Citations

Abstract Background: There is an increasing recognition that many young women with breast cancer will have favorable outcomes without chemotherapy. We sought to characterize decision-making surrounding adjuvant chemotherapy treatment (CT) in this population for whom chemotherapy has historically been a standard of care. Methods: As part of an ongoing, multi-center, prospective cohort of young women diagnosed with breast cancer at age 40 and younger, we identified 657 women with Stage I-III breast cancer. Participants were asked to complete surveys by mail that included questions about socio-demographics, decision-making, and treatment history within the first year following diagnosis. Tumor characteristics were ascertained via pathology and medical record review. We used Chi-square tests to compare: decisional involvement (patient-driven vs. shared vs. physician-driven), degree of confidence, and feeling informed about the CT decision (the latter two measured on a 0-10 scale, categorized as follows: 0-5=low; moderate=6-8; 9-10=high) between women who did and did not receive CT. To explore clinical appropriateness of the CT decision, we used logistic regression to assess the relationship between tumor characteristics and non-receipt of CT among women with Stage I/II disease. Results: Among women with Stage I (n=250), II (n=312), and III (n=95), disease, 66%, 95%, and 100%, received CT, respectively. A greater proportion of women who had CT were highly confident with their decision compared with women who did not have CT (80% vs. 60%, p<0.0001); women who did not have CT were more likely to report a low level of feeling informed about the CT decision compared to women who received CT (20% vs. 5%, p<0.0001). Women who did not have CT were also more likely to report the final CT decision as made by their doctor (49% vs. 28%) and less likely to report a shared decision (33% vs. 59%, p<0.0001). Non-receipt of CT in women with Stage I/II disease (n=546) was associated within having node negative disease, T1 (vs. T2 or larger), Her2- negative, and hormone receptor positive tumors. Conclusion: Although non-receipt of CT would be expected to be viewed favorably by patients and doctors, we found that women who received CT felt more confident and better informed than those who received no CT. Given that women who did not have CT were also less likely to perceive the CT decision as shared, improved communication together with better decisional support may be beneficial, especially for women who do not receive adjuvant chemotherapy. Citation Format: Shoshana M Rosenberg, Karen Sepucha, Kathryn J Ruddy, Lidia Schapira, Steven Come, Virginia Borges, Evan Morgan, Nancy U Lin, Shari Gelber, Rulla M Tamimi, Ann H Partridge. Decision-making surrounding adjuvant chemotherapy in young women with early stage breast cancer [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 P2-10-03.

Abstract The post-genomic era ushered in a cadre of techniques to study epigenetic mechanisms involved in disease progression and cancer. One understudied mechanism of gene expression/transcriptional control is 3-dimensional architecture of the genome. Several high-throughput technologies have been adapted to examine 3D genome architecture; in particular those derived from chromatin conformation capture (3C) sequencing technologies. Of 3C-derived techniques, HiC-seq, is the most extensive, and examines all chromatin-chromatin contact sites within a genome, elucidating the entire 3D genome architecture. Although, HiC-seq technique was published 2009, it has been under-utilized in research laboratories due to its technical complexity, expense, and requirement for large volumes of starting material (50 million cells/500 μg of DNA). Other barriers to use of HiC-seq include the requirement for specialized equipment and laborious extraction techniques. However, the benefits of HiC-seq are high for cancer researchers because a genome-wide "snap-shot" of the entire 3D genome of the cancer is displayed. This allows for analysis of higher-order epigenetic control of gene expression. Furthermore, understanding the chromatin conformation of the genome provides new insights into the cellular disease state and potentially novel therapeutic approaches to drug-resistant cancers. Our study presents significant technical innovations, permitting HiC-seq technique to be adopted in laboratories without extensive experience in 3C-seq technologies, and with the use of standard equipment and reagents, as well as smaller volumes of starting materials. Our modified technique utilizes up to 100 fold lower amounts of starting material (500,000 cells/5-10 μg of DNA) per reaction. This adaptation of HiC-seq preparation offers the potential for simultaneous extraction of total RNA and