included 1 CR (BrCa, 17mo), PR in 15/34 OvCa (44%; 3-28+mo) and 6/8 BrCa (5-24+ mo), and stabilization in 14/34 OvCa (41%; 3-25+ mo) and a BrCa pt (11mo) for a clinical benefit rate of 85% OvCa, 100% BrCa. RPPA (N=10) showed high FOXO3 and NFκB1 preC1 correlated with time on study (r=0.822, p=0.0035; r=-0.832, p=0.0028, respectively). The change post-preC1 correlated with time on study for the combination of eIF4E/G, caspase 7, pPI3K, FOXO3a, p62, E-cadherin, PCNA, Bim, and Bcl2 (r=-0.855, p=0.0068). Post-preC1 TUNEL results trended to correlate with response (p=0.07). PBMC PAR concentrations and PARP1/XRCC1 polymorphisms did not correlate with response. Conclusions: O 400mg q12h x14 with C/AUC5 q21d is active and tolerable in Br/OvCa BRCAmut+ pts despite interactive marrow suppression. Exploratory translational studies indicate FOXO3 and NFkB1 may be predictive for response to therapy, requiring a prospective validation. Clinical trial information: NCT00647062.

In order to optimally integrate radiotracer breast imaging within the breast clinic, anatomy and pathology should be easily correlated with functional nuclear medicine breast images. As a first step in the development of a hybrid functional/anatomic breast imaging platform with biopsy capability, a conventional X-ray mammography gantry was modified to image the compressed breast with positron emitters. Phantom studies with the positron emission mammography (PEM) device showed that a 1-cc hot spot could be detected within 5 min. A preliminary clinical trial demonstrated in vivo visualization of primary breast cancer within 4 min. For sites where positron-emitting radionuclides are available, PEM promises to achieve low-cost directed functional examination of breast abnormalities, with the potential for achieving X-ray correlation and image-guided biopsy.

Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.

Background: C, O, and C+O have documented activity in BRCA1/2mut+ or BRCA-like breast and ovarian cancers (Br/OvCa). The effect of drug sequence on DNA damage and cell death is unknown. Our in vitro modeling suggests that exposure to O prior to C (O>C) reduced double stranded DNA damage and cell loss. Our trial tests the hypothesis that C>O causes more cellular injury. Methods: Eligible pts have recurrent women's cancers, good end organ function, and evaluable disease. A 3+3 dose escalation run-in defined the O tablet dose in combination with C (AUC 4). The study will now randomize pts to schedule A or B (below), allowing intra-pt and inter-cohort analysis of PK/PD endpoints. PBMCs will be collected C1/2 for measurement of platination and DNA damage/repair; DNA repair protein integrity will be assessed on archival tissues. Clinical benefit, response frequency and duration, and toxicity will be ascertained. Mutation carriers will undergo progression biopsy for analysis of BRCA1/2 re-expression mutations. Results: The phase I portion is complete. 12 women (8Ov/3Br/1Endometrial[En]) have been accrued on 3 dose levels (DLs). Median prior number of regimens was 5. No DLT have been seen in 5 evaluable pts on DL3 (O tablet 200mg q12h/C AUC4 [1 pt pending]). Gr3 AEs included neutropenia (44%), and gr2 were anemia (56%), fatigue (22 %), C hypersensitivity (22%), thrombocytopenia (11%), and nausea (11%). 1 pt (DL2; stable disease) died of unrelated bleeding during C4. Clinical benefit has been observed in 8 evaluable pts with PR in 2 BRCA1mut+ OvCa (9+, 11+ mo), stabilization > 4mo in 6 pts (4OvCa,1BrCa, 1EnCa), and 3 are TETE. Conclusions: O in tablet formulation at 200mg q12h x 7d with C AUC4 q21d is active and tolerable, with observed interactive marrow suppression. Subsequent women will be randomized to examine schedule dependence of activity and toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1754. doi:1538-7445.AM2012-1754

5019 Background: We targeted the VEGF pathway at multiple points by combining the VEGFR2/Raf kinase inhibitor sorafenib (S) with bevacizumab (B), a selective anti-VEGF antibody. We hypothesized tha...

