Journal Article
. 2017 Mar;7().
doi: 10.1038/srep43294.

Personalized chemotherapy selection for breast cancer using gene expression profiles

Kaixian Yu 1 Qing-Xiang Amy Sang 2 Pei-Yau Lung 1 Winston Tan 3 Ty Lively 2 Cedric Sheffield 2 Mayassa J Bou-Dargham 2 Jun S Liu 4 Jinfeng Zhang 1 
  • PMID: 28256629
  •     43 References
  •     6 citations


Choosing the optimal chemotherapy regimen is still an unmet medical need for breast cancer patients. In this study, we reanalyzed data from seven independent data sets with totally 1079 breast cancer patients. The patients were treated with three different types of commonly used neoadjuvant chemotherapies: anthracycline alone, anthracycline plus paclitaxel, and anthracycline plus docetaxel. We developed random forest models with variable selection using both genetic and clinical variables to predict the response of a patient using pCR (pathological complete response) as the measure of response. The models were then used to reassign an optimal regimen to each patient to maximize the chance of pCR. An independent validation was performed where each independent study was left out during model building and later used for validation. The expected pCR rates of our method are significantly higher than the rates of the best treatments for all the seven independent studies. A validation study on 21 breast cancer cell lines showed that our prediction agrees with their drug-sensitivity profiles. In conclusion, the new strategy, called PRES (Personalized REgimen Selection), may significantly increase response rates for breast cancer patients, especially those with HER2 and ER negative tumors, who will receive one of the widely-accepted chemotherapy regimens.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.
S Chan, K Friedrichs, +21 authors, 303 Study Group.
J Clin Oncol, 1999 Nov 24; 17(8). PMID: 10561296
Highly Cited.
Seventeen-gene signature from enriched Her2/Neu mammary tumor-initiating cells predicts clinical outcome for human HER2+:ERα- breast cancer.
Jeff C Liu, Veronique Voisin, +6 authors, Eldad Zacksenhaus.
Proc Natl Acad Sci U S A, 2012 Mar 31; 109(15). PMID: 22460789    Free PMC article.
Cell line derived multi-gene predictor of pathologic response to neoadjuvant chemotherapy in breast cancer: a validation study on US Oncology 02-103 clinical trial.
Kui Shen, Yuan Qi, +9 authors, Lajos Pusztai.
BMC Med Genomics, 2012 Nov 20; 5. PMID: 23158478    Free PMC article.
Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis.
Davide Mauri, Nicholas Pavlidis, John P A Ioannidis.
J Natl Cancer Inst, 2005 Feb 03; 97(3). PMID: 15687361
Highly Cited.
Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871).
Adam Pavlicek, Maruja E Lira, +12 authors, James G Christensen.
Mol Cancer Ther, 2013 Oct 11; 12(12). PMID: 24107449
Prediction of benefit from adjuvant treatment in patients with breast cancer.
Jennifer Eng-Wong, Claudine Isaacs.
Clin Breast Cancer, 2010 Jul 01; 10 Suppl 1. PMID: 20587405
Optimizing chemotherapy regimens for patients with early-stage breast cancer.
Efrat Dotan, Lori J Goldstein.
Clin Breast Cancer, 2010 Jul 01; 10 Suppl 1. PMID: 20587409
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
Brian D Lehmann, Joshua A Bauer, +4 authors, Jennifer A Pietenpol.
J Clin Invest, 2011 Jun 03; 121(7). PMID: 21633166    Free PMC article.
Highly Cited.
The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer.
Marieke E Straver, Annuska M Glas, +7 authors, Sjoerd Rodenhuis.
Breast Cancer Res Treat, 2009 Feb 14; 119(3). PMID: 19214742
A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
Monika Graeser, Afshan McCarthy, +10 authors, Nicholas C Turner.
Clin Cancer Res, 2010 Aug 31; 16(24). PMID: 20802015    Free PMC article.
Highly Cited.
Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.
Marc Buyse, Sherene Loi, +18 authors, TRANSBIG Consortium.
