Christine Mau

Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC) ± bevacizumab - results of the randomised GeparQuinto study (GBG 44).

BACKGROUND We tested the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment. METHODS Patients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide (EC) with or without bevacizumab. Patients without clinical response were randomised to receive weekly paclitaxel (80 mg/m(2)) with or without everolimus (5mg p.o. daily, after a step-wise dose-escalation starting from 2.5mg bid) for 12 weeks before surgery. To detect an increase in pathological complete response (pCR; ypT0 ypN0) from 5% to 12.1% (odds ratio 2.62) 566 patients had to be recruited. The trial was stopped prematurely due to completion of accrual in the main study. FINDINGS Of 1948 patients initially starting neoadjuvant treatment 403 were randomised. A total of 18 (4.6%) patients, 7 (3.6%) treated with paclitaxel and everolimus and 11 (5.6%) treated with paclitaxel alone had a pCR (odds ratio 0.36 (OR) (95% confidence interval (CI), 0.24-1.6) p=0.34). Overall response rate in breast and lymph nodes at surgery was 52.2% after paclitaxel plus everolimus and 61.7% after paclitaxel alone (p=0.063). Breast conserving treatment was performed in 54.4% of patients with the combination treatment and 61.9% with paclitaxel alone (p=0.20). Mucosal inflammation, thrombocytopenia, neutropenia, infection, and skin rash were more frequent when everolimus was added to paclitaxel. INTERPRETATION Neoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate. Long-term outcome is awaited. FUNDING Novartis, Roche, and Sanofi-Aventis.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Predictive value of HER2 serum levels in patients treated with lapatinib or trastuzumab – a translational project in the neoadjuvant GeparQuinto trial

Background:We were able to demonstrate a predictive value of serum HER2 (sHER2) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial. However, the role of sHER2 in patients receiving neoadjuvant therapy (NT) with lapatinib is still unclear.Methods:The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients. The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients, of whom 109 (52%) patients received trastuzumab and 101 (48%) lapatinib at three different time points.Results:Twenty-two percent of patients had elevated baseline sHER2 levels (>15 ng ml−1). A decrease of sHER2 levels (>20%) in the trastuzumab and lapatinib-treated group during NT was seen in 44% and 24% of the patients, an increase of sHER2 levels (>20%) was seen in 6% and 41% of patients, respectively. Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission (pCR) rates in the entire study cohort (OR 1.8, 95% CI 1.02–3.2, P=0.043). A decline of sHER2 levels (>20%) during NT was a predictor for pCR in the lapatinib-treated patient group (OR: 11.7, 95% CI 1.3–110, P=0.031).Conclusion:Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy. Elevated baseline sHER2 levels (>15 ng ml−1) and a decrease of sHER2 levels (>20%) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

S3-6: Neoadjuvant Chemotherapy of Paclitaxel with or without Rad001: Results of the Non-Responder Part of the GEPARQUINTO Study (GBG 44).

Background: The oral signal transduction inhibitor everolimus (RAD001 = R), binds selectively to mTOR (mammalian target of rapamycin), an intracellular protein kinase implicated in the control of cellular proliferation of activated T-lymphocytes and neoplastic cells. Phase II data suggested that R can enhance the clinical efficacy of endocrine treatment in the metastatic and neoadjuvant setting. The GeparQuinto phase III study had 3 settings (HER2−positive: trastuzumab vs lapatinib; HER2−negative: +/− bevacizumab (Bev); HER2−negative non-responder: +/− R). Primary aim of the last setting was to improve pathological complete response (pCR) for patients with HER2−negative breast cancer not responding to 4x epirubicin/cyclophosphamide (EC) +/− Bev by adding R to weekly paclitaxel as neoadjuvant chemotherapy. Patients and Methods: Patients with untreated HER2−negative breast cancer were eligible if their tumors were stage cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1). Only patients without response ( Results: Between 11/07 and 15/06/11 402 P were randomized to Pac (N=201) and Pac+R (N=201). Median age was 51.0 and 50.0 [-R/+R] years. Median clinical tumor size was 40/40 mm; 62%/55% had cT2, 18% / 20% cT3, and 16.7% / 16.7% cT4a-d tumors; 88% / 89% had non-lobular; 35% / 33% grade 3; 55% / 57% node-positive; and 29% / 27% ER and PgR-negative (triple-negative) disease. The futility interim analysis was performed in 02/10, futility boundary was not reached and the trial was continued. After the other 2 settings completed accrual in 06/10, recruitment to the 3rd setting dropped such that it appeared not possible to recruit the full number of patients.. The trial will therefore close recruitment on June, 30th 2011 with an estimated statistical power of 65%. Results on histological response and surgical outcome will be reported. Conclusion: This will be the first report on efficacy data of neoadjuvant R + Pac for patients with early breast cancer. The results of the GeparQuinto study will have to be set into context with the results from the Bolero studies in metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-6.

Breast Cancer during Pregnancy: An Interdisciplinary Approach in Our Institution

Background: Breast cancer is the most common cancer diagnosed during pregnancy. Case Report: We report on a case of a 26-year-old woman who was diagnosed with right-sided breast cancer in her 15th week of gestation. We discussed possible treatment scenarios and the patient opted for neoadjuvant therapy with taxanes and anthracyclines during pregnancy, followed by delivery and then followed by surgery, antibody therapy, and radiotherapy. The patient received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 weekly for 12 cycles, followed by 4 cycles of epirubicin and cyclophosphamide (90/600 mg/m2) every 3 weeks. Complete clinical response was seen after preoperative chemotherapy. After delivery of a healthy child at 40 weeks of gestation, she received breast-conserving surgery and axillary dissection. Anti-HER2 antibody treatment with trastuzumab was started concomitantly with adjuvant radiotherapy. Endocrine treatment with a gonadotropin-releasing hormone (GnRH) analog and tamoxifen for 5 years was planned to be started after radiotherapy. Conclusion: Treatment of breast cancer during pregnancy requires an interdisciplinary approach and careful consideration of the patient’s stage of disease, the gestational age, and the preferences of the patient and her family.

Prophylactic Surgery: For Whom, When and How

Risk-reducing surgery has proved to be a reasonable procedure in healthy women with a definitely elevated risk of developing cancer. Here we consider the elevated risk of breast and ovarian cancer. There is a clear indication for such surgery in healthy women with a pathogenic BRCA1/2 mutation. For these patients, a risk-reducing bilateral mastectomy leads to a verifiable reduction in mortality from breast cancer, particularly for young patients. In most cases, surgery is combined with breast reconstruction. The pros and cons of surgical treatment and the different surgical techniques have to be explained to and carefully considered with the patient. As yet, no unequivocal data for the benefits of intensifying early detection have been ascertained with respect to mortality from breast carcinoma. In index patients with a BRCA mutation, the surgical treatment should depend on the prognosis of the primary disease. A lower age at onset and a better prognosis of the primary disease make a contralateral mastectomy (CPM) more reasonable. In the case of BRCA mutation-related cancer, a reduction of mortality through CPM has been proven. A risk-reducing adnexectomy is basically recommended for BRCA mutation carriers. Healthy premenopausal women need a subsequent hormone replacement therapy. The prognosis of the patients is dominated by the ovarian carcinoma. This can be prevented by risk-reducing salpingo-oophorectomy in 95% of the cases.