G. N. Hortobagyi

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer

PURPOSE Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Overall Survival and Cause-Specific Mortality of Patients With Stage T1a,bN0M0 Breast Carcinoma

PURPOSE With mammographic screening, the frequency of diagnosis of stage T1a,bN0M0 breast cancer has increased. Prognosis after locoregional therapy and benefit from adjuvant systemic therapy are poorly defined. We reviewed T1a,bN0M0 breast cancer cases registered in the Surveillance, Epidemiology, and End Results (SEER) Program to investigate the impact of prognostic factors on breast cancer-specific (BCSM) and non-breast cancer-related mortality. METHODS We identified T1a,bN0M0 breast cancer cases registered in the SEER Program from 1988 to 2001, and used the Kaplan-Meier product limit method to describe overall survival (OS). We estimated the probabilities of death resulting from breast cancer and from other causes, and analyzed associations of patient and tumor characteristics with OS, BCSM, and non-breast cancer-related mortality using the log-rank test, Cox proportional hazards models, and a competing-risk model. We constructed nomograms to assist physicians in adjuvant therapy decision making. RESULTS We identified 51,246 T1a,bN0M0 cases. Median follow-up was 64 months (range, 1 to 167 months). Median age at diagnosis was 65 years (range, 20 to 101 years). Ten-year probabilities of all-cause mortality and BCSM were 24% and 4%, respectively. Characteristics associated with increased probability of BCSM included age younger than 50 years at diagnosis, high tumor grade, estrogen receptor-negative status, progesterone receptor-negative status, and fewer than six nodes removed at axillary dissection. The constructed nomograms allow a comparison of predicted breast cancer-specific survival and non-breast cancer-specific survival in individual patients. CONCLUSION Overall, the prognosis of patients with T1a,bN0M0 breast cancer is excellent. However, subgroups of patients who are at higher risk of BCSM and who should be considered for adjuvant systemic therapy can be identified.

Effect of Molecular Disease Subsets on Disease-Free Survival in Randomized Adjuvant Chemotherapy Trials for Estrogen Receptor–Positive Breast Cancer

PURPOSE The majority of estrogen receptor (ER)-positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy. METHODS We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study. RESULTS The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%. CONCLUSION Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.

Pharmacogenomics and clinical biomarkers in drug discovery and development.

The fields of pathology and clinical pharmacology are in an era of rapid evolution, reflecting continuous technological advancements in molecular diagnostics focused on improving drug efficacy and reducing toxicity. The discovery and refinement of the human genome sequence, further understanding of epigenetic events, and the expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors, and sophisticated computational biology are having an unprecedented impact on the pharmaceutical industry. This review focuses on the discovery and development of DNA-based gene sequence tests and RNA-based gene expression profiles as applied to the prediction of response, resistance, and toxicity of both new and existing anticancer, cardiovascular, and anti-inflammatory drugs. This review will also consider the potential of emerging biomarkers designed to assist in the clinical development of these agents.

Abstract P5-10-02: Clinical Outcome of Two Sequences of Administering Paclitaxel (P) and Anthracyclines (A) as Primary Systemic Therapy (PST) and Adjuvant Chemotherapy (ACT) in Breast Cancer (BC) Patients: A Retrospective Analysis from the M. D. Anderson Cancer Center (MDACC)