J Natl Cancer Inst, 2006 Sep 07; 98(17). PMID: 16954471
Highly Cited.
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.
B Fisher, J Bryant, +13 authors, H D Bear.
J Clin Oncol, 1998 Aug 15; 16(8). PMID: 9704717
Highly Cited.
Neoadjuvant chemotherapy in ER+ HER2- breast cancer: response prediction based on immunohistochemical and molecular characteristics.
E H Lips, L Mulder, +6 authors, S Rodenhuis.
Breast Cancer Res Treat, 2011 Apr 08; 131(3). PMID: 21472434
Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).
Laura J Esserman, Donald A Berry, +32 authors, I-SPY 1 TRIAL Investigators.
Breast Cancer Res Treat, 2011 Dec 27; 132(3). PMID: 22198468    Free PMC article.
Highly Cited.
Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer.
Adel Tabchy, Vicente Valero, +14 authors, Lajos Pusztai.
Clin Cancer Res, 2010 Sep 11; 16(21). PMID: 20829329    Free PMC article.
An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735.
Kenneth E Hook, Scott J Garza, +12 authors, Adam Pavlicek.
Mol Cancer Ther, 2012 Jan 10; 11(3). PMID: 22222631
Individualization of therapy using Mammaprint: from development to the MINDACT Trial.
Stella Mook, Laura J Van't Veer, +2 authors, Fatima Cardoso.
Cancer Genomics Proteomics, 2007 Sep 20; 4(3). PMID: 17878518
Insight or confusion: survival after response-guided neoadjuvant chemotherapy in breast cancer.
Melinda L Telli.
J Clin Oncol, 2013 Sep 05; 31(29). PMID: 24002503
Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials.
Michele De Laurentiis, Giuseppe Cancello, +13 authors, Sabino De Placido.
J Clin Oncol, 2008 Jan 01; 26(1). PMID: 18165639
Highly Cited.
A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.
Christos Hatzis, Lajos Pusztai, +27 authors, W Fraser Symmans.
JAMA, 2011 May 12; 305(18). PMID: 21558518    Free PMC article.
Highly Cited.
Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.
Takayuki Iwamoto, Giampaolo Bianchini, +14 authors, Lajos Pusztai.
J Natl Cancer Inst, 2010 Dec 31; 103(3). PMID: 21191116
Highly Cited.
Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients.
N Harbeck, M Schmitt, +12 authors, Chemo-N 0 Study Group.
Eur J Cancer, 2013 Mar 16; 49(8). PMID: 23490655
In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.
Klaus P Hoeflich, Carol O'Brien, +14 authors, Mark R Lackner.
Clin Cancer Res, 2009 Jul 02; 15(14). PMID: 19567590
Highly Cited.
Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer.
Kenneth R Hess, Keith Anderson, +14 authors, Lajos Pusztai.
J Clin Oncol, 2006 Aug 10; 24(26). PMID: 16896004
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
Yixin Wang, Jan G M Klijn, +11 authors, John A Foekens.
Lancet, 2005 Feb 22; 365(9460). PMID: 15721472
Highly Cited.
Adjuvant taxanes: more to the story.
Devika Gajria, Andrew Seidman, Chau Dang.
Clin Breast Cancer, 2010 Sep 02; 10 Suppl 2. PMID: 20805064
Predictions of the pathological response to neoadjuvant chemotherapy in patients with primary breast cancer using a data mining technique.
M Takada, M Sugimoto, +12 authors, M Toi.
Breast Cancer Res Treat, 2012 Jun 13; 134(2). PMID: 22689089
Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.
Gunter von Minckwitz, Michael Untch, +14 authors, Sibylle Loibl.
J Clin Oncol, 2012 Apr 18; 30(15). PMID: 22508812
Highly Cited.
Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer.
John A Foekens, David Atkins, +17 authors, Yixin Wang.
J Clin Oncol, 2006 Mar 01; 24(11). PMID: 16505412
NCBI GEO: archive for functional genomics data sets--update.
