Skip to main content
SpringerLink
Log in

Predictive biomarkers for molecularly targeted therapies and immunotherapies in breast cancer

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Globally, breast cancer is the most common malignancy in women. Substantial efforts have been made to develop novel therapies, including targeted therapies and immunotherapies, for patients with breast cancer who do not respond to standard therapies. Consequently, new targeted therapies, such as cyclin-dependent kinase 4 and 6 inhibitors, poly (ADP-ribose) polymerase inhibitors, phosphoinositide 3-kinase inhibitor, and antibody–drug conjugates targeting human epidermal growth factor receptor 2 or trophoblast cell surface antigen-2, and immune checkpoint inhibitor targeting programmed cell death-1, have been developed and are now in clinical use. However, only some patients have benefited from these novel therapies; therefore, the identification and validation of reliable or more accurate biomarkers for predicting responses to these agents remain a major challenge. This review summarizes the currently available predictive biomarkers for breast cancer and describes recent efforts undertaken to identify potential predictive markers for molecularly targeted therapies and immune checkpoint inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Agilent Technologies (2020) Agilent receives expanded FDA approval for PD-L1 IHC 22C3 pharmDx in triple-negative breast cancer. https://www.agilent.com/about/newsroom/presrel/2020/13nov-ca20029.html. Accessed 13 Nov 2020

  • Alva AS, Mangat PK, Garrett-Mayer E, Halabi S, Hansra D, Calfa CJ, Khalil MF, Ahn ER, Cannon TL, Crilley P, Fisher JG, Haslem DS, Shrestha S, Antonelli KR, Butler NL, Warren SL, Rygiel AL, Ranasinghe S, Bruinooge SS, Schilsky RL (2021) Pembrolizumab in patients with metastatic breast cancer with high tumor mutational burden: results from the targeted agent and Profiling Utilization Registry (TAPUR) Study. J Clin Oncol 39:2443–2451. https://doi.org/10.1200/JCO.20.02923

    Article  PubMed  CAS  Google Scholar 

  • Ambrogi F, Fornili M, Boracchi P, Trerotola M, Relli V, Simeone P, La Sorda R, Lattanzio R, Querzoli P, Pedriali M, Piantelli M, Biganzoli E, Alberti S (2014) Trop-2 is a determinant of breast cancer survival. PLoS ONE 9:e96993. https://doi.org/10.1371/journal.pone.0096993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Papai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D, and Group S-S (2019) Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929–1940. https://doi.org/10.1056/NEJMoa1813904

    Article  Google Scholar 

  • Andre F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, Rubovszky G, Yamashita T, Kaufman B, Lu YS, Inoue K, Papai Z, Takahashi M, Ghaznawi F, Mills D, Kaper M, Miller M, Conte PF, Iwata H, Rugo HS (2021) Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol 32:208–217. https://doi.org/10.1016/j.annonc.2020.11.011

    Article  PubMed  CAS  Google Scholar 

  • Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30:2718–2724. https://doi.org/10.1200/JCO.2011.39.0708

    Article  PubMed  CAS  Google Scholar 

  • Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O’shaughnessy J, Moroose RL, Santin AD, Abramson VG, Shah NC, Rugo HS, Goldenberg DM, Sweidan AM, Iannone R, Washkowitz S, Sharkey RM, Wegener WA, Kalinsky K (2019) Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380:741–751. https://doi.org/10.1056/NEJMoa1814213

    Article  PubMed  CAS  Google Scholar 

  • Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortes J, O’shaughnessy J, Dieras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS, Investigators ACT (2021a) Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 384:1529–1541. https://doi.org/10.1056/NEJMoa2028485