Background: P-and A-based regimens are widely used as PST and ACT of early BC. It is unknown whether the efficacy of such combinations is affected by their sequence of administration. The purpose of this retrospective analysis was to assess the clinical outcome of two different sequences of P and A in pts receiving PST and ACT. Methods: We analyzed 3,010 pts (1,414 PST and 1,596 ACT) with stage I — III BC treated between 1994 -2009. These pts were identified through our prospective online MDACC breast cancer database. Pts treated with trastuzumab, docetaxel or adriamycin/cyclophosphamide-regimen were excluded. Pathological complete response (pCR) was defined as no residual invasive disease in breast and ipsilateral axillary lymph nodes. Results: PST cohort included 1.071 pts (75%) with clinical stage I-IIIA and 343 (24.2%) stage IIIB-IIIC BC; 1,188 pts (84%) received the sequence P→A and 226 pts (16%) A→P. In the PST cohort 958 pts (67.7%) and 161 (11.3%) had hormone-receptor (HR) positive (+) and HER-2 + BC, respectively. ACT cohort consisted of 1,503 pts (94%) with pathological stage I-IIIA and 93 (5.82%) stage IIIB-IIIC. 1,196 pts (75%) received the sequence P→A, and 400 pts (25%) A→P. In the ACT cohort 1,122 (70.3%) and 93 (3.9%) had HR+ and HER2+ BC, respectively. Both cohorts of pts were balanced by HR-status, clinical stage, and menopausal status. The combined p-values for ACT and PST cohorts were calculated and they were significant for both RFS (p=0.022) and OS (p=0.002). In univariate analysis the sequence A→P was associated with inferior outcome. In Cox multivariate analysis, after stratification for period at diagnosis and adjustment for age, clinical stage, HR status, grade, and LVI the A→P sequence administered as PST was associated with significantly higher risk of relapse (HR 1.49; CI 1. 10-2.03; p=0.01) but not death (HR 1.28; CI 0.90-1.84; p=0.17). In the ACT cohort, the Cox multivariate analysis, after stratification for age, HR status, HER2 the sequence A→P was significantly associated with higher risk of death (HR 2.02; CI 1.33-3.06; p=0.001) but not relapse (HR 1.21; CI 0.82-1.79; p=0.33). Conclusions: The P→A sequence compared to the A→P sequence is associated with lower risk of relapse and death in PST and ACT, respectively. This retrospective analysis is hypothesis-generating and should lead to a prospective randomized trial to compare the two sequences as PST or ACT in locally advanced or early BC, respectively. Primary Systemic Therapy (N=1,414) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-02.

Abstract P6-12-02: Survival differences between patients with metastatic inflammatory and non-inflammatory breast cancer

Background: Very little is known about the survival of patients with inflammatory breast cancer (IBC) and distant metastasis. Furthermore, the American Joint Committee on Cancer classification of breast cancer does not recognize metastatic IBC as a distinct entity within stage IV. We hypothesized that the survival of patients with IBC and distant metastasis is worse than the survival of patients with stage-matched non-IBC. Patients and Methods: We retrospectively reviewed 5314 consecutive patients with stage III or IV breast cancer (IBC or non-IBC) who were treated at our institution between 1986 and 2012. A total of 1079 patients presented with IBC (stage III: 861; stage IV: 218) and 4235 non-IBC (stage III: 2781; stage IV: 1454). We compared the time to distant metastasis from initial diagnosis, distant metastasis–free survival (DMFS), and overall survival (OS) in stage-matched patients with IBC or non-IBC. Results: The median follow-up periods were 3.3 years for patients with stage III disease (range, 0-32.2 years) and 1.8 years for patients with stage IV disease (range, 0-19.9 years). The total number of recorded events (metastasis/death) was 1657 for stage III, while the numbers of deaths for stage III and IV were 1337 and 973, respectively. In patients with stage III, the time to distant metastasis was shorter in IBC than in non-IBC (median 1.3 vs. 1.7 years, P P P P = .83). In multivariate analysis, the diagnosis of IBC remained significantly associated with mortality after adjusting for potential confounders. De novo stage IV IBC presented more frequently with multiple sites of metastasis than de novo stage IV non-IBC ( P = .02). In patients with de novo stage IV disease, OS was shorter in IBC than in non-IBC (2.3 vs. 3.4 years, P = .004). In the multicovariate Cox model, while ethnicity, tumor grade, hormone receptor status and HER2 status, site of metastasis, number of sites of metastasis, and definitive breast surgery by 1 year were all significant factors in OS for stage IV breast cancer, the diagnosis of IBC conferred a hazard ratio of 1.33 (95% confidence interval: 1.05 - 1.69) in multivariate analysis. Conclusion: Our findings suggest that IBC patients with metastasis at diagnosis have worse outcomes than stage-matched non-IBC patients. IBC patients presenting with de novo stage IV disease should be considered as a separate subcategory of stage IV in the tumor-node-metastasis classification because their clinical course and prognosis are different from those of patients with stage IV non-IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-02.

