Courtney Vito

Pathologic complete response rates in triple-negative, HER2-positive, and hormone receptor-positive breast cancers after anthracycline-free neoadjuvant chemotherapy with carboplatin and paclitaxel with or without trastuzumab

BACKGROUND Pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) is considered a surrogate for improved survival. Platinum-containing NCT, particularly in patients with HER2+ and triple-negative breast cancers (TNBC) may increase pCR rates. METHODS Tumor characteristics, pCR rates (no invasive disease in breast and lymph nodes), toxicities, and survival in patients who received carboplatin, a taxane, and trastuzumab (HER2+ disease) between April 2009 and December 2011, were reviewed. RESULTS Thirty eight patients (39 tumors) completed a median of 4 cycles of NCT. Eighteen of 39 (46%) tumors were HER2+, 8/18 (44%) responded with pCR; 13/18 HER2+ tumors were HR+ (72%) and 4/13 (31%) had a pCR. Ten of 39 (26%) tumors were TNBC; 6/10 (60%) had a pCR. At a median of 25-months no recurrences were observed in patients with pCR. CONCLUSIONS Prospective studies of anthracycline-free platinum-containing NCT are warranted in LABC patients with HER2+ and TNBC.

Rural and urban disparities in the evolution of sentinel lymph node utilization in breast cancer

BACKGROUND Sentinel lymph node biopsy (SLNB) has become the preferred method for axillary nodal staging. The authors examined SLNB utilization in urban versus rural settings as this procedure was adopted and hypothesized that SLNB rates among urban populations increased faster, while the technology shift and acceptance of SLNB were slower at rural centers. METHODS The Surveillance, Epidemiology and End Results database was used to identify patients with invasive node-negative ductal or lobular breast cancer diagnosed from 1998 to 2008. Exclusion criteria were distant metastatic disease, T4 tumors, or incomplete data. Residential setting was divided into groups on the basis of population density. RESULTS The overall rate of SLNB increased with time (from 10% in 1998 to 73% in 2008). The adoption of SLNB was slower in rural settings than among urban populations (P < .001). By 2003, only urban areas were using SLNB in >50% of cases. Overall, there was a 2-year lag between the increases in SLNB utilization rates in these groups. There was a significant difference in SLNB rates according to tumor size. CONCLUSION The overall rate of SLNB remained near 50% and was lower in rural locations in 2004. By 2008, the SLNB rate for T1 and T2 tumors had increased to >50% in all population categories. SLNB utilization was lower in all population categories as tumor size increased. There was an overall 2-year lag in the adoption of SLNB in less populated areas. Although this may represent a more conservative approach, the difference may be attributable to a shortage of experienced surgeons, lack of training, or lack of technological support at smaller institutions.

Characterization of patient-derived tumor xenografts (PDXs) as models for estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers.

The research was to appraise the utility of the patient-derived tumor xenografts (PDXs) as models of estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers. We compared protein expression profiles by Reverse Phase Protein Array (RPPA) in tumors that resulted in PDXs compared to those that did not. Our overall PDX intake rate for ER+ breast cancer was 9% (9/97). The intake rate for ER+HER2+ tumors (3/16, 19%) was higher than for ER+HER2- tumors (6/81, 7%). Heat map analyses of RPPA data showed that ER+HER2- tumors were divided into 2 groups by luminal A/B signature [protein expression of ER, AR, Bcl-2, Bim (BCL2L11), GATA3 and INPP4b], and this expression signature was also associated with the rate of PDX intake. Cell survival pathways such as the PI3K/AKT signaling and RAS/ERK pathways were more activated in the specimens that could be established as PDX in both classes. Expression of the ER protein itself may have a bearing on the potential success of an ER+ PDX model. In addition, HER2 and its downstream protein expressions were up-regulated in the ER+HER2+ patient tumors that were successfully established as PDX models. Moreover, the comparison of RPPA data between original and PDX tumors suggested that the selection/adaptation process required to grow the tumors in mice is unavoidable for generation of ER+ PDX models, and we identified differences between patient tumor samples and paired PDX tumors. A better understanding of the biological characteristics of ER+PDX would be the key to using PDX models in assessing treatment strategies in a preclinical setting.