Hi-C processed chromatin for sequencing. To optimize our technique we utilized the estrogen-responsive breast cancer cell line, MCF7. This cell line is typically utilized to study potential drug therapies in the context of estrogen-sensitive cancers. We stream lined HiC-seq by optimizing nuclei extraction and allowing for collection of a cytoplasmic fraction for mRNA extraction and sequencing analysis. We also optimized enzymatic digestion, ligation and DNA extraction methods by utilizing newer enzymatic chemistries, commercially available silica column extraction methods and reagents in place of multiple phenol-based DNA extraction methods. Our quality control results suggest that sample processing for reduced amounts of material is similar if not superior to conventional HiC-seq. We leverage this powerful genomic high-throughput technique in order to simultaneously examine the 3D architecture and transcriptional profiles of MCF7 breast cancer cells. Our computational workflow includes further quality controls using HiC-User Pipeline software from the Bahraham Institute and the R Bioconductor package HiTC package. Overall our optimizations in MCF7 breast cancer cells, and post-acquisition work-flow, make HiC-seq an accessible technology. These innovations permit simultaneous analysis of architectural and transcriptional profiles in cancer cells. Citation Format: Jennifer D Davis, Christian Ross, Hu Li, Amy Brock. Examining 3-dimensional genome architecture and transcriptional profiles using an optimized HiC-seq protocol in breast cancer cells [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 P2-03-16.

Abstract Background: Breast tumors exhibit intratumor heterogeneity resulting in targeted therapy resistance and other challenges in disease management. To address the sources of heterogeneity, we performed a unique, in-depth analysis of clonal architecture in primary chemoradiation-naïve breast cancers. We combined DNA content-based flow cytometry and ploidy analysis with aCGH and next-generation sequencing (NGS) in multiple biopsies from the tumors and involved lymph nodes (LNs). Material and methods: We used DNA content-based flow sorting to isolate nuclei from distinct populations of diploid and aneuploid tumor cells in surgical tumor samples from two chemoradiation-naïve patients. Each sorted tumor cell population was interrogated with aCGH and exome NGS. In Patient #1, we used 12 fresh frozen sections morphologically mapped from within a HER2+, ER+, PR- primary invasive ductal carcinoma (IDC) of histological grade 3 with LN involvement and 2-3 sections from 2 out of 5 LNs. In Patient #2, 11 morphologically mapped fresh frozen sections were analyzed from a grade 2, ER+, PR+, HER2+, BRCA2 mutant LN- IDC. In parallel, matching samples were processed for IHC assays. Results: We identified multiple co-existing aneuploid populations within the biopsies. The 17 primary and LN biopsies from Patient #1 fell into 6 distinct ploidy groups albeit with aberrant but homogenous aCGH profiles, characterized by SARC amplification and homozygous deletions in ROBO1 and ROBO2. In contrast a dominant ploidy was identified throughout Patient #2 but with heterogeneous aCGH profiles. Mutation profiles obtained through exome sequencing further confirmed that ploidy was the main driver in Patient #1 whereas copy number aberrations played the key role in Patient #2 with the BRCA2 mutation (R3129X). A dendrogram based on exome variant calls of the aneuploid populations in Patient #1 strongly correlated with ploidy group and further revealed the specific clonal population characterized by a 5N ploidy and homozygous mutations in TP53 and PIK3CA as the progenitor to the ploidies present in the distant LNs. Strikngly, both patients had no HER2 amplification or mutation across their clonal populations, contradicting the initial IHC staining in a single core biopsy. Conclusions Rather than inferring the presence of distinct tumor cell populations, our novel flow-sorting based approach of first identifying the clonal populations and then interrogating their genomes, provides an objective method of exploring the sources and clinical significance of tumor heterogeneity. Our approach of clonal analysis has broad implications in the study of tumor heterogeneity and the identification of drivers in breast and other solid tumors that can advance more effective treatment and clinical management of patients with this disease. Citation Format: Princy Francis, Lucretia M Alvarez, Elizabeth Lenkiewicz, Mia Champion, Lisa Evers, Karen L Anderson, Ann E McCullough, Michael T Barrett, Barbara Pockaj. Deep clonal profiling identifies distinct mechanisms of heterogeneity and evolution in breast cancer [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 P2-03-07.