Abstract PD03-08: Statin use and improved outcome in primary inflammatory breast cancer: retrospective cohort study

Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC. Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors. Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.

Abstract OT2-3-10: Phase II study of panitumumab, nab-paclitaxel, and carboplatin for patients with primary inflammatory breast cancer (IBC) without HER2 overexpression

Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. The outcome for patients with IBC is bleak despite multimodality treatment approaches. 10-year disease-free survival rates after combined anthracycline and taxane-containing chemotherapy, surgery, and radiation are only 20%–25%. Our recent study found EGFR overexpression, a predictive factor of poor outcome, in 12 of 40 (30%) patients with IBC. Panitumumab has shown activity against EGFR overexpressing breast cancer xenograft model. Trial design: This is a single center, open-label, phase II study to evaluate the safety and efficacy of panitumumab in combination with preoperative chemotherapy. The treatment regimen consists panitumumab 2.5 mg/Kg given intravenously alone for the first week, followed by weekly panitumumab, nab-paclitaxel (100mg/m2) and carboplatin (2 AUC) (PNC) for 12 weeks. Patients then will receive 5-FU, epirubicin, and cyclophosphamide (FEC) every 3 weeks for 4 cycles prior to surgery. Eligibility criteria: 1) Histological confirmation of breast carcinoma with pathologic evidence of dermal lymphatic invasion and clinical diagnosis of IBC, including diffuse erythema, heat, ridging, and peau d9orange; 2) Normal HER2 expression; 3) No prior therapies for IBC; 4) Adequate hematologic, cardiac, renal and hepatic functions. Specific aims: 1) Primary objective is to determine the pathologic complete response (pCR) rate in patients with primary IBC without HER2 overexpression; 2) Secondary objectives are to determine the disease-free survival (DFS), overall survival (OS), the safety and tolerability of PNC regimens and the correlates of pathologic response rate and EGFR expression level. Statistical methods: 1) Previous studies have shown that this IBC patient population achieved a 13% pCR rate on the standard of care. We assume a beta (0.26, 1.74) prior distribution for the pCR rate. This prior distribution has a mean of 13% and a standard deviation of 19%. 2) We will stop the trial early if P (pCR rate >/= 13%) is Present accrual and target accrual: To date, 13 patients have been enrolled. Target accrual is 40 patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-10.

Abstract P3-10-05: Response to neoadjuvant systemic therapy (NST) in inflammatory breast cancer (IBC) according to estrogen receptor (ER) and HER2 expression.