    Article  PubMed  CAS  Google Scholar 

  • Bardia A, Tolaney SM, Punie K, Loirat D, Oliveira M, Kalinsky K, Zelnak A, Aftimos P, Dalenc F, Sardesai S, Hamilton E, Sharma P, Recalde S, Gil EC, Traina T, O’shaughnessy J, Cortes J, Tsai M, Vahdat L, Dieras V, Carey LA, Rugo HS, Goldenberg DM, Hong Q, Olivo M, Itri LM, Hurvitz SA (2021b) Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Ann Oncol 32:1148–1156. https://doi.org/10.1016/j.annonc.2021.06.002

    Article  PubMed  CAS  Google Scholar 

  • Baretti M, Le DT (2018) DNA mismatch repair in cancer. Pharmacol Ther 189:45–62. https://doi.org/10.1016/j.pharmthera.2018.04.004

    Article  PubMed  CAS  Google Scholar 

  • Barroso-Sousa R, Jain E, Cohen O, Kim D, Buendia-Buendia J, Winer E, Lin N, Tolaney SM, Wagle N (2020a) Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann Oncol 31:387–394. https://doi.org/10.1016/j.annonc.2019.11.010

    Article  PubMed  CAS  Google Scholar 

  • Barroso-Sousa R, Keenan TE, Pernas S, Exman P, Jain E, Garrido-Castro AC, Hughes M, Bychkovsky B, Umeton R, Files JL, Lindeman NI, Macconaill LE, Hodi FS, Krop IE, Dillon D, Winer EP, Wagle N, Lin NU, Mittendorf EA, Van Allen EM, Tolaney SM (2020b) Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer. Clin Cancer Res 26:2565–2572. https://doi.org/10.1158/1078-0432.CCR-19-3507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529. https://doi.org/10.1056/NEJMoa1109653

    Article  PubMed  CAS  Google Scholar 

  • Baselga J, Cortes J, Im SA, Clark E, Ross G, Kiermaier A, Swain SM (2014) Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol 32:3753–3761. https://doi.org/10.1200/JCO.2013.54.5384

    Article  PubMed  CAS  Google Scholar 

  • Bianchini G, Kiermaier A, Bianchi GV, Im YH, Pienkowski T, Liu MC, Tseng LM, Dowsett M, Zabaglo L, Kirk S, Szado T, Eng-Wong J, Amler LC, Valagussa P, Gianni L (2017) Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res 19:16. https://doi.org/10.1186/s13058-017-0806-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bilanges B, Posor Y, Vanhaesebroeck B (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20:515–534. https://doi.org/10.1038/s41580-019-0129-z

    Article  PubMed  CAS  Google Scholar 

  • Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, Monsey J, Goel N, Aronson AB, Li S, Ma CX, Ding L, Mardis ER, Ellis MJ (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237. https://doi.org/10.1158/2159-8290.CD-12-0349

    Article  PubMed  CAS  Google Scholar 

  • Bratman SV, Yang SYC, Iafolla MAJ, Liu Z, Hansen AR, Bedard PL, Lheureux S, Spreafico A, Razak AA, Shchegrova S, Louie M, Billings P, Zimmermann B, Sethi H, Aleshin A, Torti D, Marsh K, Eagles J, Cirlan I, Hanna Y, Clouthier DL, Lien SC, Ohashi PS, Xu W, Siu LL, Pugh TJ (2020) Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nature Cancer. https://doi.org/10.1038/s43018-020-0096-5

    Article  PubMed  Google Scholar 

  • Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676–3685. https://doi.org/10.1200/JCO.2005.07.032

    Article  PubMed  CAS  Google Scholar 

  • Cardillo TM, Rossi DL, Zalath MB, Liu D, Arrojo R, Sharkey RM, Chang CH, Goldenberg DM (2020) Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer. Oncotarget 11:3849–3862. https://doi.org/10.18632/oncotarget.27766

    Article  PubMed  PubMed Central  Google Scholar 

  • Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortes J, Curigliano G, Dieras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP (2018) 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)dagger. Ann Oncol 29:1634–1657. https://doi.org/10.1093/annonc/mdy192

