Lessons from the neoadjuvant setting on how best to choose adjuvant therapies.

AIMS: To review the recent literature on neoadjuvant treatment of breast cancer with respect to insights that might be used for better using systemic treatment in early breast cancer. RESULTS: Much more insight was gained during recent years on how to use information on pathologic complete response (pCR). pCR appears to be a valid surrogate for long-term survival mainly in triple-negative and HER2-positive disease. Patient with breast cancer of these subtypes can be relieved from poor prognosis if they achieve a pCR after neoadjuvant treatment. It can even be speculated that the extent of local and post-surgical systemic treatment can be further reduced. Patients without pCR show a high risk of early recurrence and are at high need for new treatment options. These advantages lead to the recommendation that use of neoadjuvant treatment should not be indicated by tumor size but far more by tumor subtype. As pCR appears to be more sensitive to detect treatment effects than disease-free survival, the neoadjuvant approach identifies easier promising treatments and can even discriminate optimal approaches for biologically defined subgroups. A recent meta-analysis examining pattern of neoadjuvant chemotherapy suggests that luminal-B type tumors require longer duration of treatment, triple-negative tumors require dose-intensified anthracycline-taxane-based treatment of only short duration, and HER2-positive tumors require longer duration (if hormone-receptor positive) and an optimal dose of taxanes. As biomarkers can be easily assessed on tumor tissue before, during, and after treatment, there is increasing data available on markers that e.g. potentially predict resistance to anti-HER2 treatment, predict response to anti-angiogenic drugs as well as efficacy of PARP inhibitors. Validation of these candidate markers remains a challenging task, as patients cohort are usually small and finding studies are compromised by multiple testing. CONCLUSION: With the acquired new knowledge from neoadjuvant studies will help to individualize treatment based on biological behavior of breast cancer subtypes.

Prediction of Response to Neoadjuvant Chemotherapy: New Biomarker Approaches and Concepts.

SUMMARY: About 10-25% of breast cancer patients achieve a pathologically confirmed complete response after neoadjuvant chemotherapy. Tissue samples of pretreatment core biopsies are a valuable resource for translational research aiming towards predictive biomarkers for selecting patients who are likely to benefit from neoadjuvant therapy. The German Breast Group (GBG) and the AGO-B Group (AGO = Working Group Gynecological Oncology) have extensive experience in conducting neoadjuvant clinical trials. Technologies as immunohistochemistry on tissue microarrays and standardized reverse transcription-polymerase chain reaction (RT-PCR) approaches on formalin-fixed paraffin-embedded samples allow high-throughput investigation of protein and mRNA biomarkers. With these approaches, we could demonstrate that molecular tumor subtypes and immunological infiltrates are valuable and independent predictors of therapy response. New biomarkers such as poly(ADPribose) polymerase (PARP) might be useful for the prediction of response to conventional and new targeted therapies. This review summarizes current research projects focusing on biomarker discovery in the neoadjuvant setting.

Multicenter Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial.

The combination of bendamustine (B) and paclitaxel (P) as anthracycline-free treatment option in patients with advanced breast cancer has been evaluated in the previous RiTa I trial. The regimen of weekly B 70 mg/m(2) and P 90 mg/m(2) with a pause every 4th week was established as an effective regimen with low toxicity. The aim of the present RiTa II study was to investigate the potential of BP as anthracycline-free combination therapy. The primary objective was to determine the progression-free survival (PFS); secondary endpoints were safety, tolerability, overall response rate (ORR) and overall survival (OS). 26 patients were available, 15 received BP as first-line, 11 as beyond first-line treatment. 27% patients had triple-negative breast cancer (TNBC). Median PFS and OS were 7.3 months (95% confidence interval (CI): 5.5-10.9) and 14.9 months (95% CI: 9.9-22.9), respectively. The 1-year PFS rate was 20.3% and the 1-year OS rate 71.2%. The ORR was 42.3%, including 4 complete and 7 partial remissions. TNBC patients reached an ORR of 71.4%. Anthracycline-pretreated patients showed an ORR of 43.8%, confirming bendamustine's lack of cross-resistance to anthracycline agents. BP represents a favorable option with moderate toxicity in pretreated metastatic breast cancer and offers a possibility for application in anthracycline-pretreated and TNBC patients.