Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ 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 vivoConclusions: 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.

Acceptance of adjuvant chemotherapy recommendations in early-stage hormone-positive breast cancer.

BACKGROUND: The role of systemic chemotherapy in early-stage, estrogen receptor (ER)-positive, and Her2-negative breast cancer remains an area of active investigation. The decision to recommend chemotherapy is multifactorial, and some patients decline recommended chemotherapy. We sought to identify patient factors leading to refusal of adjuvant therapy. MATERIALS AND METHODS: Data were collected from National Comprehensive Cancer Network Outcomes database and used to identify patients with primary, unilateral, T1-T2, N0, ER+, Her2-disease diagnosed from 2005-2011. Patient and clinical characteristics were analyzed for associations with physician recommendation for chemotherapy and patient acceptance of chemotherapy. A logistic regression model was used to identify patient and tumor characteristics associated with recommendation for and acceptance of chemotherapy. RESULTS: A total of 329 patients were identified. Chemotherapy was recommended in 191 patients (58.1%) and not in 138 (41.9%). Young age (odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.2-12.7), large tumor size (6.69, 95% CI: 3.31-13.5), and high Oncotype DX scores (11.2, 95% CI: 4.5-27.9) were more likely to receive a recommendation. About 71 patients (37.1%) refused chemotherapy. Patients younger than age 50 (20.9, 95% CI: 2.5-172.0), larger tumor size (3.4, 95% CI: 1.3-8.7), Oncotype DX score > 31 (31.3, 95% CI: 3.3-295.0), privately insured (8.2, 95% CI: 1.9-34.7), and Hispanic ethnicity (5.2, 95% CI: 1.6-16.8) were more likely to accept chemotherapy. CONCLUSIONS: Physician recommendations for adjuvant chemotherapy for early-stage ER + breast cancer varied by commonly considered factors. Patient acceptance varied by similar factors but was also influenced by race and insurance status. This may be explained by cultural or social factors not well understood or not overcome by physician guidance.

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.

Predictors of Antiestrogen Recommendation in Women With Estrogen Receptor-Positive Ductal Carcinoma In Situ.

BACKGROUND: Antiestrogen (anti-e) use in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS) has been shown to reduce the incidence of noninvasive and invasive breast cancer. Few studies have evaluated factors associated with anti-e recommendation in ER+ DCIS. METHODS: The California Cancer Registry was queried for female patients diagnosed with ER+ DCIS and treated with lumpectomy or unilateral mastectomy from 2004 to 2011. Patient demographics, comorbidities, and clinical characteristics were analyzed for association with anti-e recommendation. RESULTS: Of 5,527 patients identified, 76.4% patients underwent lumpectomy and 23.6% underwent unilateral mastectomy. Of the total cohort, 31.6% patients were recommended anti-e therapy, 60.4% were not, and the remaining 8.0% were recommended anti-e, but administration was not documented. Performance of lumpectomy predicted anti-e use compared with mastectomy (odds ratio [OR], 2.08; 95% CI, 1.77-2.43). Asian/Pacific Islanders were more often recommended anti-e therapy when compared with whites (OR, 1.28; 95% CI, 1.10-1.49). Patients younger than 70 years were more often recommended anti-e (age, 18-49 years: OR, 1.38; CI, 1.12-1.71; and age, 50-69 years: OR, 1.43; CI, 1.20-1.71). CONCLUSIONS: Despite current guidelines to consider the use of anti-e therapy, recommendation of anti-e after surgical treatment of DCIS is low, having been recommended to 40% of patients, and used by fewer than one-third. Significant predictors include lumpectomy compared with unilateral mastectomy, Asian/Pacific Islander race, younger age, and number of comorbidities. Further work is merited to understand patterns of anti-e therapy recommendation by providers in patients with DCIS.

Time to Treatment: Measuring Quality Breast Cancer Care.

BACKGROUND: To optimize breast cancer care, several organizations have crafted guidelines to define best practices for treating breast cancer. In addition to recommended therapies, 'timeliness of treatment' has been proposed as a quality metric. Our study evaluates time to surgical treatment and its effect on overall survival (OS). METHODS: The National Cancer Data Base (NCDB) was used to identify women diagnosed with invasive breast cancer between 2004 and 2012. Time from diagnosis to surgical treatment was calculated and grouped according to predetermined time intervals. Univariate and multivariate Cox proportional hazard models were used to assess patient and treatment factors related to OS. RESULTS: Overall, 420,792 patients initially treated with surgery were identified. Increased time to surgical treatment >12 weeks was associated with decreased OS [hazard ratio (HR) 1.14, 95 % confidence interval (CI) 1.09-1.20]. When stratified by pathologic stage, stage I patients treated at 8 to <12 weeks (HR 1.07, 95 % CI 1.02-1.13) and >12 weeks (HR 1.19, 95 % CI 1.11-1.28), as well as stage II patients treated at >12 weeks (HR 1.16, 95 % CI 1.08-1.25), had decreased OS compared with patients treated at <4 weeks. Other variables associated with decreased survival were treatment at a community cancer program, Medicaid or Medicare insurance, Black race, increasing age, mastectomy, moderately and poorly differentiated tumor grade, increasing T and N stage, and higher Charlson Index Group. CONCLUSION: The survival benefit of expedited time to initial surgical treatment varies by stage and appears to have the greatest impact in early-stage disease. Prior to establishing standard metrics, further quantification of the impact on patient outcomes is needed.