2520 Background: The PARPi O has single-agent activity against BRCA1/2 mutation carriers (Br/Ov mut+) Br/OvCa. We hypothesized addition of C to O to stress the DNA repair machinery would further im...

TPS163 Background: Despite the tremendous promise of new signal transduction and angiogenesis inhibitors, these targeted drugs have met with mixed results so far in the clinic. In solid tumors, inhibition of multiple targets may be necessary for significant clinical effects. Dasatinib is an inhibitor of all SRC-family kinases, as well as BCR-ABL, c-KIT, multiple EPH-family kinases, PDGFβ receptor and other tyrosine kinases. Bevacizumab is a humanized IgG1 monoclonal antibody that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF) with high affinity. Attenuation of both c-Src and VEGF pathways simultaneously provides the potential for synergistic antitumor activity, as there is a extensive interaction between these pathways. VEGFR transmits its downstream signal through multiple pathways involving c-Src (including activation of the prosurvival FAK pathway). Alternatively, VEGF production is known to be Src-mediated (including via STAT5 signaling). Thus, inhibition of ...

Background: N9831 is the only randomized phase III trial comparing safety and efficacy of the addition of trastuzumab (H) to doxorubicin and cyclophosphamide then paclitaxel (Arm A: AC→T) either following (Arm B: AC→T→H) or starting concurrently with paclitaxel (Arm C: AC→T+H→H) for women with resected Stage I-III invasive HER2+ breast cancer. The 3 yr cumulative incidence of NYHA class III or IV congestive heart failure or sudden cardiac death was previously reported: 3.3% in Arm C, 2.8% in Arm B (Perez EA, et al. JCO 2008). The comparison of AC→T to AC→T+H→H was reported in a joint analysis of N9831 and NSABP B-31 in 2005 and updated in 2007, demonstrating a 52% reduction in risk of a disease event (Romond E et al., NEJM 2005; Perez EA, et al. ASCO 2007).Materials and Methods: Primary endpoint is disease-free survival (DFS). At the second planned interim analysis of Arm A vs. Arm B, the O’Brien-Fleming boundary (OFB) was crossed. NCCTG Independent Data Safety Monitoring Committee approved the release of these data as well as the data pertaining to Arm B vs. Arm C due to slow pace of events [expected 647 events in 4 yr follow-up period (f/u) vs. actual 334 events in 4.5 yr f/u]. Shortly thereafter, there were sufficient events to perform the first planned interim analysis of B vs. C. We present the results of each of these pairwise comparisons taking into account the potential for crossover to Arm C after the release of the joint analysis findings in 2005.Results: From 5/2000 to 4/2005, 2448 eligible women were enrolled for the Arm A (n=1087) vs. Arm B (n=1097) comparison. Median f/u is 5.5 yrs. with 386 events. The addition of trastuzumab sequentially to AC→T significantly improved DFS, univariately [HR(Arm B/Arm A)=0.70, 95% CI: 57-86%, logrank p=0.0005] and after adjusting for age, tumor size, number of positive nodes, and ER [PPH: HRadj=0.67 (95% CI: 0.55-0.82)]. 5 yr DFS was increased from 72% with AC→T to 80% with AC→T →H.From 5/2000 to 4/2005, 1903 eligible women were enrolled for the Arm B (n=954) vs. Arm C (n=949) comparison. Median f/u is 5.3 yrs. with 312 events. The log-rank p-value testing whether DFS differs with respect to starting time of trastuzumab was 0.019. [Not crossing pre-specified OFB for statistical significance]. After adjusting for tumor size, number of positive nodes, and ER, HRadj(Arm C/Arm B)=0.75 (95% CI: 0.60-0.94)]. 5 yr DFS was increased from 80% with AC→T →H to 84% for AC→T+H →H.Conclusions: DFS is significantly improved with the addition of 52 weeks of H (sequentially or concurrently) to AC→ T. There is a statistically significant 33% reduction in the risk of an event with the sequential addition of H following AC→T. There is a strong trend for a 25% reduction in the risk of an event with starting H concurrently with T relative to sequentially after T. Therefore, based on a positive risk/benefit ratio, we recommend that trastuzumab be incorporated in a concurrent fashion with T chemotherapy.Acknowledgements: NIH CA25224, Breast Cancer Research Foundation, Genentech. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 80. NOTE: This abstract was accepted for presentation at the Symposium after the Abstract Book went to press.