Abstract Background: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial (Alliance) reported a false negative rate (FNR) of 12.6% with sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy in women presenting with node-positive breast cancer. Proposed methods to decrease the FNR include clip placement in the positive node at initial diagnosis with confirmation of resection of the clipped node at surgery and inclusion of residual metastatic cells identified by immunohistochemistry (IHC) for cytokeratins and disease measuring <0.2mm on H&E in the definition of node positivity after chemotherapy. Herein we evaluate the impact of these methods on FNR. Methods: Z1071 was a prospective multi-institutional trial in which women with clinical T0-4,N1-2,M0 breast cancer underwent both SLN surgery and axillary dissection (ALND) after neoadjuvant chemotherapy. The primary endpoint defined nodal metastasis as disease >0.2mm on H&E. Slides were submitted for central IHC staining when H&E-negative, unless performed locally. For this analysis, we expanded the definition of node positivity to include metastases less than 0.2mm on H&E and metastatic deposits identified by IHC. In 171 cases, a clip was placed in the node at initial biopsy and in these cases the SLNs and ALND were evaluated by x-ray or pathology to document clip location. FNR in the clip cohort is reported using the primary endpoint definition of node positive disease (>0.2mm on H&E). Results: In the 113 cases where the clip was found in the SLN the FNR was 6.4% (1.8-15.5%). In the 29 cases where the clip was found in the ALND specimen, the FNR was 22.2% (6.4-47.6%). IHC was available on 470 of 525 patients with cN1 disease and 2 SLNs resected. Using the definition of H&E metastasis >0.2mm, the FNR in these patients was 11.3% (34/301, 8.0-15.4%) which decreased to 8.7% (27/311, 5.6-11.8%) when including any disease <0.2mm. SLNs from 16 patients had disease <0.2mm in size. Seven patients previously classified as false negative SLN changed to true positive with identification of disease in the SLN. Nine patients changed from node-negative to node-positive with the only disease being <0.2mm disease found in the SLN. Nodal pathologic complete response rate changed from 36.0% to 33.8% with the inclusion of metastases <0.2mm. NResidual disease identified in SLNs or ALNDFNR (%)95% CINode positive definitionSLN metastases >0.2mm by H&E470301 (64.0%)11.38.0-15.4SLN metastasis any size on IHC or H&E470311 (66.2%)8.75.6-11.8Clip locationClip in SLN11462 (54.4%)6.41.8-15.5Clip in ALND2918 (62.1%)22.26.4-47.6Clip location unknown2920 (69.0%)14.33.0-36.3Clip not placed354207 (58.5%)13.59.1-18.9 Conclusion: Placement of a clip at initial diagnosis of node positive disease with identification of the clip during the SLN surgery reduces the FNR. Use of IHC with inclusion of metastases <0.2mm in the definition of residual nodal disease in women with node positive breast cancer after chemotherapy also improves the accuracy of SLN surgery. Use of one or both of these methods should be considered when performing SLN in this setting. Citation Format: Judy C Boughey, Karla V Ballman, William F Symmans, Linda M McCall, Elizabeth A Mittendorf, Gretchen M Ahrendt, Lee G Wilke, Bret Taback, Kelly K Hunt. Methods impacting the false negative rate of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4,N1-2) who receive neoadjuvant chemotherapy – Results from a prospective trial – ACOSOG Z1071 (Alliance) [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 P2-01-02.

