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

Routine Genetic Testing of Germline Breast Cancer Susceptibility ─ Challenges and Opportunities

Information on germline BRCA (g*BRCA*) 1/2 pathogenic or likely pathogenic mutations has predictive value for response to platinating agents and poly(ADP-ribose) polymerase inhibitors (PARPi) and survival outcomes of breast cancer (BC) patients. In the OlympiA trial, the benefits of adjuvant olaparib for high-risk patients with human epidermal growth factor receptor 2 (HER2)-negative BC and g*BRCA* mutations were demonstrated. These results highlight that, in addition to establishing BC risk, determining g*BRCA1/2* status has a broader role in treatment decision-making, particularly for BC patients who may benefit from PARPi. Notably, olaparib is the only PARPi currently approved in Switzerland for treating early high-risk BC patients with g*BRCA1/2* mutations. Rates of germline genetic testing in people with and without cancer are suboptimal in Switzerland and worldwide. Nowadays, despite the favorable OlympiA results, testing criteria for BC remain mostly restricted to patients fulfilling certain high-risk criteria for being mutation carriers, and few studies describe *BRCA* testing in BC patients with characteristics excluded in the OlympiA trial. Many unsolved questions remain, such as the number of patients who could potentially benefit from PARPi, whether to use treatment decision as a testing criterion for screening, and whether universal genetic testing for all BC patients is warranted. This review provides an overview of the rationale for targeting *BRCA1/2*. In addition, unmet needs and opportunities for testing *BRCA1/2* status are discussed, and differences in the testing criteria in existing guidelines are summarized

Re-Challenging Taxanes in Recurrent Breast Cancer in Patients Treated with (Neo-)Adjuvant Taxane-Based Therapy

Background: Docetaxel and paclitaxel are among the most active substances for the treatment of breast cancer. As both drugs are used today in adjuvant regimens, efficacy data from pivotal trials in the metastatic setting in taxanenaive populations cannot reliably be used as references. Patients and Methods: The Taxane Re-Challenge Cohort Study identified participants from 6 prospective (neo-)adjuvant taxane-based studies with recurrent disease and collected data on their subsequent treatment. Out of 381 recurrent patients, 106 (27.8%) were re-challenged with a taxane-based treatment as first- or later-line therapy for recurrent disease. Results: Taxanes were used as first-line therapy in 74 patients and showed a response rate of 48.6% (including complete responses in 27.0%). The response rate was dependent on the disease-free interval ( 2 years: 63.3%; p = 0.04) and visceral metastasis (present: 62.5%; not present 32.4%; p = 0.01). Patients without visceral metastasis and with a disease-free interval of > 2 years achieved the longest overall survival. Hormone and HER2 receptor status were not predictive; however, triple-negative tumors responded in 50.0%. The overall response rate of later-line taxane-based treatment was 28.2%. Conclusion: Re-challenging taxanes appears to be effective and therefore represents a reasonable option in this population.Hintergrund: Docetaxel und Paclitaxel gehören zu den aktivsten Substanzen in der Behandlung des Mammakarzinoms. Da sie heute häufig bereits zur adjuvanten Behandlung eingesetzt werden, können Effektivitätsdaten von früheren Studien mit Taxan-naiven, metastasierten Patientinnen nicht mehr als zuverlässig angesehen werden. Patienten und Methoden: Für die Taxane Re-Challenge Kohortenstudie haben wir Teilnehmerinnen 6 prospektiver Taxanbasierter (neo-)adjuvanter Studien mit rezidivierter Erkrankung identifiziert und Daten zur weiteren Behandlung gesammelt. Bei 106 (27,8%) von 381 Patientinnen mit einem Rezidiv oder einer Metastase wurde erneut ein Taxan in der ersten oder späteren Behandlung eingesetzt. Ergebnisse: Taxane wurden in der Erstlinie bei 74 Patientinnen angewandt und zeigten eine Ansprechrate von 48,6% (inklusive Komplettremissionen in 27,0%). Die Ansprechrate war vom krankheitsfreien Intervall ( 2 Jahre: 63,3%; p = 0,04) und dem Vorhandensein viszeraler Metastasen (vorhanden: 62,5%; nicht vorhanden: 32,4%; p = 0,01) abhängig. Patientinnen ohne viszerale Metastasen und mit einem krankheitsfreien Intervall > 2 Jahre überlebten am längsten. Hormon- und HER2-Rezeptorstatus waren für das Ansprechen nicht prädiktiv, jedoch sprachen tripelnegative Tumoren in 50.0% auf die erneute Taxan-Therapie an. Die Gesamtansprechrate auf ein erneutes Taxan in der späteren Linie betrug 28.2%. Schlussfolgerung: Der Wiedereinsatz von Taxanen erscheint effektiv und steht somit als sinnvolle Option für mit Taxanen (neo-)adjuvant vorbehandelte Patientinnen zur Verfügung

Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study

Purpose We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). Patients and Methods In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy. Results The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. Conclusion The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy. (C) 2013 by American Society of Clinical Oncolog

Prognosis of women with primary breast cancer diagnosed during pregnancy: Results from an international collaborative study

Purpose: We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). Patients and Methods: In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy. Results: The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. Conclusion: The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy

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.status: publishe