Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2020

Open Access 01-09-2020 | Breast Cancer | Preclinical study

Genetic mutation profile of Chinese HER2-positive breast cancers and genetic predictors of responses to Neoadjuvant anti-HER2 therapy

Authors: Kai Li, Ning Liao, Bo Chen, Guochun Zhang, Yulei Wang, Liping Guo, Guangnan Wei, Minghan Jia, Lingzhu Wen, Chongyang Ren, Li Cao, Hsiaopei Mok, Cheukfai Li, Jiali Lin, Xiaoqing Chen, Zhou Zhang, Ting Hou, Min Li, Jing Liu, Charles M. Balch, Ning Liao

Published in: Breast Cancer Research and Treatment | Issue 2/2020

Login to get access

Abstract

Purpose

Despite the therapeutic success of existing HER2-targeted therapies, tumors respond quite differently to them. This study aimed at figuring out genetic mutation profile of Chinese HER2-positive patients and investigating predictive factors of neoadjuvant anti-HER2 responses.

Methods

We employed two cohorts. The first cohort was comprised of 181 HER2-positive patients treated at Guangdong Provincial People’s Hospital from 2012 to 2018. The second cohort included 40 patients from the first cohort who underwent HER2-targeted neoadjuvant chemotherapy. Genetic mutations were characterized using next-generation sequencing. We employed the most commonly used definition of pathological complete response (pCR)-eradication of tumor from both breast and lymph nodes (ypT0/is ypN0).

Results

In Chinese HER2-positive breast cancer patients, TP53 (74.6%), CDK12 (64.6%) and PIK3CA (46.4%) have the highest mutation frequencies. In cohort 2, significant differences were found between pCR and non-pCR groups in terms of the initial Ki67 status, TP53 missense mutations, TP53 LOF mutations, PIK3CA mutations and ROS1 mutations (p = 0.028, 0.019, 0.005, 0.013, 0.049, respectively). Furthermore, TP53 LOF mutations and initial Ki67 status (OR 7.086, 95% CI 1.366–36.749, p = 0.020 and OR 6.007, 95% CI 1.120–32.210, p = 0.036, respectively) were found to be predictive of pCR status.