Partners' clinic: an innovative gender strengths‐based intervention for breast cancer patients and their partners immediately prior to initiating care with their treating physician

It is well documented that women with breast cancer report high levels of distress [1]. However, partners of breast cancer patients are often as distressed as patients themselves [2]. A partner is an important component of the patient’s support system during a breast cancer diagnosis and throughout treatment [1]. Women have better psychological adjustment to their illness if their partners are emotionally supportive, but this is often where partners struggle the most [3,4]. Furthermore, positive relationships with many supportive friends do not compensate for a problematic partner relationship [3,5]. Despite this knowledge, there are few successful therapeutic models that foster an environment where women and their partners can identify their unique contributions to coping and make positive emotional connections during times of acute stress. The purpose of this correspondence is to describe a unique gender strengths-based intervention (Partners’ Clinic), report distress screening and satisfaction data for both the patient and their partners, and demonstrate the feasibility of providing a couples intervention early in the treatment continuum. Partners’ Clinic engages women and their partners in a psychoeducational consultation with clinician-educators immediately prior to their initial surgical consultation. Partners’ Clinic was developed using a psychoeducational and gender strengths-based theoretical framework. Educating pairs about their illness, treatment, and coping skills while integrating cognitive-behavioral and supportive therapeutic components can lead to reduced illness related distress [4,6]. The foundation of a gender strength-based approach is based on the belief that positive change occurs in the context of authentic relationships, every person has unique strengths, the importance of valuing differences, and the need to collaborate [6,7]. The goal is to maximize the ability of women and men to increase their emotional connection and problem solving skills despite the challenges of cancer. (See examples in Intervention)

Complete pathologic response of HER2-positive breast cancer liver metastasis with dual anti-HER2 antagonism.

BackgroundAlthough breast cancer frequently metastasizes to the bones and brain, rarely breast cancer patients may develop isolated liver metastasis. There is increasing data that anti-HER2 targeted therapy in conjunction with systemic chemotherapy may lead to increased rates of pathologic complete response in the primary breast cancer. However, little is known about its effects on metastatic liver disease.Case presentationWe report the treatment of a 54-year-old female who was diagnosed with HER2-positive invasive ductal carcinoma and synchronous breast cancer liver metastasis (BCLM). The patient underwent eight cycles of standard docetaxel with two anti-HER2 targeted agents, trastuzumab and pertuzumab. Subsequent radiographic imaging demonstrated complete radiographic response in the primary lesion with an approximate 75% decrease in the liver metastasis. After informed consent the patient underwent modified radical mastectomy that revealed pathologic complete response. Re-staging demonstrated no new disease outside the liver and a left hepatectomy was performed for resection of BCLM. Final pathologic examination revealed no residual malignant cells in the liver specimen, indicating pathologic complete response. Herein, we discuss the anti-HER2 targeted agents trastuzumab and pertuzumab and review the data on dual HER2 antagonism for HER2-positive breast cancer and the role of surgical resection of BCLM.ConclusionsThe role of targeted agents for metastatic HER2-positive breast cancer is under active clinical trial investigation and we await the maturation of trial results and long-term survival data. Our results suggest that these agents may also be effective for producing considerable pathologic response in patients with BCLM.

Rural and urban disparities in the evolution of sentinel lymph node utilization in breast cancer.

71 Background: Sentinel lymph node biopsy (SLNB) has become the preferred method for axillary nodal staging. We examined SLNB utilization in urban versus rural settings as this procedure was adopted. We hypothesized that SLNB rates in urban centers quickly increased prior to 2000, while the technology shift and acceptance of SLNB was slower in rural centers. METHODS The SEER registry was used to identify patients with invasive ductal or lobular breast cancer from 1998-2008. Exclusion criteria included evidence of distant metastatic disease, T4 tumors, no curative-intent operation performed, or incomplete staging data. Residential setting was divided into three groups based on population density: rural, intermediate population, and urban. RESULTS The overall rate of SLNB increased with time (9.5% in 1998 to 72.7% in 2008). The adoption of SLNB was slower in rural settings than in urban populations (p<0.001). By 2003, only urban areas were utilizing SLNB in over 50% of cases. When stratified by population density, there was a significant difference in SLNB rates according to type of surgery performed (lumpectomy vs mastectomy) as well as by T-stage, with lower T-stage positively correlating with the likelihood of SLNB usage in all categories. Overall, there was a two-year lag in the adoption of between the increases in SLNB utilization rates in these groups. CONCLUSIONS Since 1998, the use of SLNB for breast cancer has slowly increased throughout the United States. Though widely accepted as the preferred staging method, the overall rate of SLNB remained near 50% and was lower in rural locations in 2004. By 2008, the SLNB rate for T1-T2 had increased to over 50% in all population categories. There was an overall 2-year lag in adoption of SLNB in less populated areas. While this may represent a more conservative approach as noted by the higher utilization in small tumors, the difference may be attributable to a shortage of experienced surgeons, lack of training, or lack of technological support at smaller institutions. The provision of continued training in emerging technologies for rural surgeons, such as SLNB, should remain a priority in continuing surgical education.

