Abstract
Background
Circulating tumor DNA (ctDNA) provides a promising noninvasive alternative to evaluate the efficacy of neoadjuvant chemotherapy (NCT) in breast cancer.
Methods
Herein, we collected 63 tissue (aspiration biopsies and resected tissues) and 206 blood samples (baseline, during chemotherapy (Chemo), after chemotherapy (Post-Chemo), after operation (Post-Op), during follow-up) from 32 patients, and preformed targeted deep sequencing with a customed 1021-gene panel.
Results
As the results, TP53 (43.8%) and PIK3CA (40.6%) were the most common mutant genes in the primary tumors. At least one tumor-derived mutation was detected in the following number of blood samples: 21, baseline; 3, Chemo; 9, Post-Chemo; and 5, Post-Op. Four patients with pathologic complete response had no tissue mutation in Chemo and Post-Chemo blood. Compared to patients with mutation-positive Chemo or Post-Chemo blood, the counterparts showed a superior primary tumor decrease (median, 86.5% versus 54.6%) and lymph involvement (median, 1 versus 3.5). All five patients with mutation-positive Post-Op developed distant metastases during follow-up, and the sensitivity of detecting clinically relapsed patients was 71.4% (5/7). The median DFS was 9.8 months for patients with mutation-positive Post-Op but not reached for the others (HR 23.53; 95% CI, 1.904–290.9; p < 0.0001).
Conclusions
Our study shows that sequential monitoring of blood ctDNA was an effective method for evaluating NCT efficacy and patient recurrence. Integrating ctDNA profiling into the management of LABC patients might improve clinical outcome.
Trial registration
This prospective study recruited LABC patients at Peking Union Medical College Hospital (ClinicalTrials.gov Identifier: NCT02797652).
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Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
King TA, Morrow M (2015) Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol 12(6):335–343
Alawad AA (2014) Evaluation of clinical and pathological response after two cycles of neoadjuvant chemotherapy on Sudanese patients with locally advanced breast cancer. Ethiop J Health Sci 24(1):15–20
Takahashi H, Kagara N, Tanei T, Naoi Y, Shimoda M, Shimomura A, Shimazu K, Kim SJ, Noguchi S (2017) Correlation of methylated circulating tumor DNA With response to neoadjuvant chemotherapy in breast cancer patients. Clin Breast Cancer 17(1):61–69
Bottini A, Berruti A, Tampellini M, Morrica B, Brunelli A, Gnocchi E, Brizzi MP, Aguggini S, Fara E, Alquati P et al (1997) Influence of neoadjuvant chemotherapy on serum tumor markers CA 15–3, MCA, CEA, TPS and TPA in breast cancer patients with operable disease. Tumour Biol 18(5):301–310
Wang YJ, Huang XY, Mo M, Li JW, Jia XQ, Shao ZM, Shen ZZ, Wu J, Liu GY (2015) Serum tumor marker levels might have little significance in evaluating neoadjuvant treatment response in locally advanced breast cancer. Asian Pac J Cancer Prev 16(11):4603–4608
Zhou X, Li Y (2016) Local recurrence after breast-conserving surgery and mastectomy following neoadjuvant chemotherapy for locally advanced breast cancer—a meta-analysis. Breast Care 11(5):345–351
Vargo JA, Beriwal S, Ahrendt GM, Soran A, Johnson RR, McGuire K, Bhargava R (2011) Molecular class as a predictor of locoregional and distant recurrence in the neoadjuvant setting for breast cancer. Oncology 80(5–6):341–349
Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 17(4):223–238
Siravegna G, Marsoni S, Siena S, Bardelli A (2017) Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 14(9):531–548
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM et al (2014) Detection of circulating tumor DNA in early-and late-stage human malignancies. Sci Transl Med 6(224):224ra224
Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I et al (2015) Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 7(302):302ra133
Riva F, Bidard FC, Houy A, Saliou A, Madic J, Rampanou A, Hego C, Milder M, Cottu P, Sablin MP et al (2017) Patient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem 63(3):691–699
Kim JY, Park D, Son DS, Nam SJ, Kim SW, Jung HH, Kim YJ, Park G, Park WY, Lee JE et al (2017) Circulating tumor DNA shows variable clonal response of breast cancer during neoadjuvant chemotherapy. Oncotarget 8(49):86423–86434
Chen YH, Hancock BA, Solzak JP, Brinza D, Scafe C, Miller KD, Radovich M (2017) Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. NPJ Breast Cancer 3:24
Lehner J, Stotzer OJ, Fersching D, Nagel D, Holdenrieder S (2013) Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy. Clini Chimica Acta 425:206–211