Tanya Barrett, Stephen E Wilhite, +14 authors, Alexandra Soboleva.
Nucleic Acids Res, 2012 Nov 30; 41(Database issue). PMID: 23193258    Free PMC article.
Highly Cited.
TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer.
Susanna Stinson, Mark R Lackner, +17 authors, David Dornan.
Sci Signal, 2011 Jun 16; 4(177). PMID: 21673316
Highly Cited.
Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind.
J Verweij, M Clavel, B Chevalier.
Ann Oncol, 1994 Jul 01; 5(6). PMID: 7918121
Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update.
Manfred Kaufmann, Gabriel N Hortobagyi, +17 authors, Gunter von Minckwitz.
J Clin Oncol, 2006 Apr 20; 24(12). PMID: 16622270
Highly Cited.
Response-guided neoadjuvant chemotherapy for breast cancer.
Gunter von Minckwitz, Jens Uwe Blohmer, +16 authors, Sibylle Loibl.
J Clin Oncol, 2013 Sep 05; 31(29). PMID: 24002511
Highly Cited.
A gene-expression signature as a predictor of survival in breast cancer.
Marc J van de Vijver, Yudong D He, +18 authors, René Bernards.
N Engl J Med, 2002 Dec 20; 347(25). PMID: 12490681
Highly Cited.
Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.
Priya Rastogi, Stewart J Anderson, +15 authors, Norman Wolmark.
J Clin Oncol, 2008 Feb 09; 26(5). PMID: 18258986
Highly Cited.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193).
George W Sledge, Donna Neuberg, +4 authors, William C Wood.
J Clin Oncol, 2003 Feb 15; 21(4). PMID: 12586793
Highly Cited.
Breast cancer assessment tools and optimizing adjuvant therapy.
Catherine Oakman, Libero Santarpia, Angelo Di Leo.
Nat Rev Clin Oncol, 2010 Oct 27; 7(12). PMID: 20975745
RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells.
Joshua A Bauer, Fei Ye, +5 authors, Jennifer A Pietenpol.
Breast Cancer Res, 2010 Jun 26; 12(3). PMID: 20576088    Free PMC article.
Effect of training-sample size and classification difficulty on the accuracy of genomic predictors.
Vlad Popovici, Weijie Chen, +15 authors, Lajos Pusztai.
Breast Cancer Res, 2010 Jan 13; 12(1). PMID: 20064235    Free PMC article.
pathCHEMO, a generalizable computational framework uncovers molecular pathways of chemoresistance in lung adenocarcinoma.
Nusrat J Epsi, Sukanya Panja, Sharon R Pine, Antonina Mitrofanova.
Commun Biol, 2019 Sep 12; 2. PMID: 31508508    Free PMC article.
Correlation-centred variable selection of a gene expression signature to predict breast cancer metastasis.
Shiori Hikichi, Masahiro Sugimoto, Masaru Tomita.
Sci Rep, 2020 May 15; 10(1). PMID: 32404965    Free PMC article.
Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer.
Sarra M Rahem, Nusrat J Epsi, Frederick D Coffman, Antonina Mitrofanova.
EBioMedicine, 2020 Oct 26; 61. PMID: 33099086    Free PMC article.
Maximizing the reusability of gene expression data by predicting missing metadata.
Pei-Yau Lung, Dongrui Zhong, +2 authors, Jinfeng Zhang.
PLoS Comput Biol, 2020 Nov 07; 16(11). PMID: 33156882    Free PMC article.
Mutational signatures and mutable motifs in cancer genomes.
Igor B Rogozin, Youri I Pavlov, +5 authors, David N Cooper.
Brief Bioinform, 2017 May 13; 19(6). PMID: 28498882    Free PMC article.
Neoadjuvant Chemotherapy for Breast Cancer: Past, Present, and Future.
Mariko Asaoka, Shipra Gandhi, Takashi Ishikawa, Kazuaki Takabe.
Breast Cancer (Auckl), 2021 Jan 07; 14. PMID: 33402827    Free PMC article.