Dual mTOR kinase inhibitor MLN0128 sensitize HRþ/HER2þ breast cancer patient-Derived xenografts to trastuzumab or fulvestrant

Purpose: Therapeutic strategies against hormonal receptor–positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future “co-clinical” trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR.

Abstract P4-21-35: Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC)

Background: Pathologic complete response (pCR) to HER2-targeting neoadjuvant therapy (NT) predicts for improved survival (Cortazar et al, Lancet, 2014). The addition of pertuzumab to trastuzumab and docetaxel increased pCR rates, and, as first line treatment for MBC led to longer overall survival ([OS] Swain et al, NEJM 2015). Avoidance of anthracyclines in the adjuvant setting for HER2+ BC reduced the risk of secondary hematologic malignancies without a detriment to OS (Slamon et al, NEJM, 20111). Finally, nab-paclitaxel (nab) might provide an advantage over other taxanes via decreased use of steroids and may lead to increased response rates (RR). We designed a study of pertuzumab (pert), trastuzumab (trast), and nab, testing the feasibility and efficacy of this regimen in the LABC and metastatic breast cancer settings. Materials and Methods: Pts with Stages II-III LABC received six cycles of NT with pert (day 1 q 21 days), trast, and nab 100 mg/m2 (both given IV, weekly). Pts with untreated MBC received the same regimen until progression, toxicities, or patient or physician preference led to stopping therapy. Primary endpoints included pCR (LABC) and RR and progression-free survival (PFS) in MBC. Forty pts with LABC and 25 pts with MBC were to be accrued. The study was designed to test whether the pCR rate of Neosphere (Gianni et al, Lancet Oncol, 2012, > 45.8%) and the PFS rate of CLEOPATRA (median of > 18.5 months) can be matched or exceeded. Procurement of serial samples for assessment of tumor gene expression, circulating tumor cells, miRNA, and serum DNA profiling for exploratory biomarker analysis was carried out. Results:Twenty-two of 28 already enrolled pts with LABC (clinical stage II:15, stage III: 7) completed NT. The median age was 53 (34-77). The pCR rate was 86% (6/7) for hormone receptor negative (HR-) and 40% (6/15) for HR+ pts, with an overall pCR of 55%. Three pts without pCR following NT had residual BC with a HER2 negative phenotype. Eighteen of 22 pts required nab dose modifications. The most frequent toxicities following NT included elevated liver function tests:27%, peripheral neuropathy:23%, hematological toxicities:17%, diarrhea:18%, infusion reactions:18%. In the MBC cohort there were 13 of 16 enrolled pts with > 2 months of follow-up. The median age was 47 (31-65), 62% had HR+ disease. A CR rate of 4/13 (31%) and confirmed RR of 77% were observed. The median number of cycles with pert, trast, nab was 9 (3+ to 41); 11 of 13 pts required dose modifications or delays (3 of the delays were due to primary breast surgery performed upon response to treatment). At a median follow-up of 19 months, PFS and OS estimates are 63% (95% CI 0.09-0.93), and 89% (95% CI 0.61-1.0). Conclusion: The non-anthracycline-containing regimen of pertuzumab, trastuzumab, and nab-paclitaxel induced a high pCR rate in HER2+ BC. PFS is encouraging in MBC. Outcome of the fully accrued cohorts inclusive of residual cancer burden scores in the LABC cohort, and correlative data with exploratory biomarker analysis will be presented. Citation Format: Somlo G, Frankel P, Yeon C, Yuan Y, Yim J, Kruper L, Taylor L, Mortimer J, Waisman J, Jones V, Vito C, Paz B, Huria A, Li D, Gaal C, Tong T, Tumyan L. Phase II trial of pertuzumab, trastuzumab, and nab-paclitaxel in patients (pts) with HER2 overexpressing (HER2+) locally advanced or inflammatory breast cancer (LABC) or untreated stage IV metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-35.