Abstract Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several chemotherapy drug classes, including taxanes. Peripheral neuropathies have been shown to lead to pain, falls, and difficulty in walking and performing activities of daily living in a variety of patient populations. Although the prevalence of CIPN has been noted in cancer patients, the development of self-reported symptoms, gait changes and balance changes during treatment have not been well explored to date. We hypothesized that the use of taxane-based chemotherapy will result in significant changes in spatiotemporal gait and balance parameters, as well as self-reported quality of life and function. Methods We characterized the alterations in gait and balance that occur in non-metastatic breast cancer patients during taxane chemotherapy. We evaluated (1) spatiotemporal gait parameters, including cadence and step length, and (2) balance parameters, including time-to-contact and 95% ellipse area, using each patient as her own control. Laboratory assessment of gait and balance was conducted at baseline and at completion of therapy in selected patients. We compared the natural history of changes in gait and balance parameters with changes in CIPN status as measured by validated patient reported outcomes, including EORTC QLQ-C30, CIPN-20, and Brief Pain Inventory Short Form (BPI-SF), and the Duke Activity Status Index (DASI). Time points included pre-chemotherapy, after each cycle of chemotherapy, and one month after the end of therapy to collect information on neuropathy, pain and functional capacity. The preliminary data were illustrated using individual plots; trend lines (changing over time) were based on least square means at each time point, which were estimated using the linear mixed models for repeated measures. Results To date, 15 patients with localized breast cancer have been enrolled; patient recruitment is ongoing. The median age is 42 years (range 25-67). Ten patients (67%) received weekly paclitaxel, 1 patient (7%) received paclitaxel every 2 weeks, and 4 patients (27%) received docetaxel every 3 weeks. Preliminary results with these 15 patients, based on least square means at each timepoint, showed trends in several parameters. As treatments progressed, patients tended to develop more difficulty in quiet balance and in their ability to actively shift weight in the sagittal and frontal planes. From the CIPN-20, they also tended to develop increased difficulty with sensory and motor systems. From the QLQ-C30, their global health status also tended to worsen. For most of these parameters, the largest changes were observed between the 2nd and 3rd treatments, though some changes were not observed until the 4th treatment. From the BPI-SF, no trends in pain symptoms or pain interference were observed within this preliminary cohort. Conclusions Gait and balance testing is feasible in the clinical setting. Preliminary observations suggest that balance, function and quality of life may all be affected by taxane therapy, even without pain symptoms. The findings of this study will enable us to better characterize the neurotoxic effect of taxanes and to ultimately test the effectiveness of preventative measures and interventions. Funding by NCI R03CA182165-01. Citation Format: Maryam B Lustberg, Scott Monfort, Janani Singaravelu, Raquel E Reinbolt, Xueliang Pan, Bhuvaneswari Ramaswamy, Rachel M Layman, Robert Wesolowski, Ewa Mrozek, Erin Macrae, Charles Shapiro, Robyn Patrick, Charles L Loprinzi, Ajit Chaudhari. Longitudinal evaluation of taxane-induced neuropathy in early stage breast cancer [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 P1-09-04.