Conclusion

TP53 LOF mutations and initial Ki67 status in HER2-positive breast cancer are predictive of pCR status after HER2-targeted NACT.
Literature
1.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013PubMed
2.
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):164–172PubMed
3.
Untch M, Fasching PA, Konecny GE, Hasmuller S, Lebeau A, Kreienberg R, Camara O, Muller V, du Bois A, Kuhn T et al (2011) Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 29(25):3351–3357PubMed
4.
Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im S-A et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32
5.
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V et al (2012) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379(9816):633–640PubMedPubMedCentral
6.
Loibl S, Gianni L (2017) HER2-positive breast cancer. Lancet 389(10087):2415–2429PubMed
7.
von Minckwitz G, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A et al (2019) Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380(7):617–628
8.
Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, Fulton LL, Dooling DJ, Ding L, Mardis ER et al (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70
9.
Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Nik-Zainal S, Martin S, Varela I, Bignell GR et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486(7403):400–404PubMedPubMedCentral
10.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352PubMedPubMedCentral
11.
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 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 7:11479PubMedPubMedCentral
12.
Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC et al (2016) Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534(7605):47–54PubMedPubMedCentral
13.
Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, Sotiriou C, Fumagalli D, Jimenez J, Aura C et al (2015) PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 33(12):1334–1339PubMedPubMedCentral
14.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M et al (2010) American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795PubMedPubMedCentral
15.
Kastan MB, Berkovich E (2007) p53: a two-faced cancer gene. Nat Cell Biol 9(5):489–491PubMed
16.
17.
18.
MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, Jostins L, Habegger L, Pickrell JK, Montgomery SB et al (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335(6070):823–828PubMedPubMedCentral
19.
Zhang G, Wang Y, Chen B, Guo L, Cao L, Ren C, Wen L, Li K, Jia M, Li C et al (2019) Characterization of frequently mutated cancer genes in Chinese breast tumors: a comparison of Chinese and TCGA cohorts. Ann Transl Med 7(8):179PubMedPubMedCentral
20.
Sablina AA, Chumakov PM, Levine AJ, Kopnin BP (2001) p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling. Oncogene 20(8):899–909PubMed
21.
Jackson JG, Pant V, Li Q, Chang LL, Quintas-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y et al (2012) p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21(6):793–806PubMedPubMedCentral
22.
Tonnessen-Murray C, Ungerleider NA, Rao SG, Wasylishen AR, Frey WD, Jackson JG (2018) p53 mediates vast gene expression changes that contribute to poor chemotherapeutic response in a mouse model of breast cancer. Transl Oncol 11(4):930–940PubMedPubMedCentral
23.
Tonnessen-Murray CA, Frey WD, Rao SG, Shahbandi A, Ungerleider NA, Olayiwola JO, Murray LB, Vinson BT, Chrisey DB, Lord CJ et al (2019) Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. J Cell Biol 218(11):3827–3844PubMedPubMedCentral
24.
Bougeard G, Sesboue R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugieres L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D et al (2008) Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 45(8):535–538PubMed
25.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMed
26.
Soussi T, Beroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1(3):233–240PubMed
27.
Girardini JE, Napoli M, Piazza S, Rustighi A, Marotta C, Radaelli E, Capaci V, Jordan L, Quinlan P, Thompson A et al (2011) A Pin1/mutant p53 axis promotes aggressiveness in breast cancer. Cancer Cell 20(1):79–91PubMed
28.
Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V et al (2009) A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 137(1):87–98PubMed
29.
Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR, Cai WW, Lozano G, Roop DR (2007) An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations. J Clin Invest 117(7):1893–1901PubMedPubMedCentral
30.
Bonnefoi H, Piccart M, Bogaerts J, Mauriac L, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Blot E et al (2011) TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1–00): a randomised phase 3 trial. Lancet Oncol 12(6):527–539PubMedPubMedCentral
31.
Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28(6):622–629PubMed
32.
33.
Darb-Esfahani S, Denkert C, Stenzinger A, Salat C, Sinn B, Schem C, Endris V, Klare P, Schmitt W, Blohmer JU et al (2016) Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy. Oncotarget 7(42):67686–67698PubMedPubMedCentral
34.
Fountzilas G, Giannoulatou E, Alexopoulou Z, Zagouri F, Timotheadou E, Papadopoulou K, Lakis S, Bobos M, Poulios C, Sotiropoulou M et al (2016) TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting. Oncotarget 7(22):32731–32753PubMedPubMedCentral
35.
Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ et al (2016) Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol 34(6):542–549PubMed
36.
Guarneri V, Dieci MV, Frassoldati A, Maiorana A, Ficarra G, Bettelli S, Tagliafico E, Bicciato S, Generali DG, Cagossi K et al (2015) Prospective biomarker analysis of the randomized CHER-LOB study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer. Oncologist 20(9):1001–1010PubMedPubMedCentral
37.
Bayraktar S, Royce M, Stork-Sloots L, de Snoo F, Gluck S (2014) Molecular subtyping predicts pathologic tumor response in early-stage breast cancer treated with neoadjuvant docetaxel plus capecitabine with or without trastuzumab chemotherapy. Med Oncol 31(10):163PubMed
38.
Gluck S, Ross JS, Royce M, McKenna EF Jr, Perou CM, Avisar E, Wu L (2012) TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine +/- trastuzumab. Breast Cancer Res Treat 132(3):781–791PubMed
39.
Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, Suzuki N, Fernandes A, Rosenquist T, Medverec Z et al (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 104(29):12129–12134PubMed
40.
L'Esperance S, Popa I, Bachvarova M, Plante M, Patten N, Wu L, Tetu B, Bachvarov D (2006) Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Int J Oncol 29(1):5–24PubMed
41.
Singla H, Kaur RP, Shafi G, Vashistha R, Banipal RPS, Kumar V, Munshi A (2019) Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab. Mol Biol Rep 46(1):823–831PubMed
42.
Loi S, Michiels S, Lambrechts D, Fumagalli D, Claes B, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Piccart MJ, Joensuu H et al (2013) Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst 105(13):960–967PubMedPubMedCentral
43.
Denkert C, Loibl S, Müller BM, Eidtmann H, Schmitt WD, Eiermann W, Gerber B, Tesch H, Hilfrich J, Huober J et al (2013) Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Ann Oncol 24(11):2786–2793PubMed
Metadata
Title
Genetic mutation profile of Chinese HER2-positive breast cancers and genetic predictors of responses to Neoadjuvant anti-HER2 therapy
Authors
Kai Li
Ning Liao
Bo Chen
Guochun Zhang
Yulei Wang
Liping Guo
Guangnan Wei
Minghan Jia
Lingzhu Wen
Chongyang Ren
Li Cao
Hsiaopei Mok
Cheukfai Li
Jiali Lin
Xiaoqing Chen
Zhou Zhang
Ting Hou
Min Li
Jing Liu
Charles M. Balch
Ning Liao
Publication date
01-09-2020
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-020-05778-0

Other articles of this Issue 2/2020

Breast Cancer Research and Treatment 2/2020 Go to the issue

Clinical trial

Clinical decision trees support systematic evaluation of multidisciplinary team recommendations

Review

Dynamic contrast-enhanced magnetic resonance imaging for risk-stratified screening in women with BRCA mutations or high familial risk for breast cancer: are we there yet?

Review

Patient preferences for locoregional therapy in early-stage breast cancer

Preclinical study

CDH2/N-cadherin and early diagnosis of invasion in patients with ductal carcinoma in situ

Clinical trial

External validation and modification of nomogram for predicting positive resection margins before breast conserving surgery

Epidemiology

Evaluation of a beneficial effect of adjuvant chemotherapy in patients with stage I triple-negative breast cancer: a population-based study using the SEER 18 database
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits