Trials In Triple-negative Breast Cancer Research Articles

Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer.

Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment.

Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE

Background: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous clinical breast cancer subtype that currently lacks approved targeted therapies. Research aimed at understanding the mutational and transcriptional landscape of TNBC is being achieved through gene expression analysis and large-scale genomic projects, resulting in identification of potential drug targets. Design: A review of PubMed and conference databases was carried out to identify randomized clinical trials in TNBC as well as early phase trials of emerging targeted therapies.Results and Discussion: The role of platinums and poly(ADP-ribose) polymerase inhibitors continues to be a focus of clinical trials with attention now on developing a predictive biomarker that identifies “BRCA-like” tumours. The previously identified six TNBC subtypes has been revised to four and has provided further insight into the role of the androgen receptor and immune system, both of which are emerging as promising targets in select patients either as monotherapy or in combination with other immune therapies, chemotherapy or targeted therapy. Other novel targets include MET inhibition and signaling pathways such as the MAPK, PI3K and JAK/STAT pathways. Antibody-drug conjugates are also of interest. Targeting the angiogenesis and epidermal growth factor receptor pathways have had limited efficacy in the treatment of TNBC. Conclusions: As researchers begin to understand the underlying biology of TNBC and identify predictive biomarkers, more select patient populations are being treated with targeted therapies, which is a promising step forward in filling the current void of approved targeted treatment options for patients with TNBC.Key Words: androgen receptor, breast cancer, breast cancer molecular subtypes, cancer treatment, immune checkpoint blockade, targeted therapy, triple-negative breast cancer.

Abstract B44: A systems approach combining genomics, advocacy, and emerging novel therapeutics to address triple-negative breast cancer (TNBC) outcomes disparities

Abstract Background: Genomic analyses of patient tumors have unearthed an overwhelming number of recurrent somatic alterations in genes that have dramatic effects on tumor biology, patient drug responses, and clinical outcomes. In one study, high-grade triple negative breast cancer (TNBC) accounts for 34% of breast cancers in African American women versus 21% in white women. African American women have biologically more aggressive disease, independent of social determinants, and suffer the highest mortality rates. In advanced TNBC, a poor prognosis subtype, there is an urgent need to translate this emerging patient genomic data into new therapeutic paradigms. Objectives: Our study focuses on emerging compounds that are already approved (i.e., Dasatinib) or in testing for human use and we expect that this work will serve as a prelude to one or more clinical trials in TNBC. We seek to determine if the treatment of metastatic TNBC recurrence with more targeted genotype-specific agents could improve the outcomes/survival of all women in this particularly aggressive poor prognosis subset, including African American women. Methods: To guide the development of genotype-specific therapies in TNBC, we have established an isogenic cell-line drug screen that measures the impact of gene activation on a panel of emerging, clinically relevant compounds targeting a variety of cancer pathways. Using engineered isogenic cells, we generated an unbiased and quantitative chemical-genetic interaction map that measures the influence of 51 aberrant cancer genes on 90 drug responses. We believe that this approach can identify core synthetic lethal interactions, which underlie drug sensitivity and can be used as a foundation to identify patient populations that will selectively respond to drug treatments. Results: Using our systems approach, our interaction map highlights both known and novel connections between oncogene activation and drug responses and provides a modular roadmap for the exploration of synthetic lethal relationships. Applied to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene including resistance to AKT/PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic-lethal manner. Ensuring that the voice of the patient is represented in our scientific inquiry, advocacy has played a significant role in the development and realization of this project. Aligning experiential and professionalized expertise, trained advocates explore relentless challenges and opportunities for moving the science forward. Conclusion: A novel systems biology approach that uses module maps of oncogenes and emerging therapeutics can define synthetic-lethal interactions and actionable therapeutics to help decrease TNBC outcomes/survival disparities in African American women. Citation Format: Alicia Y. Zhou, Maria M. Martins, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan Shamji, Stuart Schreiber, Nevan J. Krogan, Kevan M. Shokat, Frank McCormick, Susan Samson, Andrei Goga, Sourav Bandyopadhyay. A systems approach combining genomics, advocacy, and emerging novel therapeutics to address triple-negative breast cancer (TNBC) outcomes disparities. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B44.

Concordance of intrinsic subtyping and risk of recurrence (ROR) scores between matched primary and metastatic tissue from Triple Negative Breast Cancer Trial (TNT).

1019 Background: The majority of triple negative breast cancers are of basal-like subtype (BLBC). There is uncertainty about concordance of intrinsic subtypes and ROR scores by PAM50 between matche...

Abstract P3-06-31: Patient-derived xenografts accurately predict patient response in breast cancer patients

Abstract PURPOSE/OBJECTIVES: A growing body of evidence demonstrates that patient-derived xenografts (PDXs) represent living tumor models that accurately reflect the biology of the primary patient tumor. More importantly, we have previously shown that PDX models show responses to therapeutic agents that are concordant with patient clinical response and can be used to direct personalized cancer treatments (Stebbing, 2014). Here we report the ability of PDX models to predict for patient response to drug treatment in a cohort of breast cancer patients. MATERIALS/METHODS: Tumors were resected from patients with either primary or metastatic breast cancer and implanted into immunodeficient mice to establish PDX models. Successfully engrafted PDX models were expanded and randomized for drug sensitivity testing. Tumor growth inhibition and tumor regression were captured and results were correlated with a patient’s clinical response. In some cases, PDX results were used to personalize cancer treatment and some patients used PDX-directed treatments over multiple lines of therapy. RESULTS: A total of 42 tumors from 40 patients were implanted resulting in 21 successfully engrafted PDX models (50% engraftment rate). Notably, engraftment rates were much higher for patients with triple negative breast cancer (TNBC) and resulted in 7 successful PDX models from 8 TNBC patients (87.5% engraftment rate). Drug sensitivity testing was offered to patients with established PDX models. Drugs and drug combinations tested included standard and nonstandard chemotherapy as well as biologics. At that time of this publication, 4 patients (3 TNBC and 1 HER2+) with completed drug sensitivity tests also had clinical data available resulting in 7 clinical correlations; 4 retrospective and 3 prospective. In all 7 cases, the PDX model accurately predicted patient clinical response demonstrating an accuracy of 100%. Five of the drug tests predicted drug sensitivity and 2 tests predicted resistance, indicating the potential of the PDX platform to predict for both sensitivity and resistance to therapy. The 3 prospective correlations resulted in concordant clinical benefit in 2 patients for duration greater than 6 months each. CONCLUSIONS: These data support the use of the personalized PDX model as a platform for therapeutic decision making that can guide treatment for patients with breast cancer. A prospective clinical trial in TNBC is currently underway. Citation Format: Lisa Stow, Amanda Katz, Hanna Irie, Elisa Port, Justin Stebbing, Daniel Ciznadija, Angela Davies, Keren Paz. Patient-derived xenografts accurately predict patient response in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-31.

Defining a Role and Predicting Benefit From Platinum-Based Therapy in Breast Cancer: An Evolving Story

There are three evolving stories that have the potential to improve outcomes for patients with localized triple-negative breast cancer (TNBC), a phenotypically defined breast cancer subtype that often occurs in individuals harboring germline BRCA1 mutations, including up to 20% of unselected individuals and 50% with a strong family history. When occurring sporadically without a germline mutation, TNBC shares many clinical and molecular features with BRCA1associated cancers, including defective DNA repair, which may be a result of methylation-induced silencing of BRCA or mutations in other genes that encode proteins involved in DNA repair. The first story, as exemplified in the article by Sikov et al that accompanies this editorial, is that the DNA–damaging agent carboplatin significantly improves the pathologic complete response (pCR) rate when added to a neoadjuvant chemotherapy regimen that includes a taxane, anthracycline, and alkylating agent, confirming the results of a similar trial. The second story involves using predictive biomarkers to identify tumors that are particularly sensitive to DNA-damaging agents, including germline mutations in genes that encode proteins that are essential for DNA damage repair and somatic markers that identify so-called BRCAness in sporadic cancers. The third story centers on using response to neoadjuvant therapy as a pharmacodynamic biomarker, exemplified by the strong inverse association between pCR in the breast and axilla and risk of recurrence. Although it is clear that platinum-containing agents are potentially useful in TNBC, it is unclear which patients benefit from them and how to best use them. The platinum story in breast cancer dates back to 1988, when Sledge et al noted partial responses in seven of 19 patients (47%) unselected for breast cancer subtype who received cisplatin as first-line therapy for metastatic disease. Other reports followed, confirming activity for cisplatin and carboplatin when used as first-line cytotoxic therapy in otherwise unselected patients, although efficacy was limited when used beyond first-line treatment, and attempts to combine platinum-containing agents with taxanes met with variable success. On the basis of preclinical data indicating synergy when platinum-based drugs were combined with trastuzumab in human epidermal growth factor receptor 2 (HER2)/neu positive disease, the carboplatin-docetaxel-trastuzumab regimen was found to be an effective adjuvant regimen, although adding carboplatin to a trastuzumab-taxane regimen in metastatic disease produced only modest clinical benefit. This brings us to the next chapter in the evolving platinum story, which includes two randomized phase II neoadjuvant trials in TNBC. The first report of the GeparSixto trial by von Minckwitz et al included 293 patients with operable and locally advanced TNBC who received weekly paclitaxel and liposomal doxorubicin plus bevacizumab, either alone or in combination with weekly carboplatin (area under the curve [AUC] 2, then reduced to AUC 1.5) for up to 18 weeks. The addition of carboplatin significantly improved the pCR rate in the breast and axilla (58% v 37%; P .05), although it also substantially increased toxicity without affecting breast conservation rates. The second study, by Sikov et al from the Alliance Clinical Trials Group, included 493 patients with operable and locally advanced TNBC who received weekly paclitaxel for 12 weeks followed by doxorubicin-cyclophosphamide every 2 weeks. Paclitaxel was given alone or in combination with carboplatin (AUC 6 every 3 weeks for four cycles); using a 2 2 factorial design, patients were also randomly assigned to receive chemotherapy alone or in combination with bevacizumab. The addition of carboplatin was associated with an improved pCR rate in the breast and axilla (54% v 41%; P .0029); similar benefits were observed in the absence (49% v 39%) and presence (60% v 43%) of bevacizumab. Although numerically more patients who were not initially considered candidates for breast conservation were deemed potential candidates after therapy when carboplatin was used (57% v 44%), the difference was not statistically significant, and the actual rates were not reported. Neither trial was adequately powered to determine carboplatin-reduced recurrence, nor were patients observed long enough to observe such a difference if it existed. Why use platinum-containing agents in TNBC? This brings us to our second evolving story, dating back to 2000, when it was recognized that BRCA-mutant cells were sensitized to the antineoplastic effects of DNA-damaging agents such as platinum, and that neoadjuvant platinum monotherapy was highly effective in BRCA mutation– associated breast cancer. It was also recognized that sporadic TNBC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 1 JANUARY 1 2015

Triple-negative breast cancer: future prospects in diagnosis and management

Triple-negative breast cancer (TNBC) is an aggressive subtype comprising about 10-20% of breast cancer patients with an overall poor prognosis. Recently, it was found to be a heterogeneous disease that has been classified into six subtypes based on molecular signature. In preclinical trials, these subtypes have different active signaling pathways with variable response to chemotherapy. To improve treatment outcome of TNBC, therapy should be tailored according to the active driving signaling aberration. Molecular testing represents the optimal way to stratify patients, but it has some difficulties to be implemented in routine clinical practice. This article provides an assumption for stepped diagnostic algorithm of TNBC based on immunohistochemistry markers in addition to a suggested tailored therapeutic strategy for advanced TNBC based on the driving aberrations. Furthermore, most TNBC patients develop early relapse despite adjuvant chemotherapy. We provide a design for future adjuvant therapy for the disease. This design is based on targeting proposed active pathways in breast cancer stem cells responsible for regenerating the tumor and disease relapse. Finally, we provide a proposed design for future clinical trials in TNBC to allow for investigation of different medications in this heterogeneous disease based on upfront patient stratification and then allocation to the suitable treatment arms.

Abstract P5-10-01: A systems approach to combine genomics and emerging therapeutics to discover new treatments for TNBC

Abstract Genomic analyses of patient tumors have unearthed an overwhelming number of recurrent somatic alterations in genes that undoubtedly have dramatic effects on breast tumor biology, clinical outcomes and responses to therapeutics. In triple negative breast cancer (TNBC), there is an urgent need to translate this emerging patient genomic data into new therapeutic paradigms. To develop genotype-specific therapies, we have established an isogenic cell-line drug screen that measures the impact of gene activation on a panel of emerging, clinically relevant compounds targeting a variety of cancer pathways. We seek to uncover genotype-dependent sensitivity to drugs, synthetic lethal relationships, and validate in breast cancer cells and in vivo mouse models. We focused on emerging compounds that are already approved or in testing for human use and we expect that this work will serve as a prelude to one or more clinical trials in TNBC. RESULTS: We have developed a synthetic-lethal interaction mapping strategy to uncover the impact of gene activation on responses to a panel of emerging therapeutics. We believe that this approach can identify core synthetic lethal interactions which underlie drug sensitivity and can be used as a foundation to identify patient populations that will selectively respond to drug treatments. We have developed a high-throughput screening platform that can rapidly and accurately assess the proliferative capacity of cell lines in response to a panel of inhibitors. We have generated a panel of isogenic cell lines which closely mimic the impact of recurrent gene mutations and overexpression common in breast cancer. We have currently generated 23 cell lines expressing wild-type and/or mutant forms of these genes. To date we have screened 12 known oncogenes against our panel of 94 emerging therapeutic compounds. Using this systems approach, the resulting interaction map highlights both known and novel connections between oncogene activation and drug responses and provides a modular roadmap for the exploration of synthetic lethal relationships. Based on the coordinate activity of multiple drugs targeting the same pathway, we identified oncogenes that can drive resistance to EGFR inhibitors and PI3K/AKT inhibitors. We also recapitulated a known synthetic lethal relationship between MYC and CDK inhibition which we have previously described and we are now evaluating in a clinical trial. Therefore, our approach identified both resistance and synthetic lethal relationships that have been independently described, indicating that this platform is a good model for predicting synthetic lethality in vivo. Several novel and previously uncharacterized connections were also uncovered, including novel connections between MYC activity and several promising drugs in clinical development. Synthetic-lethal interactions discovered using this chemical-genetic systems approach and their mechanistic validation will be described in the presentation. Furthermore, the important role of patient advocacy in developing this project will be described. CONCLUSION: A novel systems biology approach that uses chemical-genetic maps of oncogenes and emerging therapeutics can define synthetic-lethal interactions and actionable therapeutics for breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-10-01.

Kinome reprogramming response to MEK inhibition: A window-of-opportunity trial in triple-negative breast cancer (TNBC).

512 Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract submission. Toxicities included grade 2 (2pts) or grade 1 (1pt) rash, grade 1 diarrhea (1pt), and grade 1 nausea (1pt). Two of the 9 pts profiled did not have sufficient pre-treatment tumor for kinome analysis. Molecular subtypes included 6 BBC patients (one of which was CL after T), 2 CL patients (one of which was BBC after T), and 1 normal-like patient (which was BBC after T). MEK1/2 inhibition and kinase reprogramming was seen in 6 of the 7 tumors where both pre- and post T samples could be analyzed. The results show kinome reprogramming in response to MEK1/2 inhibition occurs in human tumors similar to preclinical modeling in TNBC cell lines and credentialed engineered mouse models; the kinase reprogramming pattern differed between BBC and CL. Conclusions: MEK1/2 inhibition upregulates and activates specific receptor tyrosine kinases in BBC that are different from CL.A subset of BBC and CL may have plasticity, changing their molecular subtype and kinome profile, and responding heterogeneously to MEK1/2 inhibition. Analysis of kinome reprogramming identifies upregulation of druggable targets for individual patients that suggest rational combinations with MEK inhibition in TNBC. Clinical trial information: NCT01467310.

Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: A collaborative effort of the BIG-NCI NABCG.

1008 Background: Most TNBC trials focusing on biology of the basal-like subtype (BLBC) allow borderline (1-10% staining) estrogen receptor (ER) and progesterone receptor (PgR) expression by immunohistochemistry (IHC); however the optimal ER and PgR cut points to enrich for non-luminal subtypes has not been studied. In this study,we compared quantitative ER/PgR status with gene expression-based intrinsic subtype in order to determine if borderline cases should be included in TNBC trials. Methods: ER, PgR, and HER2 status was determined by central review of tumors collected from three phase III randomized trials: GEICAM 9906 (n=820), NCIC CTG MA.5 (n=476) and MA.12 (n=398). PAM50 intrinsic subtyping (BLBC, HER2-enriched, Luminal A, Luminal B and Normal-like) was performed using the qRT-PCR-based assay. Quantitative ER/PgR expression by IHC and subtype was tested using ANOVA and Fisher’s exact test. Results: Of 1,694 tumors, 15% were BLBC, 21% HER2-Enriched, 33% Luminal A, 25% Luminal B and 4% Normal-like. BLBC subtypes were significantly associated with low expression of ER and PgR (median = 0.05%) compared to other subtypes (p < 0.001). The vast majority of BLBC (96%) did not express any ER or PgR protein by IHC. BLBC represented 73% of TNBC (borderline cases not included) and significantly more than the additional TNBC with borderline ER/PgR (p < 0.001). Within borderline ER/PgR and HER2-negative cases only, 17% were BLBC and 46% were luminal subtypes (Table). Conclusions: BLBC rarely express ER or PgR by IHC. The majority of borderline TNBC (1-10% ER/PgR) are not BLBC; half of them are categorized as luminal categories that may be endocrine sensitive. TNBC trials seeking to target BLBC tumor biology should use the ASCO/CAP guidelines of 0% as the cutoffs for ER and PgR negativity. [Table: see text]

