In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast ...cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).
Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).
A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of ...durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.
GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).
A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5years (range 23–76); 47 patients (27%) were younger than 40years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P=0.287), corresponding to OR=1.45 (95% CI 0.80–2.63, unadjusted Wald P=0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR=2.22, 95% CI 1.06–4.64, P=0.035; interaction P=0.048). In both arms, significantly increased pCR (P<0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P=0.045) and for PD-L1-immune cell in placebo arm (P=0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.
Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.
ClinicalTrials.gov number: NCT02685059.
The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) score high and/or germline (g) or tumour (t) BRCA1/2 ...mutation is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD.
Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety.
A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% 90% confidence interval (CI) 44.5% to 65.3% versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients.
GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
•Randomised phase II GeparOLA study investigated olaparib plus paclitaxel (PO) in early HER2-negative HRD breast cancer.•Addition of olaparib to chemotherapy could not exclude pCR ≤55% but was significantly better tolerated than carboplatinum.•Stratified subgroup analysis shows higher pCR rates with PO in cohorts <40 years and those with HR-positive tumours.•Overall, pCR rate in the gBRCA1/2 carriers was significantly higher than in non-carriers.•Combination of olaparib with paclitaxel prompts further investigation of olaparib as part of NACT in primary HRD tumours.
Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo ...(NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287).
Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS).
A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred.
Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.
•Significant improvement of secondary endpoints iDFS, DDFS and OS by adding durvalumab to neoadjuvant chemotherapy.•Survival improvement although no adjuvant checkpoint inhibitor therapy was given.•Long-term effect is seen in pCR as well as non-pCR patients.•The improved survival outcome with checkpoint inhibitor therapy is only partially explained by the increased pCR rate.•Our results suggest that additional long-term antitumour effects are present.
Purpose
Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li‐Fraumeni syndrome ...(LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.
Methods
The German Consortium for Hereditary Breast and Ovarian Cancer (GC‐HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.
Results
TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.
Conclusion
The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC‐HBOC criteria for genetic testing.
TP53‐associated tumor syndrome is a rare predisposition syndrome. Our analysis of the tumor spectrum and age of onset in 35 index patients supports the evidence for a less severe phenotype in families identified by gene panel testing for hereditary breast and ovarian cancer.
Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we ...wanted to identify predictors of CPF (represented by peak oxygen uptake: VO
) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO
reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33-46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35-50). The strongest predictor for reaching the reference VO
value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3-8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO
, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.
Female BRCA mutation carriers have an increased lifetime risk for breast and ovarian cancer compared to the general population. Women who carry this mutation have several options to deal with their ...cancer risk, such as risk-reducing surgeries or intensified breast cancer screening. Previous research has shown that preferences in this scenario are highly dependent on affected women's personalities and value systems. To support these women in the decision-making process, a structured decision support consisting of decision coaching combined with a decision aid might be helpful.
A randomized controlled trial will be conducted in order to compare usual care with structured decision support alongside usual care. The decision support program entails nurse-led decision coaching as well as an evidence-based patient decision aid. Nurses are qualified by a 4-day training program in informed decision-making and decision coaching. Six centers for Familial Breast and Ovarian Cancer in Germany will be included in the study, with a planned sample size of 398 women. The primary outcome is the congruence between the preferred and the actual played role in the decision-making process as measured by the Control Preferences Scale. It is hypothesized that the structured decision support will enable women to play the preferred role in the decision-making process. Secondary outcomes include the knowledge and attitudes about preventive options, decisional conflict, depression and anxiety, coping self-efficacy, impact of event, and self-concept. A process evaluation will accompany the study.
The EDCP-BRCA study is the first study to implement and evaluate decision coaching combined with a decision aid for healthy BRCA mutation carriers worldwide. TRIAL REGISTRATION {2A}: DRKS-ID: DRKS00015527. Registered 30 October 2019.
Zusammenfassung
Hintergrund
Vor mehr als 20 Jahren wurde das Deutsche Konsortium Familiärer Brust- und Eierstockkrebs (DK) mit Unterstützung der Deutschen Krebshilfe e. V. gegründet. Ziel des ...Verbundes spezialisierter Zentren ist seither die umfassende Betreuung von Familien mit einer erblichen Belastung für gynäkologische Krebserkrankungen. Dieses Betreuungsangebot reicht von der Risikoidentifikation über Gendiagnostik bis zur Entwicklung risikoadaptierter präventions- und zielgerichteten Therapiekonzepte.
Fragestellung
In den letzten Jahren hat kaum ein Sektor in der Medizin eine so rasante Entwicklung genommen wie die molekulargenetische Diagnostik in der Onkologie.
Ergebnisse
Den damit einhergehenden Herausforderungen, insbesondere im Hinblick auf die Translation in die Klinik, begegnet das Konsortium mit innovativen und zukunftsorientierten Entwicklungen.
Breast cancer surveillance programs for the general population are not adequate for the small number of women with hereditary breast and ovarian cancer syndrome. Breast cancer screening for women in ...Germany starts at the age of 50 years, but nearly half of all women with familial risk are already diagnosed with breast cancer at that time. Moreover, mammography alone is not suitable for an early diagnosis of breast cancer in young women from high-risk families. Their typical dense breast tissue causes a high rate of false-negative cases. Therefore, national and international prospective clinical trials were initiated to offer a multimodal breast cancer surveillance program including magnetic resonance tomography for the breast and semi-annual screening intervals to women with BRCA1/2 mutations and those from high-risk families who tested negative for BRCA1/2 mutations. This program will currently be evaluated by the 15 centers of the German Consortium for Hereditary Breast and Ovarian Cancer.
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