Abstract
Background
We examined tumor genotype characteristics of human epidermal growth factor receptor
2 (HER2)-positive relapsed (R-) and de novo (dn-) metastatic breast cancer (MBC) in
trastuzumab-treated patients who were previously not exposed to this agent.
Materials and Methods
We analyzed genotypes obtained upon deep sequencing from 113 HER2-positive primary
tumors from 69 patients with R-MBC and 44 patients with dn-MBC.
Results
Mutations were observed in 90 (79.6%) tumors, 56 R-MBC and 34 dn-MBC (median number
per tumor: 2; mean: 11.2; range: 0-150). The top mutated gene was TP53 (63.7%) followed by PIK3CA (24.8%) and others that were mostly co-mutated with TP53 (eg, 22 of 28 PIK3CA mutated tumors were co-mutated in TP53, 17 of these were R-MBC [P = .041]). dn-MBC had higher CEN17 average copies (P = .048). Tumor mutational burden inversely correlated with average HER2 copies (rho −0.32;
P < .001). In all patients, PIK3CA mutations and higher proliferation rate were independent unfavorable prognosticators.
In R-MBC, longer disease-free interval between initial diagnosis and relapse conferred
lower risk for time-to-progression (P < .001) and death (P = .009); PIK3CA mutations conferred higher risk for death (P = .035). In dn-MBC, surgical removal of the primary tumor before any other therapy
was favorable for time-to-progression (P = .002); higher tumor mutational burden was unfavorable for survival (P = .026).
Conclusions
Except for the overall unfavorable prognostic effect of PIK3CA mutations in trastuzumab-treated MBC, our exploratory findings indicate that the
outcome of patients with R-MBC is related to patient benefit from the preceding adjuvant
chemotherapy and provide initial evidence that tumor mutational burden may be related
to prognosis in dn-MBC, which is of potential clinical relevance and merits further
investigation.
Keywords
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References
- Changing treatment paradigms in metastatic breast cancer: lessons learned.JAMA Oncol. 2015; 1 (quiz: 549): 528-534
- Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.Breast Cancer Res. 2015; 17: 56
- Estimation of the number of women living with metastatic breast cancer in the United States.Cancer Epidemiol Biomarkers Prev. 2017; 26: 809-815
- Cancer statistics, 2018.CA Cancer J Clin. 2018; 68: 7-30
- Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.Lancet Oncol. 2011; 12: 236-244
- Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort.Lancet. 2010; 375: 377-384
- Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med. 2001; 344: 783-792
- Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed.Breast Cancer Res Treat. 2017; 161: 549-556
- Therapeutic options for HER-2 positive breast cancer: perspectives and future directions.World J Clin Oncol. 2014; 5: 440-454
- Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med. 2012; 366: 109-119
- Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group.Clin Breast Cancer. 2003; 4: 120-125
- Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it.Clin Med Insights Oncol. 2016; 10: 21-30
- Comprehensive molecular portraits of human breast tumours.Nature. 2012; 490: 61-70
- Mutational profile of metastatic breast cancers: a retrospective analysis.PLoS Med. 2016; 13: e1002201
- Genomic evolution of breast cancer metastasis and relapse.Cancer Cell. 2017; 32: 169-184.e167
- The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.Ann Oncol. 2015; 26: 259-271
- Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer.Breast Cancer Res Treat. 2011; 128: 447-456
- MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer.J Transl Med. 2016; 14: 136
- Evaluation of two highly-multiplexed custom panels for massively parallel semiconductor sequencing on paraffin DNA.PLoS One. 2015; 10: e0128818
- Sequence artefacts in a prospective series of formalin-fixed tumours tested for mutations in hotspot regions by massively parallel sequencing.BMC Med Genomics. 2014; 7: 23
- Deamination effects in formalin-fixed, paraffin-embedded tissue samples in the era of precision medicine.J Mol Diagn. 2017; 19: 137-146
- REporting recommendations for tumour MARKer prognostic studies (REMARK).Br J Cancer. 2005; 93: 387-391