Abstract Introduction: AI-induced joint symptoms negatively impact drug adherence and quality of life. Based on observations that n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects and that the mechanism of AI-induced joint symptoms may be partly due to inflammation, we hypothesized that women taking more n-3 PUFAs are less likely to develop AI-induced joint symptoms. Methods: We conducted a randomized, double-blind, placebo-controlled study comparing n-3 PUFA vs placebo in postmenopausal breast cancer patients starting adjuvant AIs. Participants were randomized to n-3 supplements [2.58 g eicosapentaenoic acid + 1.74 g docosahexaenoic acid/day; Marine Nutriceuticals, Mt. Bethel, PA] vs matched placebo for 24 weeks (wks). Primary endpoints was feasibility; secondary outcomes were self-reported symptoms as assessed by the Brief Pain Inventory short form (BPI-SF), Functional Assessment of Cancer Treatment, Breast & Endocrine Symptoms (FACTB-ES), and Stanford's Health Assessment and Disability Index (HAQ) at baseline prior to AI receipt, 12 and 24 wks. Compliance and toxicity were evaluated monthly. Serial peripheral blood n-3 PUFA levels and inflammatory cytokines (IL-6, TNFR2, IL-17) were drawn. MRI of hands/wrists was performed in selected patients using a 3 Tesla dedicated wrist coil at baseline and treatment end. Results: Forty-four women were enrolled and randomized to study drug; 42 received ≥1 cycle (4 wks) of treatment; 36 had ≥1 post treatment evaluation at wk 12 or 24. Median age was 59.5 (range 43-76); history of prior taxane (n=15, 34%). The two groups’ baseline characteristics were similar. Overall, 93% and 88% of patients took >80% of the placebo and n-3 PUFA doses, respectively. Baseline erythrocyte n-3 PUFA was similar for both groups (6.6% ± 1.6%, 7.2% ±1.9%, p=0.20), but higher in the n-3 PUFA arm by wk 24 (6.5%±1.0% vs 15.0%±3.3%, p<0.001). Most toxicities were grade 1; the n-3 PUFA arm had only 1 (2.5%) grade 3 toxicity (diarrhea). The n-3 PUFA arm reported lower mean BPI-SF scores after treatment [(-.0.28/ -0.25 at week 12/24); but not statistically significant compared to placebo (p=0.494 and 0.601)]. Based on BPI-SF, the n-3 PUFA arm reported less interference of pain symptoms compared to placebo at 12 weeks (-.72, p=0.08). This arm also had a decreased walking, activity and working (WAW) score on BPI-SF at 12 weeks (-.81 p=0.05), and reported significantly greater pain relief from medications at 12 (p=0.043) and 24 weeks (p=0.011). Both arms had similar baseline and wk 24 serum IL-6 levels; levels decreased from baseline to wk 24 in the n-3 PUFA arm (-0.54±0.25, p=0.048). There was a non-significant trend (p= 0.2) toward decreased wrist inflammation by MRI imaging at 24 wks in the n-3 PUFA arm. Conclusions: This is the first randomized pilot study to show that n-3 PUFA supplementation to prevent AI-induced joint symptoms is feasible and well tolerated. There is preliminary evidence that this intervention may help reduce the burden of AI-induced arthralgias. OSU Study #11022; ClinicalTrials.gov Identifier: NCT01478477. Grants from the National Cancer Institute (CA037447-26) to the Alliance for Clinical Trials in Oncology supported this pilot study. Citation Format: Maryam B Lustberg, Tonya Orchard, Xueliang Pan, Raquel Reinbolt, Amanda Logan, Joanne Lester, Rachel M Layman, Erin Macrae, Ewa Mrozek, Bhuvaneswari Ramaswamy, Robert Wesolowski, Michael Berger, Michael Knopp, Charles Loprinzi, Charles L Shapiro, Lisa Yee. Prevention of aromatase Inhibitor (AI)-induced joint symptoms with omega-3 fatty acid supplementation: A randomized placebo-controlled pilot study [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 P1-09-03.

Abstract Background: The development of distant metastases is the strongest prognostic factor associated with cancer mortality. Customization of treatment based on molecular profiling of a patient’s primary tumor has yielded promising results and has opened a new paradigm for treating patients with advanced disease. Nevertheless profiling the primary tumor may not reflect the actionable molecular drivers of the metastatic lesions. In the last few years a large number of genomic and proteomic studies have demonstrated that at the molecular level metastatic lesions significantly differ from matched primary tumors. The impact of metastasis site organ microenvironments on breast cancer primary tumors has been only partially explored. Since most targeted therapies work by modulating aberrantly-activated protein kinase signaling, the aim of this study was to utilize reverse phase protein arrays (RPPA) to explore whether metastatic lesions derived from different patients, but invading the same host target organ showed similarities in their signaling architecture and presented with organ-specific targetable signatures. Methods: Snap frozen material collected from 14 metastatic breast cancer patients enrolled in a prospective phase II trial ("Side Out