Colón‐Otero, Gerardo

Purpose Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted. Methods NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models. Results The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C. Conclusion The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.

Abstract Acinar cell carcinoma of the pancreas (ACC) is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic ACC who achieved prolonged survival with doxorubicin as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and primary cells in culture developed from the liver metastasis. We now report the characterization of a patient derived xenograft (PDX) mouse model originating from this patient's ACC liver metastasis tissue. Antitumor activity of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) used as single agent therapy is demonstrated. Of the targeted and cytotoxic therapies used, oxaliplatin produced a dramatic and prolonged response to therapy even after withdrawal of treatment. Bevacizumab produced a significant response, as well. Serum lipase and tissue amylase levels correlated with the antitumor response to therapy. Thus, we have developed and characterized an ACC PDX model that may be used in drug discovery for the treatment of this rare cancer for which no standard of care exists. Note: This abstract was not presented at the meeting. Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland. Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1475. doi:10.1158/1538-7445.AM2015-1475

Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) –positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. Results Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. Conclusion The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.

Abstract Background: Preplanned combined analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and North Central Cancer Treatment Group (NCCTG) (Alliance) N9831 Trial compared adjuvant chemotherapy with or without trastuzumab in women with HER2-positive breast cancer. The initial results were reported in 2005 and updated in early 2011 Methods: 4045 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The definitive analysis for OS will occur when 710 events have been reported. Results: Median time on study is 8 years. The required number of events have occurred for the definitive analysis for OS to be conducted by the end of September 2012. Updated analyses of disease free survival and related subgroups will also be presented. Supported by NCI grants U10-CA-12027, -69651, -37377, -69974, -44066, U24-CA-114732, CA25224; Breast Cancer Research Foundation; Genentech 35–03 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-5.

Abstract Background: Several randomized trials had shown the benefits of palliative care interventions in patients with metastatic cancer. However, there is a paucity of data evaluating the benefit of palliative care in racially diverse patient populations, and no systematic analysis of the effect of race/ethnicity on these interventions have been done. Recently, our group completed a randomized clinical trial showing that an Advanced Registered Nurse Practitioner (ARNP)-directed palliative care intervention for patients with metastatic cancer leads to improvement in the patients' emotional quality of life (EQoL) as determined by a validated quality of life tool, the FACT-G (PAL-1 study, Dyar et al: J Palliative Medicine 15: 890, 2012). The PAL-2 pilot study reported herein evaluated the feasibility of this program in underserved racially diverse patient populations. PAL-2 incorporated PAL-1 interventions of advanced directives discussions, hospice services education and assessment of QoL using the FACT-G tool. In addition, the PAL-2 program incorporated home visits and implementation of FACT-G driven palliative interventions. Aims: The primary endpoint was to assess the feasibility of an ARNP-directed palliative care intervention trial for racially diverse cancer patients. The ultimate goal was to use the data from this pilot study to plan for a subsequent larger randomized trial. Secondary end points included evaluation of the effects of the intervention on the patient's QoL and emotional well-being as determined by a change in FACT-G , EQoL scores, as well as measurement of knowledge about hospice as determined by changes in a hospice knowledge questionnaire (HKQ) scores. Methods: 25 adult patients with metastatic cancer were recruited. All patients completed a FACT-G and a HKQ at baseline, had an ARNP consultation, and a home visit whenever feasible, with a second ARNP consultation visit 4 weeks later. Results: Of 25 patients who participated (16 males, 9 females, mean age 57, age range 33-89, 16 Caucasians (C), 8 African Americans (AA), 1 Asian), 15 patients (8C, 7AA) completed their first and second ARNP consultation visits and 12 (5C, 7AA) completed all questionnaires and were available for secondary endpoint analysis. The main reason for failure to complete the study was disease progression. The most common interventions implemented were advanced directives discussions, assessment of family support, stress management education, assessment of psychological status, spirituality assessment, financial assistance programs, and pain and symptom management. Interventions offered but not selected by most patients included: use of computer based social networking tools, psychological interventions, occupational training and cancer support group participation. Home visits were completed in 11 patients and provided significant insight into the patients' needs and their available support. The palliative care intervention and the FACT-G tool were well accepted by patients. There was no significant change in the EQoL as a result of the intervention ( EQoL change, mean (SD)= -1.2 (13.52), median 3.7, p=0.6719). A trend was observed towards improvement in HKQ results (n=8, change from baseline score mean (SD)= 21.2 (29.58), median 15.4, p= 0.0938). Conclusions: The FACT-G tool was well received by the patients and providers, and its use can be incorporated into clinical care to direct palliative care interventions and assess their impact on patients' QoL. A nurse practitioner-directed palliative care intervention is well accepted by patients of diverse race. Significant attrition of participants due to disease progression (40%) will need to be considered in planning larger randomized trials. Randomized clinical trials evaluating the impact of race, ethnicity and socio-economic status on the benefits of different palliative care interventions in patients with metastatic cancer are feasible and needed. Citation Format: Gerardo Colon-Otero, Mary Lesperance, Fauzia Rana, Robert Shannon, Jeffrey Sloan. A nurse practitioner-directed palliative care intervention trial in racially diverse patients with metastatic cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A42.

Palliative care services are not available in most outpatient oncology practices. A program training 11 mid-level providers from oncology practices on advanced directive discussions and supportive symptom assessment and management performed by palliative care specialists was completed. A follow-up session 9 months later identified barriers to implementation. Of the 11 mid-level providers, 8 participated in the follow-up session, and 9 of the 11 providers implemented advanced directive’s discussions and symptom assessment and management for patients with metastatic cancer. Main barriers included uncertainties about reimbursement, patients’ lack of knowledge about palliative care, and lack of access to supportive services. This program successfully promoted advanced directive discussions and supportive/palliative care symptom assessment and management to community oncology practices, which will hopefully translate into improved quality of life for patients with metastatic cancer.

Abstract Metastatic solid tumors are aggressive and mostly drug resistant, leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple-negative breast cancer (TNBC). Therefore, the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the U.S. Food and Drug Administration for the treatment of various hematologic malignancies. Cell proliferation analysis, flow cytometry, quantitative PCR, and immunoblotting techniques were used to evaluate the antitumor synergy of this drug combination and identify the reexpression of epigenetically silenced tumor suppressor genes. Combinatorial treatment of metastatic TNBC and stage IV ccRCC cell lines with romidepsin/decitabine leads to synergistic inhibition of cell growth and induction of apoptosis above levels of individual drug treatments alone. Synergistic reexpression of the tumor suppressor gene secreted frizzled-related protein one (sFRP1) was observed in combinatorial drug-treated groups. Silencing sFRP1 (short hairpin RNA) before combinatorial drug treatment showed that sFRP1 mediates the growth inhibitory and apoptotic activity of combined romidepsin/decitabine. Furthermore, addition of recombinant sFRP1 to ccRCC or TNBC cells inhibits cell growth in a dose-dependent manner through the induction of apoptosis, identifying that epigenetic silencing of sFRP1 contributes to renal and breast cancer cell survival. Combinatorial treatment with romidepsin and decitabine in drug resistant tumors is a promising treatment strategy. Moreover, recombinant sFRP1 may be a novel therapeutic strategy for cancers with suppressed sFRP1 expression. Mol Cancer Ther; 11(10); 2105–15. ©2012 AACR.