    Article  PubMed  CAS  Google Scholar 

  • Carey LA, Berry DA, Cirrincione CT, Barry WT, Pitcher BN, Harris LN, Ollila DW, Krop IE, Henry NL, Weckstein DJ, Anders CK, Singh B, Hoadley KA, Iglesia M, Cheang MC, Perou CM, Winer EP, Hudis CA (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 34:542–549. https://doi.org/10.1200/JCO.2015.62.1268

    Article  PubMed  CAS  Google Scholar 

  • Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, Peters S (2019) Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 30:44–56. https://doi.org/10.1093/annonc/mdy495

    Article  PubMed  CAS  Google Scholar 

  • Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, and Panel M (2015) Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 26:1533–1546. https://doi.org/10.1093/annonc/mdv221

    Article  Google Scholar 

  • Condorelli R, Mosele F, Verret B, Bachelot T, Bedard PL, Cortes J, Hyman DM, Juric D, Krop I, Bieche I, Saura C, Sotiriou C, Cardoso F, Loibl S, Andre F, Turner NC (2019) Genomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol 30:365–373. https://doi.org/10.1093/annonc/mdz036

    Article  PubMed  CAS  Google Scholar 

  • Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P, Investigators K (2020) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396:1817–1828. https://doi.org/10.1016/S0140-6736(20)32531-9

    Article  PubMed  Google Scholar 

  • Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ (2017) A molecular portrait of microsatellite instability across multiple cancers. Nat Commun 8:15180. https://doi.org/10.1038/ncomms15180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, Demichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425–439. https://doi.org/10.1016/S1470-2045(15)00613-0

    Article  PubMed  CAS  Google Scholar 

  • Daemen A, Wolf DM, Korkola JE, Griffith OL, Frankum JR, Brough R, Jakkula LR, Wang NJ, Natrajan R, Reis-Filho JS, Lord CJ, Ashworth A, Spellman PT, Gray JW, Van’t Veer LJ (2012) Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib. Breast Cancer Res Treat 135:505–517. https://doi.org/10.1007/s10549-012-2188-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Azambuja E, Cardoso F, De Castro G, Jr., Colozza M, Mano MS, Durbecq V, Sotiriou C, Larsimont D, Piccart-Gebhart MJ, and Paesmans M (2007) Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 96:1504–1513. https://doi.org/10.1038/sj.bjc.6603756

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dean JL, Mcclendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, Knudsen ES (2012) Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 11:2756–2761. https://doi.org/10.4161/cc.21195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Demichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, Lal P, Feldman M, Zhang P, Colameco C, Lewis D, Langer M, Goodman N, Domchek S, Gogineni K, Rosen M, Fox K, O’dwyer P (2015) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 21:995–1001. https://doi.org/10.1158/1078-0432.CCR-14-2258

    Article  PubMed  CAS  Google Scholar 

  • Denkert C, Huober J, Loibl S, Prinzler J, Kronenwett R, Darb-Esfahani S, Brase JC, Solbach C, Mehta K, Fasching PA, Sinn BV, Engels K, Reinisch M, Hansmann ML, Tesch H, Von Minckwitz G, Untch M (2013) HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer. Breast Cancer Res 15:R11. https://doi.org/10.1186/bcr3384

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dieci MV, Radosevic-Robin N, Fineberg S, Van Den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D’alfonso TM, Demaria S, Castaneda C, Sanchez J, Badve S, Michiels S, Bossuyt V, Rojo F, Singh B, Nielsen T, Viale G, Kim SR, Hewitt S, Wienert S, Loibl S, Rimm D, Symmans F, Denkert C, Adams S, Loi S, Salgado R, and International Immuno-Oncology Biomarker Working Group on Breast C (2018) Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 52:16–25. https://doi.org/10.1016/j.semcancer.2017.10.003