II") were used for this analysis. Sites of metastasis were: liver (n=7), skin/chest wall (n=4), and lung (n=3). All samples were subjected to Laser Capture Microdissection (LCM) and RPPA to measure the activation/phosphorylation levels of 12 FDA approved drug targets and linked substrates. Results: Among the 7 patients with liver metastases, p70S6K, c-Abl, ERK 1/2 were highly phosphorylated in 5 cases (71.4%), ErbB2/HER2 in 4 cases (57.1%), and AKT in 3 cases (42.8%). On the contrary, of the 4 patients with skin/chest wall lesions 3 showed high activation of ErbB2/HER2, ErbB3/HER3, and ERK 1/2 (75.0%) and 2 of EGFR (50.0%). Of note, none of the skin/chest wall lesions showed activation of AKT and only 1 case presented with activated p70S6K (25.0%). Lung metastasis showed an overall low activation of all 12 analytes measured. Discussion: Although this data is based on a relatively small number of samples and needs further validation, our initial analysis revealed potentially important trends that could have an impact in the prioritization and selection of targeted agents for metastatic breast cancer trials. We found that the distribution of the 12 FDA approved drug targets and downstream substrates varies between different metastatic sites. Thus, the emergent hypothesis from this work is that breast cancer patients with liver metastases may be more susceptible to AKT-mTOR directed targeted therapeutics and patients with skin/chest wall metastasis may benefit from therapies that target EGFR and/or downstream ERK signaling. Citation Format: Mariaelena Pierobon, Stephen P Anthony, K Alex Reeder, Nicholas J Robert, Donald W Northfelt, Mohammad Jahanzeb, Linda Vocila, Julia D Wulfkuhle, Bryant Dunetz, Lance A Liotta, Emanuel F Petricoin. Pathway activation mapping of metastatic breast cancer identifies potential organ-specific signatures: Implications for patient stratification to targeted treatment [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 P1-07-23.

Abstract Background: Many newly diagnosed breast cancer patients undergo preoperative breast MRI which includes visualization of some degree of the axilla. The impact of patient characteristics and tumor biology on the fidelity of MRI imaging of the axilla in these cases is not well-studied. We sought to examine the correlation between nodal findings on breast MRI and pathologic nodal status in newly diagnosed breast cancer patients. Methods: With IRB approval, we identified 1868 consecutive breasts with invasive cancer in 1803 patients undergoing primary operation with axillary surgery from 1/2010-7/2013. Patients undergoing neoadjuvant chemotherapy (348) were excluded leaving 1510 breasts with cancer in 1455 patients. Preoperative MRI was performed in 763 patients (52%). We evaluated patient, imaging and pathology data. Results: Patients evaluated with MRI were median age 57 years. The majority of tumors were T1 (63%) and T2 (28%). MRI identified suspicious axillary nodes in 240 cases (31%), of which 123 (51%) were node positive at operation. Suspicious axillary findings on MRI predicted both nodal status and pN stage at operation (both p<0.0001). The sensitivity, specificity, accuracy, positive (PPV) and negative predictive value (NPV) of MRI for nodal disease across tumor types is shown. Pathologic Node PositiveSensitivity (95% CI)Specificity (95% CI)NPV (95% CI)PPV (95% CI)Accuracy (95% CI)All Cases (n=763)234 (31%)52.6 (46-59.1)77.9 (74.1-81.3)78.8 (75-82.1)51.3 (44.8-57.7)70.1 (66.7-73.3)Approximated Biologic Subtype (missing=24)ER+/HER2- (n=609)194 (32%)51.0 (43.8-58.2)80.0 (75.8-83.7)77.8 (73.4-81.5)54.4 (46.9-61.7)70.8 (67-74.3)HER2+ (n=69)20 (29%)65.0 (40.9-83.7)71.4 (56.5-83)83.3 (68-92.5)48.1 (29.2-67.6)69.6 (57.2-79.8)ER-/HER2- (n=61)17 (28%)58.8 (33.5-80.6)75.0 (59.4-86.3)82.5 (66.6-92.1)47.6 (26.4-70)70.5 (57.3-81.1)p value0.740.430.330.560.730.98Tumor Grade (missing=5)1 (n=259)58 (22%)32.8 (21.4-46.5)79.6 (73.2-84.8)80.4 (74.1-85.5)31.7 (20.6-45.1)69.1 (63.0-74.6)2 (n=351)124 (35%)55.6 (46.5-64.5)79.7 (73.8-84.6)76.7 (70.7-81.8)60.0 (50.4-68.9)71.2 (66.1-75.9)3 (n=148)51 (34%)66.7 (52.0-79.0)70.1 (59.8-78.8)80.0 (69.6-87.6)54.0 (41.0-66.4)68.9 (60.7-76.1)p value0.0010.00030.110.720.020.93 Diagnostic performance did not vary significantly based on patient body mass index (BMI) or approximated