BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial

Rossum, Annelot G.J. van; Schouten, Philip C.; Weber, Karsten E.; Nekljudova, Valentina; Denkert, Carsten; Solbach, Christine; Köhne, Claus‐Henning; Thomssen, Christoph; Forstbauer, Helmut; Hoffmann, G. M.; Kohls, A.; Schmatloch, Sabine; Schem, Christian; Minckwitz, Gϋnter von; Karn, Thomas; Möbus, V.; Linn, Sabine C.; Loibl, Sibylle; Marmé, Frederik

doi:10.1007/s10549-017-4444-9

Cited by 3 publications

(5 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…And lastly, the capecitabine dose and schedule differed between the studies (10 cycles of capecitabine 1000 mg/m 2 twice daily administered on day 1-14 in a three weekly schedule in the GAIN trial versus 6 cycles of capecitabine 900 mg/m² twice daily on day 1-15 every 3 weeks in the FinXX study). Interestingly, we observed a signi cant capecitabine bene t for the non-BRCA1-like group (RFS and OS P value < 0.01) and less evidence of bene t for the BRCA1-like group (RFS P value 0.42; OS P value 0.59), in contrast to the observations of Van Rossum et al [26]. Whether or not these two observations represent inconsistent patterns is di cult to determine due to the small sample size in these unplanned subgroup analyses.…”

Section: Discussioncontrasting

confidence: 99%

“…The threshold for assigning a breast tumor to the BRCA1-like group was set at ≥ 0.63 as obtained and validated in previous studies [22][23][24][25]. The BRCA1-like classi er can be used on genomic copy number variation (CNV) pro les obtained by low coverage whole genome sequencing [26,33]. Recently, we implemented several updates in the processing of CNV sequencing (CNVseq) data and validated the BRCA1-like classi cation obtained with these data.…”

Section: Brca1 -Like Classi Cationmentioning

confidence: 98%

“…Rossum et al [26]. Their retrospective analysis of the randomized GAIN study suggested that patients with BRCA1-like tumors have a selective treatment bene t from a conventional dose-dense chemotherapy regimen, containing capecitabine, if compared with non-myeloablative, intensi ed dose-dense chemotherapy.…”

Section: Our Hypothesis Of Differential Treatment Effects Was Based On Previous Observations Made By Vanmentioning

confidence: 99%

“…In data from two studies contributing to the results of the meta-analysis of Van Mackelenbergh et al [6], the GAIN trial and the CREATE-X trial, there are indications that patients with BRCA1-like TNBC tumors may bene t from capecitabine-containing treatment. First, Van Rossum et al observed a trend for improved survival in the BRCA1-like TNBC patients of the GAIN trial treated with capecitabine-containing chemotherapy compared with intensi ed dose-dense chemotherapy [26]. Second, based on the CREATE-X trial, which was limited to patients with residual disease after neoadjuvant treatment, it seems that capecitabine could have a greater role in patients with tumors that are less sensitive or partially resistant to regimens containing anthracyclines and taxanes [7].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Boo¹,

Jóźwiak²,

Joensuu³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Recent data demonstrate that patients with early-stage triple negative breast cancer (TNBC) benefit from escalating adjuvant treatment with capecitabine. However, since a substantial proportion of patients does not benefit, predictive biomarkers to select those individuals upfront are needed. Over half of all TNBCs have a BRCA1-like DNA copy number signature similar to the profile found in germline BRCA1-mutated breast cancers and indicative for homologous recombination deficiency. We evaluate this signature as a predictive biomarker for capecitabine benefit in archived specimens of the randomized controlled FinXX trial. Additionally, we compared the concordance of our DNA-based BRCA1-like classifier with the RNA-based NanoString BRCAness signature. Methods: Early-stage TNBC patients were randomized between adjuvant capecitabine-containing chemotherapy (TX+CEX: capecitabine plus docetaxel, followed by cyclophosphamide, epirubicin and capecitabine) and conventional adjuvant chemotherapy (T+CEF: docetaxel, followed by cyclophosphamide, epirubicin, and fluorouracil). Breast tumor BRCA1-like status was determined on low coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridization algorithm. We used interaction analysis in proportional hazards models to evaluate whether benefit of adjuvant capecitabine-containing versus conventional chemotherapy differs between BRCA1-like and non-BRCA1-like tumors in early-stage TNBC patients.Results: For 129 (63.9%) of the 202 TNBC patients the BRCA1-like status could be determined. Thirty-five recurrences and 32 deaths occurred during a median follow-up of 10.7 years. The capecitabine effect on recurrence-free survival did not significantly differ between the 68 patients (52.7%) with a BRCA1-like tumor (HR 0.66, 95% CI 0.24-1.81) and others (HR 0.23, 95% CI 0.08-0.70, P interaction = 0.17), also after adjustment for clinico-pathological variables. Conclusions: In the FinXX trial, the BRCA1-like status was not associated with a differential benefit from capecitabine-containing adjuvant chemotherapy compared to conventional chemotherapy in the TNBC subgroup. Based on this study, it is unlikely that the BRCA1-like classifier can be used to distinguish patients who do and do not benefit from capecitabine-enriched standard adjuvant chemotherapy.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Brca1 -Like Classi Cationmentioning

confidence: 98%

Section: Our Hypothesis Of Differential Treatment Effects Was Based On Previous Observations Made By Vanmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Boo¹,

Jóźwiak²,

Joensuu³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The threshold for assigning a breast tumour to the BRCA1 -like group was set at ≥0.63 as obtained and validated in previous studies [ 15 , 28 – 30 ]. The BRCA1 -like classifier can be used on genomic copy number variation (CNV) profiles obtained by low-coverage whole genome sequencing [ 39 , 40 ]. Recently, we implemented several updates in the processing of CNV sequencing (CNVseq) data and validated the BRCA1 -like classification obtained with these data.…”

Section: Methodsmentioning

confidence: 99%

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

et al. 2022

View full text Add to dashboard Cite

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial. Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm. Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17). Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.

show abstract

Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation

Ladan

Gent

Jager

2021

Cancers

View full text Add to dashboard Cite

Germline BRCA mutations result in homologous recombination deficiency (HRD) in hereditary breast and ovarian cancer, as well as several types of sporadic tumors. The HRD phenotype makes these tumors sensitive to DNA double strand break-inducing agents, including poly-(ADP-ribose)-polymerase (PARP) inhibitors. Interestingly, a subgroup of cancers without a BRCA mutation also shows an HRD phenotype. Various methods for selecting patients with HRD tumors beyond BRCA-mutations have been explored. These methods are mainly based on DNA sequencing or functional characteristics of the tumor. We here discuss the various tests and the status of their clinical validation.

show abstract

BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial

Abstract: The BRCA1-like profile is not associated with survival benefit for a non-myeloablative, intensified regimen in this study population. Considering the limited cohort size, capecitabine might have additional benefit for TNBC patients.

Cited by 3 publications

References 38 publications

Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation

Contact Info

Product

Resources

About