Clinical and correlative science results in a phase II study of UCN-01in combination with irinotecan in recurrent triple-negative breast cancer (TNBC).

3047 Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing “mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan (I) combined with UCN-01, a nonselective Chk1 inhibitor, showed promising activity in TNBC in our phase I study. The primary objective of the phase II trial was to determine the efficacy and toxicity. Correlatives included assessing tumor molecular subtype, TP53, PTEN and pathways targeted by UCN-01. Methods: Pts with measurable, metastatic (met) TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial peripheral blood mononuclear cells (PBMC) and optional tumor biopsies were collected. Results: Twenty five pts were enrolled. All had prior A and T. The median no. of prior regimens for met disease was 3 (range 1-4). Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a clinical benefit rate (CR+PR+SD>6 mos) of 3/25 (12%), 95% CI (3, 31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 24h post UCN-01, but close to baseline by d8. Immunostain of cleaved caspase 3 (CC3), pHistone H3 (pHH3), γH2AX, and pS6 were done on serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 was reduced 24h post UCN-01. Results for other markers were variable. One case with TP53 deletion showed an induction of CC3, with an increase in pHH3 and γH2AX, suggesting abrogation of cell cycle arrest and enhanced DNA damage. Among 15 with sufficient specimen for analysis, most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% CI: 2.9, - ) mos in wild type populations (p=0.004). Conclusions: This regimen had limited activity in TNBC. Despite the long half-life, drug activity is not detectable by d8 based on PBMC analysis. Our data indicates that future trials in TNBC should consider p53 status.

Triple-negative breast cancer: an update on neoadjuvant clinical trials.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC.

Abstract P1-11-07: Results of a Phase II Study of Neoadjuvant Platinum/Taxane Based Chemotherapy and Erlotinib for Triple Negative Breast Cancer

Abstract Introduction: Patients with triple negative breast cancer (TNBC) have a worse prognosis compared to other breast cancer subtypes, primarily due to lack of targeted treatment options. EGFR1 (epidermal growth factor receptor) is often over-expressed in TNBC and could be a promising therapeutic target. Clinical studies have shown platinums and taxanes to be effective in TNBC and in vitro data has demonstrated synergy between carboplatin, docetaxel and an EGFR inhibitor in TNBC cell lines. Aim: To evaluate the efficacy of platinum/taxane based chemotherapy in combination with a small molecule EGFR inhibitor, Erlotinib, in patients with TNBC. Methods: Patients with stage II/III TNBC were eligible for this phase II trial. All patients received 6 cycles of chemotherapy (Carboplatin AUC 6, Docetaxel 75mg/m2 every 21 d). In addition patients were equally randomized between two erlotinib arms. Patients in arm A received Erlotinib (150 mg PO d 3 - 14 every 21 d) during all 6 cycles of chemotherapy & patients in arm B received erlotinib only during the last 4 cycles of chemotherapy. This randomization was intended to reduce bias in the evaluation of the effect of erlotinib on biomarkers in a core biopsy of the tumor performed after the second cycle of chemotherapy. All but one patient underwent comprehensive BRCA analysis (Myriad Genetic Laboratories). Following neo-adjuvant therapy, all patients underwent breast surgery. The primary end point was pathological complete response (pCR: no evidence of invasive tumor in the breast & axilla). Minimal Residual Disease [MRD= Residual Cancer Burden (RCB) groups 0+1] status was also evaluated. Results: 30 eligible patients with TNBC were enrolled between 8/2007 and 6/2010. This analysis includes 28 patients since 2 patients are still on study treatment. Median age: 51yrs (range 31-68), 21%: African American, 54%: postmenopausal. Median tumor size was 3.3 cm & 39% had LN+ disease. Fifteen patients were assigned to each arm of erlotinib. Five of 28 patients (17%) carried a BRCA mutation (two BRCA1deleterious, two BRCA2 deleterious, one BRCA1 uncertain). The overall pCR and MRD (RCB 0+1) rates were 39% & 50% respectively. On univariate analysis, tumor size, LN status, menopausal status, age and number of erlotinib cycles did not correlate with pCR. However, BRCA mutation status strongly correlated with pCR, with a pCR rate of 100% in BRCA mutation carriers compared to 27% in those without BRCA mutation (p=0.006). Baseline EGFR and/or p53 expression of ≥10% was associated with a lower pCR rate in BRCA non-carriers (pCR: 12% vs. 66%, p = 0.025). Common Erlotinib related AEs were: rash (G3/4:7%) & diarrhea (G3/4:30%) with 32% of subjects requiring erlotinib dose reduction/discontinuation due to AEs. Conclusions: Pathological complete response rates of TNBC to a combination of platinum/taxane chemotherapy & an oral EGFR inhibitor are encouraging and should be explored further. The response to this regimen was significantly influenced by BRCA mutation status, indicating a need to stratify patients by their BRCA status in future TNBC trials. Tissue biomarker analysis of downstream targets of EGFR inhibition should be informative regarding the exact role of erlotinib in this patient population. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-07.