    Article  Google Scholar 

  • Dieras V, Miles D, Verma S, Pegram M, Welslau M, Baselga J, Krop IE, Blackwell K, Hoersch S, Xu J, Green M, Gianni L (2017) Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 18:732–742. https://doi.org/10.1016/S1470-2045(17)30312-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dong C, Wu J, Chen Y, Nie J, Chen C (2021) Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer. Front Pharmacol 12:628690. https://doi.org/10.3389/fphar.2021.628690

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Early Breast Cancer Trialists’ Collaborative G (2021) Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol 22:1139–1150. https://doi.org/10.1016/S1470-2045(21)00288-6

    Article  Google Scholar 

  • Emens LA, Molinero L, Loi S, Rugo HS, Schneeweiss A, Dieras V, Iwata H, Barrios CH, Nechaeva M, Nguyen-Duc A, Chui SY, Husain A, Winer EP, Adams S, Schmid P (2021) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study. J Natl Cancer Inst 113:1005–1016. https://doi.org/10.1093/jnci/djab004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fang H, Huang D, Yang F, Guan X (2018) Potential biomarkers of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer. Breast Cancer Res Treat 168:287–297. https://doi.org/10.1007/s10549-017-4612-y

    Article  PubMed  CAS  Google Scholar 

  • Fehm T, Mueller V, Banys-Paluchowski M, Fasching PA, Friedl TW, Hartkopf A, Huober J, Loehberg C, Rack B, Riethdorf S, Schneeweiss A, Meier-Stiegen F, Hoffmann O, Müller L, Wimberger P, Ruckhaeberle E, Blohmer J, Janni W (2021) Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells—results from the randomized phase III DETECT III trial Cancer Res. https://doi.org/10.1158/1538-7445.SABCS20-PD3-12

  • Ferraro E, Drago JZ, Modi S (2021) Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res 23:84. https://doi.org/10.1186/s13058-021-01459-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925–1936. https://doi.org/10.1056/NEJMoa1607303

    Article  PubMed  CAS  Google Scholar 

  • Finn RS, Liu Y, Zhu Z, Martin M, Rugo HS, Dieras V, Im SA, Gelmon KA, Harbeck N, Lu DR, Gauthier E, Huang Bartlett C, Slamon DJ (2020) Biomarker analyses of response to cyclin-dependent kinase 4/6 inhibition and endocrine therapy in women with treatment-naive metastatic breast cancer. Clin Cancer Res 26:110–121. https://doi.org/10.1158/1078-0432.CCR-19-0751

    Article  PubMed  CAS  Google Scholar 

  • Foundation Medicine (2020) FoundationOne®CDx Receives FDA approval as the first companion diagnostic to identify advanced cancer patients with solid tumors that are tumor mutational burden-high (TMB-H) and appropriate for immunotherapy treatment with KEYTRUDA® (pembrolizumab). https://www.foundationmedicine.com/press-releases/2bac198e-d31b-4e95-bfbf-28a55093b8e8. Accessed 17 June 2020

  • Foundation Medicine (2022) U.S. FDA Approves FoundationOne®CDx as a Companion Diagnostic for KEYTRUDA® (pembrolizumab) to Identify Patients with Microsatellite Instability-High (MSI-H) Solid Tumors. https://www.foundationmedicine.com/press-releases/ecc2cc7f-8490-4838-a622-1baa0bc978a8. Accessed 21 Feb 2022

  • Fumagalli D, Venet D, Ignatiadis M, Azim HA Jr, Maetens M, Rothe F, Salgado R, Bradbury I, Pusztai L, Harbeck N, Gomez H, Chang TW, Coccia-Portugal MA, Di Cosimo S, De Azambuja E, De La Pena L, Nuciforo P, Brase JC, Huober J, Baselga J, Piccart M, Loi S, Sotiriou C (2017) RNA sequencing to predict response to neoadjuvant anti-HER2 therapy: a secondary analysis of the NeoALTTO randomized clinical trial. JAMA Oncol 3:227–234. https://doi.org/10.1001/jamaoncol.2016.3824

