Robert D. Legare

Frequent Pathologic Complete Responses in Aggressive Stages II to III Breast Cancers With Every-4-Week Carboplatin and Weekly Paclitaxel With or Without Trastuzumab: A Brown University Oncology Group Study

PURPOSE To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel +/- weekly trastuzumab in resectable and locally advanced breast cancer. PATIENTS AND METHODS Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2) weekly for 16 weeks, and weekly trastuzumab was added for human epidermal growth factor receptor 2 (HER2) -positive status. The primary end point was the pathologic complete response (pCR) rate, defined as the absence of invasive disease in the breast and axillary nodes. Postoperative therapies were at the discretion of the treating physicians. RESULTS Fifty-five patients were enrolled, and of these 43 had resectable disease. The median age was 54 years (range, 31 to 74 years). Treatment was well tolerated; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia, and there were only two instances of grade 3 peripheral neuropathy. Overall, the pCR rate was 45%. The pCR rate was 43% (95% CI, 28% to 58%) in patients with resectable disease. Higher pCR rates occurred in patients with HER2-positive tumors (76% v 31% for HER2-negative tumors; P = .003), with estrogen receptor (ER) -negative tumors (75% v 27% for ER-positive tumors; P = .001), or with triple-negative tumors (67% v 12% ER-positive and HER2-negative tumors; P = .002). At a median of 28 months postoperation, recurrence-free survival (RFS) was 88.7%. If patients with ER-positive and HER2-negative tumors are excluded from analysis, patients who achieved a pCR were less likely to experience disease recurrence (RFS, 86%) than those who did not achieve a pCR (RFS, 75%). CONCLUSION Neoadjuvant carboplatin and weekly paclitaxel +/- trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline. Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received. Additional study of this regimen in high-risk patients is warranted.

Management of hematological malignancies during pregnancy.

The management of hematological malignancies during pregnancy is a challenging endeavor, which not only requires technical skills and knowledge by the clinicians but also requires sound clinical judgment and compassion, keeping in mind the patient and family preferences and, ultimately, the wellbeing of the neonate. The incidence of hematological malignancies during pregnancy is rare, ranging from 1 in 1,000 to 1 in 10,000 deliveries, impeding the design and execution of large prospective studies. The purpose of this review is to evaluate the limited existing data and make useful suggestions in the management of acute and chronic leukemias, Hodgkin and non‐Hodgkin lymphomas, plasma cell myeloma, and other hematological malignancies, such as myelodysplastic syndromes and hairy cell leukemia, during pregnancy. Am. J. Hematol. 2009.

Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals

OBJECTIVE Genetic predisposition is responsible for 5-10% of breast cancer, 10% of ovarian cancer and 2-5% of uterine cancer. The study objective was to compare genetic counseling and testing referral rates among women with breast cancer that met NCCN referral guidelines to the referral rates among women with gynecologic cancers and determine predictors of referral. METHODS Utilizing an institutional tumor registry database, patients from an academic womens oncology program were identified who met a subset of NCCN guidelines for genetic referral between 2004 and 2010. Patients diagnosed with ovarian cancer, breast cancer ≤50years of age, or uterine cancer <50years of age were included. A retrospective electronic chart review was conducted to evaluate for a genetic referral and uptake of genetic testing. RESULTS 820 women were included (216 uterine, 314 breast, and 290 ovarian cancer). The overall genetic referral rate was 21.7%. 34% of eligible breast cancer patients were referred compared to 13.4% of uterine cancer and 14.5% of ovarian cancer patients (p<0.0001). Younger age, breast cancer diagnosis, family history and earlier stage were all significant referral predictors. The odds of being referred increased with the number of affected family members. 70.8% of referred patients, consulted with genetics. Among those who consulted with genetics, 95.2% underwent testing. CONCLUSIONS Although increasing, genetic counseling remains underutilized across cancer diagnosis. Women with breast cancer are more likely to be referred than women with gynecologic cancers. Younger age, earlier stage and positive family history appear to be predictive of referral for genetic evaluation.

Addressing clinical trials: Can the Multidisciplinary Tumor Board improve participation? A study from an academic women's cancer program☆

OBJECTIVE The Tumor Board (TB) allows for an interdisciplinary approach to cancer treatment designed to encourage evidence-based treatment. However, its role in facilitating clinical trial participation has not been reported. We aimed to determine whether a prospective TB is an effective strategy for trial recruitment and to identify steps within the TB process that facilitate discussion of trial eligibility and optimize accrual. METHODS We conducted a retrospective cross-sectional analysis of women presented to Gynecologic Oncology TB between March and December 2008. Patient demographics, TB recommendations, and post-TB patient discussions were abstracted. These were compared to data derived from the Department of Oncology Research to determine research team awareness of eligible patients and confirm trial enrollment(s). Data analysis was completed with Chi-square test; risk ratios and confidence intervals were calculated as summary measures. RESULTS We reviewed 1213 case presentations involving 916 women. Overall, 358 TB recommendations (30%) identified eligible patients, of which enrollment consisted of 87 (24%) trials (6% therapeutic trials and 18% non-therapeutic trials). Compared to other types of TB recommendations, those involving trials were discussed less frequently at post-TB patient visits (79% vs. 44%). Documentation of trial discussion at the post-TB visit was more likely to result in trial participation, versus solely relying on the research staff to communicate enrollment eligibility with the treating team (RR 2.5, p=0.006). CONCLUSIONS Patients identified by the TB were 2.5-times as likely to enroll in a clinical trial, but trials were mentioned only 44% of the time. Interventions that facilitate trial discussions during post-TB meetings are needed to improve trial participation.

Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Purpose: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3–activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). Experimental Design: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 109 armed ATC (aATC) per infusion. Results: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 109 ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0–2+ patients. Conclusions: Targeting HER2+ and HER2− tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials. Clin Cancer Res; 21(10); 2305–14. ©2015 AACR.

Risk factors for breast cancer.

Breast cancer is multifaceted, and multiple risk factors most likely contribute to each case of the disease. Through further elucidation of highly penetrant autosomal dominant mutations and, perhaps more importantly, weaker polygenic influences, rational therapies to treat or prevent malignancy may develop. Determining the nature and sequence of genetic changes in premalignant breast tissue may offer the greatest opportunity to alter the process of breast cancer development. Perhaps the most difficult challenge is to understand the environmental risk factors that predispose to breast cancer. Although endogenous factors such as hormonal influence on breast cancer risk have been established, this information has not greatly affected our ability to prevent or significantly reduce the risk of disease. National and regional collaborative efforts are needed to fund research directed at defining how the environment and lifestyle factors affect the risk of cancer development.

Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma

Therapy‐related acute myelogenous leukemia and myelodysplastic syndrome (t‐AML/MDS) are being reported with increasing frequency as a complication of ABMT for Hodgkins disease and non‐Hodgkins lymphoma. At present there is no method available to predict who is at risk or is destined to develop this nearly universally fatal disorder. We therefore investigated whether clonal growth of cells is predictive of the development of t‐AML/MDS. In a patient who developed secondary AML/MDS 18 months after ABMT, X‐linked clonality analysis at the human androgen receptor locus was performed on serial banked samples, and documented transition from polyclonal to clonal hematopoiesis. Clonal cells could be identified 6 months after transplant (1 year prior to the diagnosis of t‐AML/MDS), at a time when there was no morphologic or clinical evidence of disease. Clonality analysis can be predictive of the development of t‐AML/MDS after ABMT and may offer important insights into associated risk factors and strategies to minimize the risk of t‐AML/MDS. Am. J. Hematol. 56:45–51, 1997.

Clinical characteristics and choices regarding risk-reducing surgery in BRCA mutation carriers.

Background/Aims: BRCA mutation carriers have a high lifetime risk of developing breast and ovarian malignancies. As genetic testing becomes widely available, preventative measures are a choice. We evaluated the characteristics of BRCA mutation carriers who chose prophylactic surgery (PS) compared to those who opted for surveillance. Methods: A retrospective chart review of patients with a mutation in the BRCA1 or BRCA2 genes was performed. Results: Ninety women were included, of whom 46 (51%) underwent PS. They were more likely to be a BRCA2 mutation carrier, parous, married, employed, and had a prior history of breast cancer. PS included 39 bilateral salpingo-oophorectomies and 13 mastectomies. Pathology was typically benign; however, 15% showed ductal carcinoma in situ of the breast, 8% reported infiltrating ductal carcinoma of the breast, 3% was adenocarcinoma of the fallopian tube, and 3% was adenocarcinoma of the ovary. Conclusion: It is notable that BRCA1 mutation carriers were less inclined to elect for PS. Evaluating the reasons for pursuing PS among women with a BRCA mutation is necessary and will require a larger data set. Long-term follow-up is required to describe the potential side effects of PS on quality of life.

Recruitment Strategies for a Home-Based Physical Activity Intervention for Breast Cancer Patients

Recruiting cancer patients for randomized trials investigating psychosocial interventions presents several unique challenges. This paper describes the challenges and yields for different recruitment methods used in Moving Forward, a randomized trial of a home-based moderate-intensity physical activity program for early-stage breast cancer survivors. Recruitment methods included letters sent to patients by their oncologists, direct referrals from oncologists, in-person recruitment in oncology clinics, referrals from nurses and medical assistants, passive recruitment, other mailings, and community outreach strategies. Of the 424 screenings completed, 86 (20.3%) participants were randomized. Physician letters yielded the greatest number of initial screenings (147; 34.7%) and participants randomized (28; 32.5%). In-person recruitment also proved to be a productive recruitment strategy; 14 (16.3%) of the participants were recruited via this strategy. Community outreach efforts did not provide as great a yield and were labor intensive. We discuss suggestions for recruitment of cancer patients in future trials.

Adjuvant therapy in breast cancer.

The new millennium ushers in an exciting time in the treatment of early stage breast cancer. Although worldwide incidence statistics have not changed significantly in the past decade, mortality rates have declined. This change seems to be related to public health initiatives that increase early detection and awareness and to an increase in the efficacy of adjuvant treatments, including advances in chemotherapy and the emergence of biologic treatments. Physicians from many specialties participate in multidisciplinary tumor boards. Moreover, patients, families, and advocacy groups have taken on new responsibilities, offering encouragement and support for clinical and basic research.