Selecting the neoadjuvant treatment by molecular subtype: How to maximize the benefit?

The relationship between achievement of a pathologic complete response (pCR) and favorable long-term outcome varies among breast cancer subtypes. We aimed to highlight which neoadjuvant treatment strategy could be most successful in each breast cancer subtype. A recent FDA meta-analysis on randomized neoadjuvant breast cancer trials suggests that the survival differences of patients with or without a pCR were less pronounced in luminal A-like tumors, despite the overall favorable prognosis of these patients. Moreover, even though the strong prognostic effect of pCR in HER2 positive and TNBC, the NOAH study was the only trial which showed a trend in surrogacy of pCR for long-term outcome in HER2-positive subtype. Results from GeparTrio study suggest that patients with hormone-positive tumors might need a response-guided approach, with either an intensification of treatment in case of an early response or a change to other chemotherapy in case of no early response. Furthermore, data from German neoadjuvant trials confirm that an increasing number of chemotherapy cycles is associated with a higher pCR rate, especially in patients with HER2-positive/hormone-positive tumors. In line with these suggestions, Tryphaena study showed a pCR rate that exceeding the 60% threshold, the highest pCR results presented in a large multicenter study. In TNBC, the highest pCR rate in the German neoadjuvant studies was obtained with the simultaneous application of docetaxel, doxorubicin and cyclophosphamide for 6 cycles. However, as shown in GaparQuinto and NSABP 40 trials, treatment effect in TNBC might be further maximized by adding bevacizumab, and two randomized neoadjuvant trials are expected this year to report data on the efficacy of carboplatin

Darbepoetin alfa as primary prophylaxis of anaemia in breast cancer patients treated preoperatively with Docetaxel, Doxorubicin, Cyclophosphamide : meeting abstract

Meeting Abstract : 27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Docetaxel, Adriamycin, Cyclophosphamide (TAC) is considered today as one treatment option for patients with node-positive primary breast cancer. However, treatment is associated with anaemia grade 1-4 (2-4) in up to 95% (36%) of patients. We prospectively investigated the use of a primary prophylaxis with Darbepoetin alfa once every 3 weeks in 35 patients receiving six to eight cycles of TAC as neoadjuvant treatment for breast cancer. Darbepoetin treatment started on day 1 of a TAC cycle if haemoglobin (Hb) was ≤ 14.0 g/dl. Dosage was adapted to 9 µg/kg if Hb was ≤ 13.0 g/dl on day 21 of the previous cycle, to 4.5 µg/kg if Hb was between 13.0 and 14.0 g/dl and was discontinued if Hb increased to ≥ 14 g/dl. The primary aim was to prevent Hb levels ≤ 12 g/dl before surgery. During 112 (50.2%) and 93 (41.7%) of 223 cycles, 4.5 µg/kg and 9 µg/kg Darbepoetin were given, respectively. Dosage was decreased from 9 to 4.5 µg/kg in 21 (60%) patients and 28 (12.4%) cycles. Treatment was discontinued due to Hb > 14.0 g/dl in 12 (34.3%) patients and 13 (5.4%) cycles. Hb level on day 21 of the last cycle was ≤ 12.0 g/dl in 4 (11.4%) patients. Eighteen (51.4%) patients during 36 (16.1%) cycles showed Hb levels ≤ 12 g/dl throughout treatment. No NCI-CTC grade 2 to 4 anaemia was observed. Symptoms of fatigue (FACT-AN) decreased slightly throughout treatment. Anaemia during TAC chemotherapy can be avoided by a single injection of Darbepoetin alfa every 3 weeks

Recent advances in systemic therapy. Advances in neoadjuvant (primary) systemic therapy with cytotoxic agents

Neoadjuvant therapy, also known as primary, induction, or preoperative therapy, is defined as the first systemic treatment a patient receives after cancer is diagnosed and indicates that subsequent therapies are intended. It was first used in the early 1970s for the treatment of inoperable locally advanced or inflammatory breast cancer. Based on a large body of clinical evidence and on the fact that primary breast cancer is today considered a systemic disease with a locoregional component, primary systemic therapy is now increasingly considered for women with operable disease for reducing mortality with lower toxicity, improving surgical options, and acquiring early information on response and biology of the disease

Current and future role of neoadjuvant therapy for breast cancer

Neoadjuvant systemic chemotherapy is a possible therapeutic approach for the treatment of locally advanced operable, primarily non-operable or inflammatory breast cancer. Neoadjuvant systemic chemotherapy is an option for breast cancer patients who would require adjuvant chemotherapy otherwise based on clinical and histological examination and imaging. The use of neoadjuvant systemic therapy in operable breast cancer is currently increasing because of its advantages that include higher rates of breast conserving surgery and the possibility of measuring early in-vivo response to systemic treatment. The timing of axillary sentinel lymph node diagnosis (i.e. before or after neoadjuvant chemotherapy) is critical in that it may influence the likelihood of axillary preservation. It is not yet clear if neoadjuvant therapy might improve outcomes in certain subgroups of breast cancer patients. Neoadjuvant treatment modalities require a close collaboration between oncology professionals, including surgeons, gynecologists, medical oncologists, radiation oncologists, radiologists and pathologists. The most important parameter for treatment success and improved overall survival is the achievement of a pathologic complete response (pCR), although the role of pCR in patients with luminal A like tumours might be less informative. Identification of patient subgroups with high pCR rates may allow less invasive surgical or radiological interventions. Patients not achieving a pCR may be candidates for postoperative clinical trials exploring novel systemic treatments

Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials

Introduction Despite the fact that people older than 65 years of age have the highest incidence of developing breast cancer, these patients are excluded from clinical trials in most cases. Furthermore, most physicians tend towards therapy regimens without the use of dose-dense, highly active taxane-based treatments because of a lack of data regarding toxicities of these compounds in older patients. Methods Pooled side-effect data were analyzed from four prospective, randomized clinical trials in which patients of different age groups (60 years, between 60 and 64 years, and 64 years) with primary breast cancer received taxane-based chemotherapy. Results Dose delays, dose reductions, hospitalization, and therapy discontinuation increased with age. Hematologic toxicities and some nonhematologic toxicities were generally more common in older patients. Leucopenia increased from 55.3% in patients aged 60 years to 65.5% in patients aged 64 years (P<0.001), and neutropenia increased from 46.9% to 57.4% (P<0.001). There was no difference, however, in clinically more relevant febrile neutropenia between the different age groups. Thrombopenia shows a similar age-dependent increase, whereas there is no difference between the age groups concerning anemia. Hot flushes and elevated liver enzymes decreased with increasing age. Conclusions The present pooled analysis of a substantial cohort of older primary breast cancer patients demonstrates that taxane-containing (neo) adjuvant chemotherapy is feasible in older patients and that toxicity can be reduced by sequential therapy regimens

Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy--the SpheroNEO study

Background Aim of this prospective study was to predict response to neoadjuvant therapy in breast cancer patients using an in vitro breast cancer spheroid model. Methods Three-dimensional spheroids were directly generated from fresh breast tumor biopsies of 78 patients eligible for neoadjuvant therapy. Cell survival was measured after in vitro exposure to the equivalent therapeutic agents in the breast cancer spheroid model. Treatment results in vitro were correlated with pathological complete response (pCR, i.e. ypT0 ypN0) determined at surgery. Results A mean cell survival of 21.8 % was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8 % in 56 patients without pCR (P = .001). The area under the receiver operator characteristic curve to predict pCR was 0.86 (95 % CI: 0.77 to 0.96) for cell survival in vitro compared to 0.80 (95 % CI: 0.70 to 0.90) for a combined model of conventional factors (hormone- and HER2 receptor, and age). A cutoff at 35 % cell survival for the spheroid model was proposed. Out of the 32 patients with values below this threshold, 21 patients (65.6 %) and one patient (2.2 %) with a cell survival greater than 35 % achieved pCR respectively; (sensitivity 95.5 % (95 % CI: 0.86 to 1.00); specificity 80.4 % (95 % CI: 0.70 to 0.91)). Extent of residual disease positively correlated with increased cell survival (P = .021). Conclusion The breast cancer spheroid model proved to be a highly sensitive and specific predictor for pCR after neoadjuvant chemotherapy in breast cancer patients

Sorafenib in the Treatment of Early Breast Cancer: Results of the Neoadjuvant Phase II Study - SOFIA

BACKGROUND Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, 'SOFIA'. PATIENTS AND METHODS INCLUSION CRITERIA WERE: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m(2). In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. RESULTS Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. CONCLUSION Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Zurich Consensus: German Expert Opinion on the St. Gallen Votes on 15 March 2009 (11th International Conference at St. Gallen: Primary Therapy of Early Breast Cancer)

A German working group of 23 breast cancer experts discussed the results from the vote at this year's St. Gallen Consensus Conference on Primary Therapy for Early Breast Cancer ( March 11-14, 2009) and came up with some concrete recommendations for day-to-day therapeutic decisions in Germany. Due the fact that the concept of the St. Gallen Consensus Conference merely allows for a minimal consensus, the objective of the working group was to provide practice-related recommendations for day-to-day clinical decisions in Germany. One area of emphasis at St. Gallen was tumor biology as a starting point for reaching individual therapeutic decisions. Intensive discussion was necessary with respect to the clinical relevance of predictive and prognostic factors. A new addition to the area of systemic therapy was a first-ever discussion of the adjuvant administration of bisphosponates and the fact that therapy with trastuzumab in HER2 overexpressing breast cancer has been defined as the standard for neoadjuvant therapy. The value of taxanes as a component of (neo) adjuvant chemotherapy as well as the value of aromatase inhibitors for the endocrine adjuvant treatment of postmenopausal patients were affirmed