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao G, Wang Z, Qu X, Zhang Z (2020a) Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer 20:179. https://doi.org/10.1186/s12885-020-6668-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gao ZH, Li CX, Liu M, Jiang JY (2020b) Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: a meta-analysis. BMC Cancer 20:1150. https://doi.org/10.1186/s12885-020-07654-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Genentech (2021) Genentech Provides Update on Tecentriq U.S. Indication for PD-L1-Positive, Metastatic Triple-Negative Breast Cancer. https://www.gene.com/media/press-releases/14927/2021-08-27/genentech-provides-update-on-tecentriq-u. Accessed 27 Aug 2021

  • Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, De La Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (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 13:25–32. https://doi.org/10.1016/S1470-2045(11)70336-9

    Article  PubMed  CAS  Google Scholar 

  • Gilardini Montani MS, Prodosmo A, Stagni V, Merli D, Monteonofrio L, Gatti V, Gentileschi MP, Barila D, Soddu S (2013) ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition. J Exp Clin Cancer Res 32:95. https://doi.org/10.1186/1756-9966-32-95

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gilson P, Merlin JL, Harle A (2021) Detection of microsatellite instability: state of the art and future applications in circulating tumour DNA (ctDNA). Cancers (basel). https://doi.org/10.3390/cancers13071491

    Article  PubMed Central  Google Scholar 

  • Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ (2016) Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29:255–269. https://doi.org/10.1016/j.ccell.2016.02.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Tredan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A (2017) MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 35:3638–3646. https://doi.org/10.1200/JCO.2017.75.6155

    Article  PubMed  CAS  Google Scholar 

  • Goutsouliak K, Veeraraghavan J, Sethunath V, De Angelis C, Osborne CK, Rimawi MF, Schiff R (2020) Towards personalized treatment for early stage HER2-positive breast cancer. Nat Rev Clin Oncol 17:233–250. https://doi.org/10.1038/s41571-019-0299-9

    Article  PubMed  Google Scholar 

  • Gradishar WJ, Moran MS, Abraham J, Aft R, Agnese D, Allison KH, Blair SL, Burstein HJ, Dang C, Elias AD, Giordano SH, Goetz MP, Goldstein LJ, Hurvitz SA, Isakoff SJ, Jankowitz RC, Javid SH, Krishnamurthy J, Leitch M, Lyons J, Matro J, Mayer IA, Mortimer J, O’regan RM, Patel SA, Pierce LJ, Rugo HS, Sitapati A, Smith KL, Smith ML, Soliman H, Stringer-Reasor EM, Telli ML, Ward JH, Wisinski KB, Young JS, Burns JL, Kumar R (2021) NCCN Guidelines(R) insights: breast cancer, Version 4.2021. J Natl Compr Canc Netw 19:484–493. https://doi.org/10.6004/jnccn.2021.0023

    Article  PubMed  Google Scholar 

  • Griguolo G, Braso-Maristany F, Gonzalez-Farre B, Pascual T, Chic N, Sauri T, Kates R, Gluz O, Martinez D, Pare L, Tsvetkova V, Pesantez D, Vidal M, Adamo B, Munoz M, Galvan P, Barbera L, Cuatrecasas M, Christgen M, Kreipe H, Monge-Escartin I, Villagrasa P, Soy D, Giarratano T, Dieci MV, Conte P, Harbeck N, Guarneri V, Prat A (2020) ERBB2 mRNA expression and response to ado-trastuzumab emtansine (T-DM1) in HER2-positive breast cancer. Cancers (basel). https://doi.org/10.3390/cancers12071902

    Article  Google Scholar 

  • Guerrero-Zotano A, Mayer IA, Arteaga CL (2016) PI3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 35:515–524. https://doi.org/10.1007/s10555-016-9637-x