Triple-negative breast cancer: current management and future options

Abstract Triple-negative breast cancer is a particularly difficult to treat and biologically aggressive disease with limited treatment options. However, a subset of patients with triple-negative tumours may respond to chemotherapy. Therefore, optimisation of chemotherapy regimens may be key in treating triple-negative breast cancer. Emerging treatment approaches include novel chemotherapeutic agents such as the epothilones. The epothilones are a group of novel microtubule-stabilising agents with demonstrated activity in anthracycline-/taxane-resistant triple-negative breast cancer, and ongoing trials are evaluating the combination of epothilones with targeted agents or inclusion of epothilones in novel combination regimens. Other interesting new treatment options include the PARP inhibitors, which are currently in clinical trials for triple-negative breast cancer.

Assays of circulating tumor cells and outcome in the triple-negative breast cancer trial TBCRC001.

Abstract Abstract #6048 Introduction. Basal-like breast cancer (BBC) has low expression of ER, PR, and HER2, and is often called triple negative (TN) BrCa. TBCRC 001 is a multicenter randomized phase II study of cetuximab (C) alone or combined with carboplatin (P) in TN BrCa. Pts randomized to Arm 1 received C alone (400 mg/m2, then 250 mg/m2 weekly) with P (AUC 2, 3 of 4 weeks) added upon progression (PD). Pts on Arm 2 received C+P throughout. The primary endpoint was objective response. To explore markers of activity and response, we measured circulating tumor cells (CTCs) in pts on study and directly compared two methods of CTC enumeration; CellSearch (Veridex) and immunomagnetic enrichment followed by flow cytometry (IE/FC). A subset of samples were isolated for molecular profiling.
 Methods. Blood was obtained from consenting pts at baseline, 7 to 14 days after the first infusion, then monthly until the end of the study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer, and the percent of CTCs staining for EGFR was also measured. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM MAb-conjugated iron particles, followed by multiparameter FC for EpCAM, CD45, and nucleic acid content. CTC results were correlated by method, and to time on study treatment. In this preliminary analysis, the endpoint is time on study treatment (to progression/toxicity, TST).
 Results: Safety and efficacy data from arms 1 and 2 have been presented (Carey et al; SABCS 2007, ASCO 2008). Of 102 TN pts enrolled in this study, 65 had CTC measurements by both methods on at least one time point. CTC levels by the two assays were highly correlated at all time points. At baseline, Spearman's rank correlation coefficient was 0.67 (p<0.0001). Using the cutoffs shown below, CTC by IE/FC or CellSearch at baseline and first follow-up correlated with TST. This relationship was observed in both arm 1 and 2.
 
 Conclusion: In this phase II trial of C or C+P in pts with TN metastatic BrCa, CTCs measured by two different techniques were highly correlated. CTC levels at baseline and 7-14 days predicted longer vs. shorter TST, suggesting that CTCs may be an early marker of response to targeted therapy. Additional molecular data on CTCs will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6048.