biologic subtype, but specificity was better for patients >age 50 (p=0.007) and sensitivity and PPV both were worse for grade 1 vs grade 2/3 tumors. Node positivity rate at operation was 48% (51/106) for patients with a solitary abnormal node on MRI and 54% (72/134) when >1 suspicious node was seen (p=0.39). However, multiple vs solitary MRI suspicious nodes correlated with ≥3 positive nodes at operation (40 [30%] vs 19 [18%], p=0.03) and pN2/pN3 disease (29 [22%] vs 12 [11%], p=0.03). Conclusion: Axillary lymph node findings on MRI for breast cancer predict nodal status and disease volume in invasive breast cancer patients. Tumor biologic subtype did not affect performance characteristics of preoperative MRI, but tumor grade did influence the sensitivity and PPV of MRI. When MRI is performed in the evaluation of newly diagnosed breast cancer, axillary findings inform pathologic nodal stage at operation regardless of tumor subtype. Citation Format: Sean C Dupont, Judy C Boughey, Tanya L Hoskin, Katrina N Glazebrook, Tina J Hieken. Value of breast MRI for preoperative axillary assessment of 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 P1-01-03.

Abstract Background First identified as an estrogen-inducible gene in a breast cancer cell line, LIV-1 is a multispan transmembrane protein of the solute-carrier family 39 with putative zinc transporter and metalloproteinase activity. As a downstream target of STAT3, it promotes the epithelial-to-mesenchymal transition that is important in the malignant progression to metastasis. LIV-1 is expressed in a number of cancers with the highest prevalence and level of expression in breast, prostate, and melanoma. Additionally, LIV-1 has been linked with malignant progression to metastasis and associated with lymph node involvement in breast cancer. Normal tissue expression is predominantly limited to hormonally regulated tissues, including breast and prostate. In metastatic breast cancer tissue samples, the current validated immunohistochemistry assay for LIV-1 has detected moderate to high expression in 82% of samples tested, with 88% positivity in hormone receptor-positive tumors and 73% in triple-negative tumors. SGN-LIV1A is an antibody-drug conjugate (ADC) composed of a humanized anti-LIV-1 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, SGN-LIV1A shows target-specific internalization and cytotoxic activity against LIV-1-positive neoplastic cell lines. Significant dose-dependent tumor regression was demonstrated in mouse xenograft models. Methods The primary objective of this first-in-human phase 1, open label, multicenter study is to evaluate the safety and tolerability, and to identify the maximum tolerated dose of SGN-LIV1A using a 3+3 dose-escalation study design. Pharmacokinetics, immunogenicity, and antitumor activity will also be evaluated (ClinicalTrials.gov #NCT01969643). Enrollment to this US-based trial began in late 2013. Eligible patients are adult females who have hormone receptor-positive/HER2-negative or triple-negative metastatic breast cancer. Tumor tissue must be positive for expression of LIV-1 per central assessment. Patients must have received at least 2 prior cytotoxic regimens in the metastatic setting and have measurable disease per RECIST v1.1. Pre-existing neuropathy ≥ Grade 2 is not permitted. SGN-LIV1A is administered intravenously every 3 weeks at protocol-defined doses starting at 0.5 mg/kg. Patients who achieve an objective response or stable disease per RECIST v1.1 are eligible to continue treatment until disease progression. At the completion of dose escalation, expansion cohorts may be opened to enroll patients with specific breast cancer subtypes to further define safety and antitumor activity. Tumor biopsies are being obtained at baseline and after one cycle of treatment to evaluate the role of LIV-1 expression, target saturation, and other tumor-specific measurements in the antitumor activity of SGN-LIV1A. Citation Format: Andres Forero, Howard Burris III, Patricia LoRusso, Jennifer Specht, Kathy Miller, Monica Mita, Minetta C Liu, Shanu Modi, Lajos Pusztai, Django Sussman, Ana Kostic. SGN-LIV1A: A phase 1 trial evaluating a novel antibody-drug conjugate in patients with LIV-1-positive breast cancer [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 OT2-3-01.