    Article  PubMed  CAS  Google Scholar 

  • Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, Huang CS, Jaliffe GG, Tryakin A, Goetz MP, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Del Mastro L, Steger GG, Kreipe H, Hegg R, Sohn J, Guarneri V, Cortes J, Hamilton E, Andre V, Wei R, Barriga S, Sherwood S, Forrester T, Munoz M, Shahir A, San Antonio B, Nabinger SC, Toi M, Johnston SRD, O’shaughnessy J, Monarch ECM (2021) Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 32:1571–1581. https://doi.org/10.1016/j.annonc.2021.09.015

    Article  PubMed  CAS  Google Scholar 

  • Harris LN, Ismaila N, Mcshane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG, Van Poznak C, Bast RC, Hayes DF, and American Society of Clinical O (2016) Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 34:1134–1150. https://doi.org/10.1200/JCO.2015.65.2289

    Article  CAS  Google Scholar 

  • Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150. https://doi.org/10.1038/s41568-019-0116-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, Pearson A, Guzman M, Rodriguez O, Grueso J, Bellet M, Cortes J, Elliott R, Pancholi S, Baselga J, Dowsett M, Martin LA, Turner NC, Serra V (2016) Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 76:2301–2313. https://doi.org/10.1158/0008-5472.CAN-15-0728

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hicks M, Macrae ER, Abdel-Rasoul M, Layman R, Friedman S, Querry J, Lustberg M, Ramaswamy B, Mrozek E, Shapiro C, Wesolowski R (2015) Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials. Oncologist 20:337–343. https://doi.org/10.1634/theoncologist.2014-0334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hortobagyi GN (2018) Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. Breast Cancer Res 20:123. https://doi.org/10.1186/s13058-018-1050-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, Andre F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O’shaughnessy J (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738–1748. https://doi.org/10.1056/NEJMoa1609709

    Article  PubMed  CAS  Google Scholar 

  • Hurvitz SA, Martin M, Press MF, Chan D, Fernandez-Abad M, Petru E, Rostorfer R, Guarneri V, Huang CS, Barriga S, Wijayawardana S, Brahmachary M, Ebert PJ, Hossain A, Liu J, Abel A, Aggarwal A, Jansen VM, Slamon DJ (2020) Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR(+)/HER2(-) breast cancer. Clin Cancer Res 26:566–580. https://doi.org/10.1158/1078-0432.CCR-19-1425

    Article  PubMed  CAS  Google Scholar 

  • Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, Juric D, Quinn DI, Moreno V, Doger B, Mayer IA, Boni V, Calvo E, Loi S, Lockhart AC, Erinjeri JP, Scaltriti M, Ulaner GA, Patel J, Tang J, Beer H, Selcuklu SD, Hanrahan AJ, Bouvier N, Melcer M, Murali R, Schram AM, Smyth LM, Jhaveri K, Li BT, Drilon A, Harding JJ, Iyer G, Taylor BS, Berger MF, Cutler RE Jr, Xu F, Butturini A, Eli LD, Mann G, Farrell C, Lalani AS, Bryce RP, Arteaga CL, Meric-Bernstam F, Baselga J, Solit DB (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189–194. https://doi.org/10.1038/nature25475

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ingold Heppner B, Untch M, Denkert C, Pfitzner BM, Lederer B, Schmitt W, Eidtmann H, Fasching PA, Tesch H, Solbach C, Rezai M, Zahm DM, Holms F, Glados M, Krabisch P, Heck E, Ober A, Lorenz P, Diebold K, Habeck JO, Loibl S (2016) Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin Cancer Res 22:5747–5754. https://doi.org/10.1158/1078-0432.CCR-15-2338

    Article  PubMed  CAS  Google Scholar 

  • Karn T, Denkert C, Weber KE, Holtrich U, Hanusch C, Sinn BV, Higgs BW, Jank P, Sinn HP, Huober J, Becker C, Blohmer JU, Marme F, Schmitt WD, Wu S, Van Mackelenbergh M, Muller V, Schem C, Stickeler E, Fasching PA, Jackisch C, Untch M, Schneeweiss A, Loibl S (2020) Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo. Ann Oncol 31:1216–1222. https://doi.org/10.1016/j.annonc.2020.05.015