- Chromosome instability and benefit from adjuvant anthracyclines in breast cancer.Br J Cancer. 2012; 107: 71-74
- Universal patterns of selection in cancer and somatic tissues.Cell. 2017; 171: 1029-1041.e1021
- Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.Genome Med. 2017; 9: 34
- Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 633-641
- Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers.Mol Cancer Ther. 2017; 16: 2598-2608
- Tumor mutational burden is a determinant of immune-mediated survival in breast cancer.Oncoimmunology. 2018; 7: e1490854
- Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67.Onco Targets Ther. 2018; 11: 2269-2275
- Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer.Oncoimmunology. 2018; 7: e1466768
- Is there a role for immunotherapy in HER2-positive breast cancer?.NPJ Breast Cancer. 2018; 4: 21
- Clonal evolutionary analysis during HER2 blockade in HER2-positive inflammatory breast cancer: a phase II open-label clinical trial of afatinib ± vinorelbine.PLoS Med. 2016; 13: e1002136
- PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.Cancer Cell. 2004; 6: 117-127
- Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab.Br J Cancer. 2013; 108: 1807-1809
- PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups.Breast Cancer Res. 2012; 14: R28
- The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis.Curr Med Res Opin. 2013; 29: 633-642
- A new genome-driven integrated classification of breast cancer and its implications.EMBO J. 2013; 32: 617-628
- Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.Breast Cancer Res Treat. 2016; 158: 307-321
- In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer.Nat Genet. 2015; 47: 1212-1219
- Conditional selection of genomic alterations dictates cancer evolution and oncogenic dependencies.Cancer Cell. 2017; 32: 155-68 e156
- Emerging landscape of oncogenic signatures across human cancers.Nat Genet. 2013; 45: 1127-1133
- Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network.Br J Cancer. 2014; 110: 2139-2143
- Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials.Oncotarget. 2016; 7: 5074-5087
- Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study.Lancet Oncol. 2017; 18: 52-62
- Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?.Br J Cancer. 2015; 112: 1445-1451
- Treatment patterns and clinical outcomes for patients with de novo versus recurrent HER2-positive metastatic breast cancer.Breast Cancer Res Treat. 2014; 145: 725-734
- Patterns of care and clinical outcomes of HER2-positive metastatic breast cancer patients with newly diagnosed stage IV or recurrent disease undergoing first-line trastuzumab-based therapy: a multicenter retrospective cohort study.Clin Breast Cancer. 2017; 17: 601-610.e602
- Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy.Breast. 2014; 23: 44-49
- Differential impact of hormone receptor status on survival and recurrence for HER2 receptor-positive breast cancers treated with trastuzumab.Breast Cancer Res Treat. 2017; 164: 221-229
- Patterns of care and clinical outcomes of first-line trastuzumab-based therapy in HER2-positive metastatic breast cancer patients relapsing after (neo)adjuvant trastuzumab: an Italian multicenter retrospective cohort study.Oncologist. 2015; 20: 880-889
- A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01).J Clin Oncol. 2016; 34: 1005
- Surgery of primary tumors in stage IV breast cancer: an updated meta-analysis of published studies with meta-regression.Med Oncol. 2012; 29: 3282-3290
- Surgery of the primary tumor improves survival in women with stage IV breast cancer in Southwest China: a retrospective analysis.Medicine. 2017; 96: e7048
- A prospective analysis of surgery and survival in stage IV breast cancer (TBCRC 013).J Clin Oncol. 2016; 34: 1006
- Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial.Lancet Oncol. 2015; 16: 1380-1388
Article info
Publication history
Published online: November 05, 2018
Accepted:
October 29,
2018
Received in revised form:
August 22,
2018
Received:
June 20,
2018
Footnotes
V.K. and K.T. contributed equally to this work as first authors.
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