Zardavas D, Irrthum A, Swanton C, Piccart M (2015) Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol 12(7):381–394
Janiszewska M, Liu L, Almendro V, Kuang Y, Paweletz C, Sakr RA, Weigelt B, Hanker AB, Chandarlapaty S, King TA et al (2015) In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer. Nat Genet 47(10):1212–1219
Bruna A, Rueda OM, Greenwood W, Batra AS, Callari M, Batra RN, Pogrebniak K, Sandoval J, Cassidy JW, Tufegdzic-Vidakovic A et al (2016) A biobank of breast cancer explants with preserved intra-tumor heterogeneity to screen anticancer compounds. Cell 167(1):260-274 e222
De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, Seoane J (2013) Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol 10(7):377–389
van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ (2009) Cooperating Investigators of the E: preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat 115(1):101–113
von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804
von Minckwitz G, Untch M, Nuesch E, Loibl S, Kaufmann M, Kummel S, Fasching PA, Eiermann W, Blohmer JU, Costa SD et al (2011) Impact of treatment characteristics on response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant chemotherapy trials. Breast Cancer Res Treat 125(1):145–156
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172
Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J et al (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19(1):40–50
Rosenberg SM, Partridge AH (2015) Management of breast cancer in very young women. Breast 24(Suppl 2):S154-158
Wang-Lopez Q, Chalabi N, Abrial C, Radosevic-Robin N, Durando X, Mouret-Reynier MA, Benmammar KE, Kullab S, Bahadoor M, Chollet P et al (2015) Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer? Crit Rev Oncol Hematol 95(1):88–104
Luen S, Virassamy B, Savas P, Salgado R, Loi S (2016) The genomic landscape of breast cancer and its interaction with host immunity. Breast 29:241–250
Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ et al (2016) The somatic mutation profiles of 2433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 7:11479
Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70
Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, Zhang H, McLellan M, Yau C, Kandoth C et al (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163(2):506–519
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM et al (2017) Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23(6):703–713
Singletary SE, Allred C, Ashley P, Bassett LW, Berry D, Bland KI, Borgen PI, Clark G, Edge SB, Hayes DF et al (2002) Revision of the American Joint Committee on cancer staging system for breast cancer. J Clin Oncol 20(17):3628–3636
Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD (2003) A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast 12(5):320–327
Lv X, Zhao M, Yi Y, Zhang L, Guan Y, Liu T, Yang L, Chen R, Ma J, Yi X (2017) Detection of rare mutations in CtDNA using next generation sequencing. J Vis Exp. https://doi.org/10.3791/56342
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339
Artzy-Randrup Y, Epstein T, Brown JS et al (2021) Novel evolutionary dynamics of small populations in breast cancer adjuvant and neoadjuvant therapy. npj Breast Cancer. https://doi.org/10.1038/s41523-021-00230-y
Caswell-Jin JL, McNamara K, Reiter JG et al (2019) Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nat Commun 10:657. https://doi.org/10.1038/s41467-019-08593-4
Murugaesu N et al (2015) Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy. Cancer Discov 5(8):821–831. https://doi.org/10.1158/2159-8290.CD-15-0412
Killelea BK et al (2015) Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg 220(6):1063–1069. https://doi.org/10.1016/j.jamcollsurg.2015.02.011
Hellman S, Weichselbaum RR (1995) Oligometastases. J Clin Oncol 13(1):8–10
Weichselbaum RR, Hellman S (2011) Oligometastases revisited. Nat Rev Clin Oncol 8(6):378–382
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Totally 14 authors are listed in manuscript. YZ and YX are the main experimental designers and writers; CW, RY and LP have assisted the management of patients and collection of samples; YG, YZ, XZ and JB helped data arrangement and analysis; YG, XX, LY and XYoffered constructive suggestion for study design and analytical methods.
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Zhou, Y., Xu, Y., Wang, C. et al. Serial circulating tumor DNA identification associated with the efficacy and prognosis of neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 188, 661–673 (2021). https://doi.org/10.1007/s10549-021-06247-y
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DOI: https://doi.org/10.1007/s10549-021-06247-y