Addressing psychosocial needs of partners of breast cancer patients: a pilot program using social workers to improve communication and psychosocial support.

INTRODUCTION: Psychosocial (PsySoc) distress in caregivers is a well-described entity, with some caregivers experiencing more distress than patients themselves. The American College of Surgeons' Commission on Cancer mandates that psychosocial services be provided to all cancer patients and their caregivers, through the entire continuum of cancer care. METHODS: We developed a program for newly diagnosed breast cancer patients and their partners. Both were screened for biopsychosocial stressors. The couple was then paired with two clinican-educators trained in communication and gender differences, who educated the couple in communication-based problem solving and provided referrals to supportive services. RESULTS: Eighty-six patients and 82 partners returned surveys. Compared to partners, patients were more likely to report feeling anxious or fearful (59 vs. 38%, p = 0.014), report difficulty in managing their emotions (46 vs. 11%, p = 0.003), and experience distress over being unable to take care of themselves (37 vs. 6%, p = 0.000). Interestingly, there was no difference between patients and partners in feeling unsupported by their partner (6 vs. 5%, p = 0.85) or in feeling down or depressed (29 vs. 30%, p = 0.96). DISCUSSION: Both patients and partners experience significant distress after a breast cancer diagnosis. We found that partners are equally likely to feel unsupported by their partner (patient) and feel down or depressed. Further study is needed to learn about both patients' and partners' significant distress over lack of support. Partner-focused PsySoc interventions should be initiated in all cancer centers to address the emotional needs of both breast cancer patients and their partners.

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.

Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is commonly used to treat locally advanced breast cancer. Pathologic complete response (pCR) predicts improved overall survival (OS); however, prognosis of patients with partial response remains unclear. We evaluated whether tumor response ratio (TRR) is a better predictor of OS than current staging methods. METHODS: Using the National Comprehensive Cancer Network Breast Cancer Outcomes Database, we identified patients with stage I-III breast cancer who had NAC and pretreatment imaging at City of Hope (1997-2010). Patient demographics, tumor characteristics, and OS were analyzed. TRR was calculated as residual in-breast disease divided by size on pre-NAC imaging. Four TRR groups were stratified; TRR 0 (pCR), TRR > 0-0.4 (strong partial response, SPR), TRR > 0.4-1.0 (weak partial response, WPR), or TRR > 1.0 (tumor growth, TG). OS was estimated by the Kaplan-Meier method and tested by the log-rank test. Cox regression was performed to evaluate associations between OS and TRR in a multivariable analysis while controlling for potential confounders. RESULTS: There were 218 eligible patients identified; 59 (27 %) had pCR, 61 (28 %) SPR, 72 (33 %) WPR, and 26 (12 %) TG. Five-year OS decreased continuously with increasing TRR:pCR (90 %), SPR (79 %), WPR (66 %), and TG (60 %). TRR was the only measure that significantly predicted OS (p = 0.0035); pathologic stage (p = 0.23) and pre-NAC clinical tumor stage (cT) (p = 0.87) were not significant. TRR continued to be statistically significant by multivariable analysis (p = 0.016). CONCLUSIONS: TRR takes into account both pretreatment and residual disease and more accurately predicts OS than pathologic stage and pre-NAC cT. TRR may be useful to more accurately assess prognosis and OS in breast cancer patients undergoing NAC.

Life expectancy after curative-intent treatment of breast cancer: impact on long-term follow-up care.

Long-term survival rates after treatment for breast cancer are directly influenced by early deaths resulting from disease. For longer-term breast cancer survivors, survival rates appear deceptively low. We hypothesize that the actual survival curve for long-term survivors approaches the overall survival of the general population. The Surveillance, Epidemiology, and End Results database (1988 to 2002) was used to identify patients with nonmetastatic breast cancer who underwent definitive surgical treatment. The survival of the general population was constructed by using national life tables with an age-matched population. Comparisons of survivals were made for 3-, 5-, and 7-year breast cancer survivor cohorts. Of 237,180 patients, 92.4 per cent survived three years, 82.1 per cent five years, and 58.1 per cent seven years. Stage I patients have equivalent or better survivals compared with the age-matched general population in all three cohorts. Stage II patients reached equivalent conditional survival between eight and nine years after diagnosis regardless of cohort. Stage III patients required achieving nine to 10 years after diagnosis to achieve equivalent survival probability, except in 7-year survivors, in whom 10 to 11 years was required. In all stages, once equivalence was reached, survival exceeded the general population over the remaining years. Initial cancer stage influences overall survival for many years after diagnosis. Patients with Stage I cancer return to the general population risk as early as three years after diagnosis, whereas higher stages can require up to nine years to achieve parity with a more generalized population. These findings should be factored into general health screening issues for long-term breast cancer survivors.

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

BACKGROUND: Although 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 PRESENTATION: We 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. CONCLUSIONS: The 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.

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.