Abstract P1-14-10: Phase II trial of neoadjuvant chemotherapy with carboplatin and nab-paclitaxel in patients with triple negative locally advanced and inflammatory breast cancer

Background: Pathologic complete response (pCR) and residual cancer burden (RCB scores of 0 [pCR] or 1[near CR]) after neoadjuvant chemotherapy (NCT) may predict for improved survival (Symmans et al. J Clin Oncol 25:4414-22, 2007). We set out to test the pCR rate with an anthracycline-free regimen of carboplatin (carb) and nab-paclitaxel (nab) in patients (pts) with triple negative breast cancer (TNBC). Materials and Methods: Forty-nine pts with stages II-III BC were to receive carb (AUC 6) on day 1 of a 28 day cycle, and nab 80 mg/m2 weekly, for a total of 4 cycles. Core biopsies were performed prior to NCT. Blood procurement for circulating tumor cell (CTC) analysis using the CellSearch platform was carried out pre-treatment, mid-treatment, and at surgery. We set out to assess the predictive value of Mammaprint (poor vs. good), BluePrint (basal, vs. luminal, vs. HER2) molecular subtype as well as microarray RNA and miRNA profiling, for pCR. Responses were also dichotomized as complete or near complete response (Symmans RCB scores of 0-1) vs. suboptimal response (RCB score > 1). Results: The median age was 53 (28-75). Pts presented with clinical stages II (63%) and III (37%). So far, 38 of the 49 pts accrued between 2/2012 and 6/2015, have undergone surgery, 68% of whom underwent modified radical mastectomy. The pCR rate (breast and lymph nodes in CR) was 53%, and RCB 0 and 1 were seen in 68% of pts. Toxicites included grade ¾ anemia (45%), thrombocytopenia (13%) and neutropenia (53%,1 pt with neutropenic fever). Dose adjustments were needed in over 80% of pts. Grades 2 or 3 peripheral neuropathy were seen in 8% each, and grades 3-4 fatigue (13%), hypokalemia (3%), and hyponatremia (3%) were observed. The median number of CTCs (pre-NCT) observed in 7 CTC positive pts of the first 27 pts who completed surgery was 1 (0-7), and 2 of the 7 pts continued to have CTCs at the time of surgery (1 CTC each), while 2 pts without CTCs pre-NCT had CTCs (1 each) detected at surgery. The final pt enrolled is expected to complete surgery by 10/2015. Results of sequential CTC assessments, MammaPrint/Blueprint and RNA/miRNA analysis of pre- and post-treatment specimens and their correlation with pCR will be presented. Conclusion: The non-anthracycline-containing regimen of carb and nab-paclitaxel induced a high pCR rate in TNBC, in preliminary analysis. Ongoing profiling may allow for future subset-specific modification of this regimen to increase pCR across all molecular subtypes of TNBC. Citation Format: Somlo G, Chung S, Frankel P, Hurria A, Koehler S, Kruper L, Mortimer JE, Paz B, Robinson K, Taylor L, Vito C, Waisman J, Yeon C, Yim J, Yuan Y, Tong T. Phase II trial of neoadjuvant chemotherapy with carboplatin and nab-paclitaxel in patients with triple negative locally advanced and inflammatory breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-10.

Abstract C28: An exploratory study of co-occurrence of breast cancer and diabetes in medically underserved Latinas

Purpose: Cancer and diabetes are two severe chronic illnesses that often co-occur. The presence of diabetes in cancer patients is associated with increased risk for poor health outcomes and decreased overall survival. Lack of access to care and under-diagnosis of diabetes makes this co-occurrence particularly troubling among the Latino population. This preliminary study explored the association of diabetes with functioning and physical health outcomes among underserved Latina breast cancer survivors (BCS). Methods: In total, 137 low income Latina BCS were recruited from the California Cancer Registry, hospital cancer registries, and community agencies. Latina BCS completed a self-report questionnaire that assessed demographic and cancer-related medial characteristics, the co-occurrence of diabetes, and functional and physical outcomes. Results: Among Latina BCS, 98 (72%) were non-diabetic and 39 (28 %) were diabetic. Latina BCS with diabetes were more likely to report less than a high school education, being uninsured, and unemployed (p Conclusions: This preliminary investigation sheds new light on emerging evidence documenting the negative associations of comorbid chronic conditions such as diabetes on patients9 outcomes. More attention to the co-occurrence of cancer and chronic disease is warranted for addressing cancer health disparities. Our descriptive analysis offers support for additional inquiry and attention to the co-occurrence of cancer and chronic disease as a target for action in improvements in quality, patient-centered care and in the reduction of persistent health disparities. Citation Format: Kimlin T. Ashing, Monica Rosales, Raynald Samoa, Lily Lai, Roberto Vargas, Courtney Vito, Arti Hurria, Mayra Serrano. An exploratory study of co-occurrence of breast cancer and diabetes in medically underserved Latinas. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C28. doi:10.1158/1538-7755.DISP13-C28