Background: Inflammatory breast cancer (IBC) is the most aggressive form breast cancer. NST, followed by local therapy (surgery and radiation therapy), is considered the current standard therapy for IBC. Among noninflammatory breast cancers, sensitivity to NST differs based on ER and HER2 status. However, whether the sensitivity to NST also differs in primary IBC based on ER status or other prognostic factors has not been studied in a large cohort. Methods: We retrospectively reviewed 1078 patients (pts) newly diagnosed with IBC from April 1989 to January 2011. Of these, 838 pts met our inclusion criterion of stage III disease at diagnosis, and 713 of these pts had received NST and surgery. Among this population, 545 pts had information available on both ER and HER2 status. We compared pathological complete response (pCR) rates (defined as no evidence of invasive disease in the breast and ipsilateral axillary limph nodes) and clinical characteristics between ER and HER2-status subgroups and analyzed their clinical outcome. We used the Kaplan-Meier method to estimate the median recurrence-free survival (RFS) after surgery and overall survival (OS), and the Cox proportional hazards regression model to test the statistical significance of potential prognostic factors in each group. Results: Overall 177 pts had ER+HER2− tumors; 75, ER+HER2+; 134, ER-HER2+; and 159, ER-HER2−. NST consisted of anthracycline-based [A] alone, a taxane [T] alone or with A+T; HER2 targeting therapies (H) were administered to 117 patients with HER2-positive breast cancer after 1998. Overall pCR rate was 14.7%. pCR rates are shown by marker subtype and NST received in the table below. pCR rate, nuclear grade, vascular invasion, clinical response to NST, adjuvant treatment, radiation therapy, and adjuvant hormonal therapy differed significantly among subgroups. The median RFS and OS for all patients was 19.2 and 33.2 months, respectively. In multivariate analysis, BMI, ER status, lymphatic invasion, radiation therapy, and pCR rate were associated with RFS, and ER status, vascular invasion, radiation therapy, and pCR rate were associated with OS. Except in the ER+HER2− group, pCR was associated with better prognosis compared to non-pCR. Adjuvant hormonal therapy improved RFS both in ER+HER2+ and ER+HER2− groups, but did not improve OS in the ER+HER2+ group. Among 209 patients with HER2+ IBC, 134 received HER2 targeting therapies in neoadjuvant or adjuvant chemotherapy, and had a trend to improvement in RFS compared to chemotherapy alone (p = 0.082). The ER-HER2− group showed poorest outcome compared to other subgroups (P Conclusions: Sensitivity to NST differs depending on the ER and HER2 status in IBC pts. pCR rates based on these subgroups appear to be low. There is a need more effective treatments in the neoadjuvant and adjuvant therapies for all subgroups of IBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-10-05.

Abstract P5-20-13: Preliminary report of a phase I/II study of entinostat (IND#NSC 706995, /M275) and lapatinib (IND#NSC 727989) in patients with HER2-positive metastatic breast cancer in whom trastuzumab has failed

Background: Entinostat is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has shown that Entinostat can enhance the activity of Lapatinib in HER2+ metastatic inflammatory and non-inflammatory breast cancer. The primary objective of the phase I portion of this study is to determine the recommended phase II dose for Entinostat in combination with Lapatinib in patients who have received Trastuzumab for HER2+ metastatic breast cancer. Methods: This is a single center, open-label study to evaluate the safety and tolerability of every other week entinostat in combination with a 28-day cycle of Lapatinib. Patients with metastatic breast cancer in whom trastuzumab has failed were included. The phase I portion of the study is a conventional 3+3 dose-escalation design. Dose levels include 0 (starting dose) Entinostat 10 mg orally every other week, I Entinostat 12 mg, and II Entinostat 15 mg. Lapatinib 1,250 mg orally is given every day without dose escalation. Toxicities are evaluated at the end of each cycle. Results: Here we report the phase I portion of the study. To date, 9 patients were enrolled, 3 were in level 0, and 6 were in level I. In Level 0, 2 patients were taken off study due to disease progression (PD) at the end of cycle one and 1 patient was taken off study due to PD at the end of cycle two. In Level I, 1 patient was taken off study due to PD at the end of cycle one and 2 patients were taken off study due to PD at the end of cycle 2. 1 patient had stable disease. The median age is 41 (range, 26–69). Seven of the nine patients are evaluable for toxicity. Most common toxicities reported by the patients are nausea grade 3 (1), fatigue grade 3 (1), muscle aches/pain grade 2 (3), skin rash grade 3 (1), paresthesias grade 2 (2), heartburn grade 1 (4), and diarrhea Grade 2 (1). Lapatinib dose was reduced in 2 patients. The most common hematological toxicities were neutropenia grade 1 (3), anemia grade 2 (1), and thrombocytopenia grade 4 (1). Conclusions: Overall, patients have tolerated the combination regimen relatively well. We have not reached the maximum tolerated dose, so patient enrollment will continue until the phase I portion of the study is complete, most likely in July 2012. We plan to proceed with phase II portion in two parallel cohorts (HER2+ inflammatory and non-inflammatory metastatic breast cancer). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-13.