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Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection. RT consisted of 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost. A Bayesian time-to-event continual reassessment method escalated dose through four levels, with a 30% targeted rate of dose-limiting toxicity (DLT) measured during the 6 weeks of treatment plus 4 weeks of follow-up. DLTs were defined as confluent moist desquamation > 100 cm 2 , nonhematologic toxicity grade ≥ 3, toxicity that requires an RT dose delay > 1 week, absolute neutrophil count < 1,000/mm 3 , platelet count < 50,000/mm 3 , or hemoglobin < 8.0 g/dL if possibly, probably, or definitely related to study treatment. Results Five DLTs occurred: Four were moist desquamation (two each at 100 and 150 mg twice a day), and one was neutropenia (at 200 mg twice a day). The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field. Conclusion Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.

Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.

Background: The value of axillary staging prior to delivery of neoadjuvant chemotherapy (NEO) for breast cancer is controversial. Our goal was to analyze the prognostic and therapeutic impact of axillary staging on recurrence., Methods: The study cohort included 161 patients undergoing comprehensive evaluation by a multidisciplinary approach during the period 1996-2006. Clinicopathologic features were assessed before and after delivery of NEO. Patients with node-positive disease before NEO underwent a post-NEO axillary lymph node dissection at time of definitive breast surgery., Results: At presentation, median age was 49 years; mean tumor size was 45 mm. The axilla was negative in 45 (28.6%) patients. Of the 114 pre-NEO node-positive patients, 65 (57%) were staged histologically. At completion of NEO, partial or complete clinical response was observed in 90.6%; complete pathologic response occurred in 23.6%. Mean residual tumor size was 10.5 mm. Of the 112 initially node-positive patients, 36 (31.6%) had no residual axillary disease post NEO. At median follow-up of 38.1 months, 21.7% patients relapsed. The pre-NEO nodal status was the strongest predictor of treatment failure. A significant risk of distant relapse was based on nodal response to NEO: 8.1% in node-negative patients, 13.9% in the downstaged group, and 22.1% in the persistently positive group (P = 0.047). Delivery of nodal irradiation decreased local recurrence in the downstaged group (12.5% versus 3.7%, P = NS)., Conclusion: Our experience suggests that comprehensive axillary staging with ultrasound and fine-needle aspiration (FNA) and sentinel lymph node biopsy prior to NEO is both prognostically and therapeutically important in predicting those patients at higher risk of recurrence.

The purpose of this study was to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with standard radiotherapy for the treatment of chest wall recurrences, and to compare actuarial rates of local-regional control with those achieved in historical controls. Patients with unresectable chest wall recurrences were enrolled in a phase I trial of concurrent gemcitabine and radiotherapy. Gemcitabine was increased at 150 mg/m(2)/week increments, starting at 300 mg/m(2)/week. Radiotherapy was delivered to the chest wall and regional nodes to a total of 60 to 70 Gy in 2 Gy daily fractions. Treatment toxicity was assessed and a comparison of treatment outcome was performed between study patients and historical groups treated with either radiotherapy alone or excision followed by radiotherapy. The dose-limiting toxicities of neutropenia and thrombocytopenia occurred at the second planned dose of 450 mg/m(2)/week after accrual of only six patients, resulting in a MTD of 300 mg/m(2)/week. Myelosuppression and skin desquamation were commonly observed. Actuarial rates of local-regional control were 100%, 50%, and 90% at 2 years for the gemcitabine with radiotherapy, radiotherapy alone, and excision followed by radiotherapy groups, respectively (p = 0.105). The difference among the Kaplan-Meier curves for overall local-regional control was statistically significant at p = 0.007 in favor of combined gemcitabine and radiotherapy. The MTD of gemcitabine is 300 mg/m(2)/week when gemcitabine is delivered concurrently with radiotherapy for unresectable chest wall failures. This novel approach suggests excellent local-regional control when compared to historical controls. A phase II trial is warranted.