    Article  PubMed  CAS  Google Scholar 

  • Krop IE, Kim SB, Martin AG, Lorusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M, Wildiers H (2017) Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18:743–754. https://doi.org/10.1016/S1470-2045(17)30313-3

    Article  PubMed  CAS  Google Scholar 

  • Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, De La Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in Tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/NEJMoa1500596

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–413. https://doi.org/10.1126/science.aan6733

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee JH, Long GV, Boyd S, Lo S, Menzies AM, Tembe V, Guminski A, Jakrot V, Scolyer RA, Mann GJ, Kefford RF, Carlino MS, Rizos H (2017) Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma. Ann Oncol 28:1130–1136. https://doi.org/10.1093/annonc/mdx026

    Article  PubMed  CAS  Google Scholar 

  • Lemery S, Keegan P, Pazdur R (2017) First FDA approval agnostic of cancer site—when a biomarker defines the indication. N Engl J Med 377:1409–1412. https://doi.org/10.1056/NEJMp1709968

    Article  PubMed  Google Scholar 

  • Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL (2018) Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379:753–763. https://doi.org/10.1056/NEJMoa1802905

    Article  PubMed  CAS  Google Scholar 

  • Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, Desnyder SM, Brewster AM, Barcenas CH, Valero V, Whitman GJ, Schwartz-Gomez J, Mittendorf EA, Thompson AM, Helgason T, Ibrahim N, Piwnica-Worms H, Moulder SL, Arun BK (2020) Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol 38:388–394. https://doi.org/10.1200/JCO.19.01304

    Article  PubMed  CAS  Google Scholar 

  • Llombart-Cussac A, Cortes J, Pare L, Galvan P, Bermejo B, Martinez N, Vidal M, Pernas S, Lopez R, Munoz M, Nuciforo P, Morales S, Oliveira M, De La Pena L, Pelaez A, Prat A (2017) HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol 18:545–554. https://doi.org/10.1016/S1470-2045(17)30021-9

    Article  PubMed  CAS  Google Scholar 

  • Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25:1544–1550. https://doi.org/10.1093/annonc/mdu112

    Article  PubMed  CAS  Google Scholar 

  • Loi S, Adams S, Schmid P, Corte´ S J, Cescon DW, Winer EP, Toppmeyer DL, Rugo HS, De Laurentiis M, Nanda R, Iwata H, Awada A, Tan AR, Wang A, Aktan G, Karantza V, and Salgado R (2017) Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): results from KEYNOTE-086. Ann Oncol 28:V608. https://doi.org/10.1093/annonc/mdx440.005

    Article  Google Scholar 

  • Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F, International Breast Cancer Study G, and The Breast International G (2019) Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol 20:371–382. https://doi.org/10.1016/S1470-2045(18)30812-X

    Article  Google Scholar 

  • Loi S, Winer E, Lipatov O, Im SA, Goncalves A, Cortes J, Lee KS, Schmid P, Testa L, Witzel I, Ohtani S, Turner N, Zambelli S, Harbeck N, Andre F, Dent R, Huang LK, Mejia J, Karantza V, and Salgado R (2020) Relationship between tumor-infiltrating lymphocytes (TILs) and outcomes in the KEYNOTE-119 study of pembrolizumab vs chemotherapy for previously treated metastatic triple-negative breast cancer (mTNBC) Cancer Res. https://doi.org/10.1158/1538-7445.SABCS19-PD5-03.

