Association of 17q22 Amplicon Via Cell-Free DNA With Platinum Chemotherapy Response in Metastatic Triple-Negative Breast Cancer

Abstract

PURPOSE To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy. MATERIALS AND METHODS In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC) tumors. RESULTS Among 71 evaluable patients, 17q21 and 17q22 amplifications were most strongly associated with improved PFS with platinum chemotherapy. There were no significant differences in clinicopathologic features or (neo)adjuvant chemotherapy among patients with 17q22 amplification. Patients with 17q22 amplification (n = 17) had longer median PFS with platinum (7.0 v 3.8 months; log-rank P = .015) than patients without 17q22 amplification (n = 54), an effect that remained significant in multivariable analyses (PFS hazard ratio 0.37; 95% CI, 0.16 to 0.84; P = .02). Among 39 patients who received the nonplatinum chemotherapy agent capecitabine, there was no association between 17q22 amplification and capecitabine PFS (log-rank P = .69). In The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium, 17q22 amplification occurred in more than 20% of both pTNBC and mTNBC tumors, whereas 17q21 was more frequently amplified in mTNBC relative to pTNBC (16% v 8.1%, P = .015). CONCLUSION The 17q22 amplicon, detected by ctDNA, is associated with improved PFS with platinum chemotherapy in patients with mTNBC and warrants further investigation.

An Overview of Circulating Cell-Free Nucleic Acids in Diagnosis and Prognosis of Triple-Negative Breast Cancer

“…The detection of specific alterations in ctDNA has shown some important clinical implications. For example, TNBC patients who had 17q22 amplification had better progression-free survival after cisplatin treatment than those without amplification [ 55 ]. The cisplatin favoring effect of 17q22 amplification may be related to the overexpression of some genes in this region, such as KIF2B, TRIM37, NR1D1, and DLX4.…”

“…The latter is involved in the G2/M cell cycle checkpoint and inhibition of DNA repair mechanisms and their overexpression can improve the TNBC sensitivity to DNA-damaging platinum chemotherapy [ 51 , 52 , 53 , 54 ]. Collier et al provided an excellent example of chromosome alteration analysis in deepening the implication of 17q22 amplification in plasma samples of 58 TNBC patients treated with cisplatin alone or in combination with paclitaxel [ 55 ]. They proved how the patients that displayed 17q22 amplification had better progression-free survival than the other ones after cisplatin treatment [ 55 ].…”

“…Collier et al provided an excellent example of chromosome alteration analysis in deepening the implication of 17q22 amplification in plasma samples of 58 TNBC patients treated with cisplatin alone or in combination with paclitaxel [ 55 ]. They proved how the patients that displayed 17q22 amplification had better progression-free survival than the other ones after cisplatin treatment [ 55 ]. Instead, Stover et al suggested a possible use of ctDNA amplification analysis as a metastatic biomarker.…”

Role of ctDNA in Breast Cancer

“…Assessment of the ctDNA percentage can help determine tumor dynamics, treatment response, and risk of relapse. ctDNA percentage correlated with progression-free survival in triple-negative breast cancer patients [ 74 , 75 ]. In addition, it can be used to assess specific gene mutations.…”

Potential predictive value of circulating tumor DNA (ctDNA) mutations for the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer

“…Additionally, Chen et al found that ctDNA mutations offer useful information for evaluating the effectiveness of targeted therapies in breast cancer patients who are resistant to trastuzumab and chemotherapy (Chen et al, 2020). Furthermore, their findings demonstrated that gene amplifications and decreased ctDNA levels were related to higher PFS in patients with advanced TNBC after chemotherapy (Wongchenko et al, 2020;Collier et al, 2021). However, there is a lack of studies predicting the efficacy of ICIs in advanced TNBC through ctDNA detected by NGS.…”