Abstract #5086 Background: The aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. However these agents have been shown to decrease bone mineral density in women with breast cancer. Exemestane, a steroidal aromatase inhibitor, may be more bone sparing than the non-steroidal aromatase inhibitors. Methods: We conducted a phase II trial of exemestane in postmenopausal women at increased risk of breast cancer to assess the effect on anterior-posterior (AP) spine and total hip bone mineral density (BMD). Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk > 1.7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were required to undergo DEXA scan of the AP spine and hip at baseline and were excluded if AP spine T-score was ≤-2.5. AP spine measurements were done twice at each time point and the results averaged. Study participants receive exemestane 25 mg, calcium carbonate 1200 mg and vitamin D 400 IU daily for two years. We report the results of a planned interim safety analysis assessing one year change in bone density in the first 18 subjects. Student's t-test was used to determine relative change from baseline in AP spine and total hip BMD. Results: To date, 30 women have enrolled in the trial and 21 have completed 1 year of exemestane. Three women discontinued agent after an average of 3 months due to joint pain. For the 21 included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 2 by prior breast cancers. The average change in AP spine BMD from baseline to 1 year (N= 21) is –1.3 %, range -10.0 to +7.0% (p=0.20 for the null hypothesis of zero overall change; 95% C.I. for the mean -3.2% to +0.7%). Average AP spine T score is -0.28 at baseline and -0.45 at one year. Change in total hip BMD is -1.4%, range -7.5% to 5.9% (p=0.058, 95% C.I. -2.8% to +0.1%). Average total hip T score is -0.05 at baseline and -0.17 at one year. Conclusions: These preliminary data suggest that exemestane 25 mg/day for one year with concurrent calcium and vitamin D has acceptable effects on bone density in postmenopausal high risk women, although there were wide ranges in effects. The observed average reduction in BMD is less than the reported effect in treatment studies of women with invasive breast cancer. Studies are in progress to determine whether exemestane use by postmenopausal women is effective in reducing the risk of invasive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5086.

1518 Background: Breast MRI volume (MRIV) and mammographic density (MD) assess the amount of fibroglandular tissue in the breast. While increased MD is associated with a 4 to 6 fold increase in breast cancer risk, the association between MRIV and breast cancer is unknown. Previous studies have shown that MRIV and MD can be modulated with hormonal interventions. We evaluated the effect of raloxifene on MRIV in premenopausal women at increased risk for breast cancer. We have previously reported that raloxifene did not change MD in this cohort. Raloxifene is indicated for the prevention and treatment of osteoporosis but not for prevention of breast cancer or for use in premenopausal women. Methods: Premenopausal women at increased risk by virtue of: Gail model risk > 1.7% over 5 years; lobular neoplasia, ductal carcinoma in situ, BRCA1/2 mutation positive, or a very strong family history were eligible for this phase II chemoprevention study. MRIs obtained at baseline and after two years on raloxifene 60 mg daily, and one year after discontinuing the drug were evaluated.T1 weighted spoiled gradient-echo MRI with fat suppression was used to determine volume using a semiautomatic method, after visual verification. Median relative change in MRIV was assessed by the Wilcoxon signed rank test. Results: 19 of 30 subjects who started study drug had breast MRI at baseline and after 2 years on raloxifene; median relative change was -16% (range -57 to +25%) (p=0.0004). 17 subjects had MRI at year 2 and one year after stopping drug. No significant change in MRIV was observed after stopping raloxifene, median relative change -9% (p=0.64). Conclusions: MRIV significantly declined while on raloxifene. In contrast no significant change in percent mammographic density in this same cohort was seen. Our findings suggest that MRIV may be a better surrogate biomarker than MD in premenopausal women at risk for breast cancer because of less variation in its measurement. MRIV should be further evaluated as a potential surrogate biomarker in prevention studies. No significant financial relationships to disclose.