Abstract Neoadjuvant endocrine therapy (ET) in patients (pts) with locally advanced estrogen receptor positive (ER+) breast cancer (BC) improves breast conservation rate, and importantly offers an opportunity for individualized assessment of tumor responsiveness to ET to guide subsequent treatment. Previous neoadjuvant ET trials demonstrated that pathologic tumor size (pT), axillary lymph node status (N), and tumor Ki67 value at surgery predicted risk of relapse. Preoperative endocrine prognostic index (PEPI) was therefore developed to assign risk scores based on these factors. Modified PEPI 0, defined by pT1-2 N0 Ki67< 2.7%, was associated with extremely low risk of recurrence without adjuvant chemotherapy. In addition, high Ki67 post 2-4 weeks (wks) of neoadjuvant ET identified resistant tumors with poor outcome. ALTERNATE trial is a three-arm phase III neoadjuvant/adjuvant ET trial designed to achieve two primary objectives. The first is to prospectively validate that modified PEPI 0 predicts > 95% relapse-free survival (RFS). The second is to determine whether fulvestrant (F), or fulvestrant (F) plus anastrozole (A), is superior to A in inducing a higher rate of modified PEPI 0. Secondary objectives include assessing RFS for pts with endocrine resistant tumor, defined by Ki67 > 10% at 4 or 12 wk, disease progression, or modified PEPI non-0, and pathologic responses of resistant tumors to neoadjuvant chemotherapy. Correlative studies include degrees of Ki67 suppression and ER level post treatment. In addition, ongoing research sequencing studies of DNA and RNA will be performed to contrast sensitive vs resistant tumors. During the first phase of the trial, 1200 pts are randomized 1:1:1 to the F, A or F/A. This provides an 82% chance, 1-sided alpha 0.025 chi-square test to detect at least 10% difference in modified PEPI 0 rate comparing F or F/A with A. While waiting for result of analysis, the A arm will continue for the 2nd phase enrollment. Only the F-containing arm(s) superior over A will be continued to the 2nd phase. During the 2nd phase, an additional 540 pts in each arm is estimated to obtain 317 pts with PEPI score 0. This will have a 90% chance, with a one-sided alpha=0.025 nonparametric Brookmeyer-Crowley type one sample survival test, rejecting that 5 year RFS rate is 95%. The maximum sample size is 2820 pts. Eligible pts include postmenopausal women with newly diagnosed clinical stage II or III ER+ (Allred score 6-8) HER2- BC. Tumor biopsy is required at baseline, 4 wk, and surgery for central Ki67 analysis. Treatment decision is individualized based on 4 wk Ki67 and modified PEPI score. Pts with Ki67 > 10% at 4 wk are switched to chemotherapy. Pts with a modified PEPI score of 0 are recommended not to receive chemotherapy, but continue the assigned ET for 1.5 years followed by 3 years of A. This trial is currently accruing pts through CTSU. This research is supported in part by NCI BIQSFP, and grants from Breast Cancer Research Foundation, Genentech, and the Investigator-Sponsored Study Program of AstraZeneca. The Clinical Trials.gov Identifier: NCT01953588. Citation Format: Cynthia X Ma, Vera Suman, A Marilyn Leitch, Souzan Sanati, Katherine DeSchryver, Gary W Unzeitig, Paul Haluska, Mark Watson, Olwen Hahn, Jo Anne Zujewski, Kelly Hunt, Eric P Winer, Cliff A Hudis, Matthew J Ellis. Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III study [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 OT2-1-04.