pCR identifies patients with a significantly better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of pCR after NRT-CHX.

No abstract

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

154 Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Methods: 315 LABC patients (cT1-cT4 /cN0-N1) were treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or—in case of breast conservation—a 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p<0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p<0.001). Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of a pCR after NRT-CHX.

Background: Despite a HER2-negative primary tumor approximately 20–30% of patients develop HER2-positive metastases (Zidan et al. 2005; Tewes et al. 2009). As previously described in the DETECT I trial (Fehm et al. 2010) determination of HER2 status on circulating tumor cells (CTCs) is one option for re-evaluating HER2-status in the metastatic setting. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2-status of CTCs reveals a clinical benefit. Trial design: DETECT III is a randomized, open-label, two arm phase III study comparing standard treatment alone vs. standard treatment plus HER2-targeted therapy with lapatinib in HER2-negative metastatic breast cancer patients with HER2-positive CTCs. Choices of chemotherapy and endocrine therapy include: docetaxel, paclitaxel, capecitabine, vinorelbine, non pegylated liposomal doxorubicin, letrozole, exemestane and anastrozole. Main eligibility criteria: 1. metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences2. evidence of ≥ 1 HER2-positive CTC3. ≥ 1 evaluable metastatic lesion according to RECIST4. Tumor evaluation within 6 weeks before randomization Specific aims: Objective: The objective of the trial is to prove the clinical efficacy of lapatinib in patients with metastasizing breast cancer who exhibit HER2-positive circulating tumor cells (CTC) although the primary tumor tissue and/or biopsies from metastatic sites were investigated for HER2 status and showed HER2-negativity. Primary endpoint: Progression free survival Secondary endpoints: Overall response rateClinical benefit rateOverall survivalDynamic of CTCQuality of lifeSafety and tolerability of lapatinib Statistical methods: The primary endpoint will be analyzed by Kaplan-Meier method using the logrank test in order to compare the PFS distributions of the two arms. Efficacy, toxicity and other event rates are calculated, providing confidence intervals. In case of comparison between patient groups, these rates will be analyzed by Fisher's exact test or test. The Kaplan Meier analysis for all event related data will be carried out overall for the whole patient population. Furthermore a Cox regression analysis will be done using the following covariates Hormone receptor status (positive/negative)Number of prior chemotherapy lines for metastatic diseasePrior endocrine therapy for metastatic diseaseEndocrine treatment vs. cytotoxic treatmentOne metastatic site vs. multiple metastatic sitesBone metastases vs. no bone involvementPerformance status ECOG Score (0/&gt; 0) Present accrual and target accrual: As only half of the patients with HER2-negative metastatic breast cancer show CTC-positivity and of those approximately 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 patients is required to enroll 228 patients. First patient was screened in February 2012. As of July 27th 2012 117 patients were screened and 21 were found to have HER2-positive CTCs Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-10.