The prognostic effects of somatic mutations in ER-positive breast cancer

Griffith, Obi L.; Spies, Nicholas C.; Anurag, Meenakshi; Griffith, Malachi; Luo, Jingqin; Tu, Dongsheng; Yeo, Belinda; Kunisaki, Jason; Miller, Christopher A.; Krysiak, Kilannin; Hundal, Jasreet; Ainscough, Benjamin J.; Skidmore, Zachary L.; Campbell, Katie M.; Kumar, Runjun D.; Fronick, Catrina C.; Cook, Lisa L.; Snider, Jacqueline; Davies, Sherri R.; Kavuri, Shyam M.; Chang, Eric C.; Magrini, Vincent; Larson, David E.; Fulton, Robert S.; Liu, Shuzhen; Leung, Samuel; David, Valeriu; Bose, Ron; Dowsett, Mitch; Wilson, Richard K.; Nielsen, Torsten O.; Mardis, Elaine R.; Ellis, Matthew J.

doi:10.1038/s41467-018-05914-x

Cited by 107 publications

(114 citation statements)

References 60 publications

(88 reference statements)

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“…2B), while MAP3K1 mutations were associated with longer DFS (HR 0.53, 95% CI, 0.3012-0.9411, log rank P ¼ 0.030). These data reflect similar poor prognosis in the adjuvant setting associated with NF1 mutations in other datasets (12,38). NF1-mutant patients had frequently received adjuvant chemotherapy (88.2%, 15/17) and adjuvant endocrine therapy (100%, 17/17).…”

Section: Prognostic Implications Of Genomic Profilessupporting

confidence: 63%

“…Germline NF1 mutation increases the risk of breast cancer especially in women under 50 years old that could lead to an increased risk of cancer-related death (9)(10)(11). Somatic mutations in NF1 are rare in primary cancer, but are associated with poor prognosis and an increased risk of recurrence (12). Loss of NF1 expression results in tamoxifen resistance in preclinical models (13).…”

Section: Introductionmentioning

confidence: 99%

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Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance

Pearson

Proszek

Pascual

et al. 2020

Clinical Cancer Research

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Purpose: Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterization of a cohort of patients with ABC. Experimental Design: Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients. Results: We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially tar-getable mutations in HER2 (in 6.19% of samples), AKT1 (7.14%), and NF1 (8.10%). Of these enriched mutations, we show that NF1 mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of NF1 resulted in endocrine therapy resistance, through both ER-dependent and-independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors in vitro. Patients with NF1 mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant. Conclusions: Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of NF1 mutations.

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Section: Prognostic Implications Of Genomic Profilessupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance

Pearson

Proszek

Pascual

et al. 2020

Clinical Cancer Research

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“…Unfortunately, in our series, sequencing data were not available for the great majority of the 1635 cases with MMR IHC results. Although eight positive cases had panel sequencing data available for 83 genes [42], this data was not sufficient to confidently infer MMR genotypic status.…”

Section: Discussionmentioning

confidence: 99%

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

Cheng

Leung

Gao

et al. 2019

Breast Cancer Res Treat

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Purpose Alterations to mismatch repair (MMR) pathways are a known cause of cancer, particularly colorectal and endometrial carcinomas. Recently, checkpoint inhibitors have been approved for use in MMR-deficient cancers of any type (Prasad et al. in JAMA Oncol 4:157-158, 2018). Functional studies in breast cancer have shown associations between MMR loss, resistance to aromatase inhibitors and sensitivity to palbociclib (Haricharan et al. in Cancer Discov 7:1168-1183. Herein, we investigate the clinical meaning of MMR deficiency in breast cancer by immunohistochemical assessment of MSH2, MSH6, MLH1 and PMS2 on a large series of breast cancers linked to detailed biomarker and long-term outcome data. Methods Cases were classified as MMR intact when all four markers expressed nuclear reactivity, but MMR-deficient when at least one of the four biomarkers displayed loss of nuclear staining in the presence of positive internal stromal controls on the tissue microarray core. Results Among the 1635 cases with interpretable staining, we identified 31 (1.9%) as MMR-deficient. In our cohort, MMR deficiency was present across all major breast cancer subtypes, and was associated with high-grade, low-progesterone receptor expression and high tumor-infiltrating lymphocyte counts. MMR deficiency is significantly associated with inferior overall (HR 2.29, 95% CI 1.02-5.17, p = 0.040) and disease-specific survival (HR 2.71, 95% CI 1.00-7.35, p = 0.042) in the 431 estrogen receptor-positive patients who were uniformly treated with tamoxifen as their sole adjuvant systemic therapy. Conclusion Overall, this study supports the concept that breast cancer patients with MMR deficiency as assessed by immunohistochemistry may be good candidates for alternative treatment approaches such as immune checkpoint or CDK4 inhibitors.

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“…IPATunity130, a pivotal randomized phase III trial evaluating ipatasertib (IPAT) + paclitaxel for PIK3CA/AKT1/PTEN-altered advanced triple-negative or hormone receptor-positive HER2-negative breast cancer, is ongoing (http://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS1117). Breast cancers with a PIK3CA mutation have a good prognosis [20]. CDH1-mutated breast cancer cells are sensitive to ROS1 tyrosine kinase inhibitors including foretinib or crizotinib [27].…”

Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

Akahane

Kanomata

Harada

et al. 2020

Preprint

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Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions.Methods: Triplet samples of genomic DNA were extracted from each patient’s normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis.Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions.Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

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The prognostic effects of somatic mutations in ER-positive breast cancer

Cited by 107 publications

References 60 publications

Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance

Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

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