Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer

Hahnen, Eric; Lederer, Bianca; Hauke, Jan; Loibl, Sibylle; Kröber, Sandra; Schneeweiß, Andreas; Denkert, Carsten; Fasching, Peter A.; Blohmer, Jens-Uwe; Jackisch, Christian; Paepke, Stefan; Gerber, Bernd; Kümmel, Sherko; Schem, Christian; Neidhardt, Guido; Huober, Jens; Rhiem, Kerstin; Costa, Serban Dan; Altmüller, Janine; Hanusch, Claus; Thiele, Holger; Müller, Volkmar; Nürnberg, Peter; Karn, Thomas; Nekljudova, Valentina; Untch, Michael; Minckwitz, Gϋnter von; Schmutzler, Rita K.

doi:10.1001/jamaoncol.2017.1007

Cited by 312 publications

(316 citation statements)

References 34 publications

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“…. Of note, the subgroup of patients with TNBC, a tumor phenotype closely associated with a high BRCA1 mutation prevalence , showed lower mutation probabilities in non‐ BRCA1/2 genes, especially for ATM and CHEK2 mutations, we identified a negative association with this subtype (Table ). Similar results were observed by Buys et al., demonstrating significantly lower mutation probabilities for both genes in patients with TNBC versus other subtypes .…”

Section: Discussionmentioning

confidence: 65%

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

et al. 2018

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The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM,CDH1,CHEK2,NBN,PALB2,RAD51C,RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2,PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.

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Section: Discussionmentioning

confidence: 65%

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

et al. 2018

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“…These results are strongly in line with recently published excellent outcome after 18 weeks of docetaxel/carbo backbone without anthracycline use. 20 Although improved pCR under NACT suggests platinumcontaining CHT 12,23,30 as a promising treatment strategy in early TNBC, survival benefits are not yet established 17,18 ; moreover, optimal therapy combinations, 13,14,16 particularly deescalated approaches and predictive markers have yet to be determined. The present translational analysis of the WSG-ADAPT-TN trial has sought to address this need to select patients for deescalated regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Such approaches may improve survival in TNBC, but evidence is not yet conclusive. Remarkably, although BRCA1 mutation—frequently associated with TNBC—is highly predictive for efficacy of carbo as a monotherapy agent, no predictive effect on survival regarding carbo addition has been demonstrated so far in the context of polychemotherapy . Relatively high chemosensitivity of BRCA1 mutation carriers to the A/T‐based CHT used as a backbone in control arms could improve their outcome sufficiently to mask a potentially predictive role of BRCA1 mutation on survival for carbo addition.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Replacement of standard weekly solvent-based paclitaxel by nab-paclitaxel (nab-pac), 15 increased dosage of alkylating agents 16 or addition of carboplatin (carbo) to A/T containing NACT 10,17 have led to increased pCR rates (49-60%), albeit with higher toxicity. Such approaches may improve survival in TNBC, [16][17][18] but evidence is not yet conclusive. Remarkably, although BRCA1 mutation-frequently associated with TNBC-is highly predictive for efficacy of carbo as a monotherapy agent, 19 no predictive effect on survival regarding carbo addition has been demonstrated so far in the context of polychemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple‐negative early breast cancer: Primary translational analysis of the WSG‐ADAPT‐TN trial

Gluz

Kolberg‐Liedtke

Prat

et al. 2019

Intl Journal of Cancer

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In the neoadjuvant WSG‐ADAPT‐TN trial, 12‐week nab‐paclitaxel + carboplatin (nab‐pac/carbo) was highly effective and superior to nab‐paclitaxel + gemcitabine (nab‐pac/gem) in triple‐negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab‐pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow‐up. Basal‐like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki‐67 (IHC; p < 0.001). For nab‐pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab‐pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event‐free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal‐like subtype, higher Ki‐67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.

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“…The German experts confirm that the BRCA determination in the tumor tissue currently has no therapeutic consequences in breast cancer. However, they point out that not all tumor mutations may be detected by germline testing [18]. The clinical relevance of tumor tissue testing should therefore be further studied, preferentially in the context of controlled clinical trials.…”

Section: Brca -Associated Advanced or Metastatic Breast Cancermentioning

confidence: 99%

ABC4 Consensus: Assessment by a German Group of Experts

Harbeck¹,

Lüftner²,

Marschner³

et al. 2018

Breast Care

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The Advanced Breast Cancer Fourth Consensus (ABC4) on diagnosis and treatment of advanced breast cancer (ABC) again took place in Lisbon, on November 2-4, 2017, and was chaired by Fatima Cardoso, MD, PhD. This year's contents focused very much on new developments in the treatment of ABC. For example, the significance of inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) in hormone receptor (HR)-positive ABC, of dual antibody blockade in human epidermal growth factor receptor 2 (HER2)-positive ABC, and of poly(ADP-ribose) polymerase (PARP) inhibition in triple-negative ABC, as well as the potential therapeutic consequences, were discussed. Other key issues were BRCA-associated breast cancer, treatment of brain metastases, and personalized therapy decision-making using molecular testing (so-called ‘precision medicine'). As in past years, an important objective of the ABC conference was cooperation with representatives of patient organizations from around the world. This cooperation was further intensified during the ABC4. Following the main conference, the ‘Global Alliance' was founded, with the goal of publicizing and coordinating measures necessary worldwide from the patient advocates' standpoint. - The ABC consensus inevitably cannot accommodate country-specific needs, due to the truly global expert panel. Therefore, a working group of German breast cancer experts commented - as in the past years - on the on-site voting results by the ABC panelists upon which the final ABC4 consensus will be based, with particular consideration of the German guidelines on diagnosis and treatment of breast cancer for everyday treatment in Germany.

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Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer

Abstract: clinicaltrials.gov Identifier: NCT01426880.

Cited by 312 publications

References 34 publications

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

Efficacy of deescalated chemotherapy according to PAM50 subtypes, immune and proliferation genes in triple‐negative early breast cancer: Primary translational analysis of the WSG‐ADAPT‐TN trial

ABC4 Consensus: Assessment by a German Group of Experts

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