  • Loibl S, Von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, Khandan F, Eidtmann H, Dohnal K, Heinrichs C, Huober J, Pfitzner B, Fasching PA, Andre F, Lindner JL, Sotiriou C, Dykgers A, Guo S, Gade S, Nekljudova V, Loi S, Untch M, Denkert C (2014) PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol 32:3212–3220. https://doi.org/10.1200/JCO.2014.55.7876

    Article  PubMed  CAS  Google Scholar 

  • Loibl S, Majewski I, Guarneri V, Nekljudova V, Holmes E, Bria E, Denkert C, Schem C, Sotiriou C, Loi S, Untch M, Conte P, Bernards R, Piccart M, Von Minckwitz G, Baselga J (2016) PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol 27:1519–1525. https://doi.org/10.1093/annonc/mdw197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Loibl S, O’shaughnessy J, Untch M, Sikov WM, Rugo HS, Mckee MD, Huober J, Golshan M, Von Minckwitz G, Maag D, Sullivan D, Wolmark N, Mcintyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr (2018) Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 19:497–509. https://doi.org/10.1016/S1470-2045(18)30111-6

    Article  PubMed  CAS  Google Scholar 

  • Lok BH, Gardner EE, Schneeberger VE, Ni A, Desmeules P, Rekhtman N, De Stanchina E, Teicher BA, Riaz N, Powell SN, Poirier JT, Rudin CM (2017) PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin Cancer Res 23:523–535. https://doi.org/10.1158/1078-0432.CCR-16-1040

    Article  PubMed  CAS  Google Scholar 

  • Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16:110–120. https://doi.org/10.1038/nrc.2015.21

    Article  PubMed  CAS  Google Scholar 

  • Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A (2019) ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 30:1232–1243. https://doi.org/10.1093/annonc/mdz116

    Article  PubMed  CAS  Google Scholar 

  • Luporsi E, Andre F, Spyratos F, Martin PM, Jacquemier J, Penault-Llorca F, Tubiana-Mathieu N, Sigal-Zafrani B, Arnould L, Gompel A, Egele C, Poulet B, Clough KB, Crouet H, Fourquet A, Lefranc JP, Mathelin C, Rouyer N, Serin D, Spielmann M, Haugh M, Chenard MP, Brain E, De Cremoux P, Bellocq JP (2012) Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review. Breast Cancer Res Treat 132:895–915. https://doi.org/10.1007/s10549-011-1837-z

    Article  PubMed  CAS  Google Scholar 

  • Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer E, Naughton M, Goetz MP, Russell C, Tripathy D, Cobleigh M, Forero A, Pluard TJ, Anders C, Niravath PA, Thomas S, Anderson J, Bumb C, Banks KC, Lanman RB, Bryce R, Lalani AS, Pfeifer J, Hayes DF, Pegram M, Blackwell K, Bedard PL, Al-Kateb H, Ellis MJC (2017) Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res 23:5687–5695. https://doi.org/10.1158/1078-0432.CCR-17-0900

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Majewski IJ, Nuciforo P, Mittempergher L, Bosma AJ, Eidtmann H, Holmes E, Sotiriou C, Fumagalli D, Jimenez J, Aura C, Prudkin L, Diaz-Delgado MC, De La Pena L, Loi S, Ellis C, Schultz N, De Azambuja E, Harbeck N, Piccart-Gebhart M, Bernards R, Baselga J (2015) PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 33:1334–1339. https://doi.org/10.1200/JCO.2014.55.2158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Makvandi M, Pantel A, Schwartz L, Schubert E, Xu K, Hsieh CJ, Hou C, Kim H, Weng CC, Winters H, Doot R, Farwell MD, Pryma DA, Greenberg RA, Mankoff DA, Simpkins F, Mach RH, Lin LL (2018) A PET imaging agent for evaluating PARP-1 expression in ovarian cancer. J Clin Invest 128:2116–2126. https://doi.org/10.1172/JCI97992

    Article  PubMed  PubMed Central  Google Scholar 

  • Malorni L, Piazza S, Ciani Y, Guarducci C, Bonechi M, Biagioni C, Hart CD, Verardo R, Di Leo A, Migliaccio I (2016) A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 7:68012–68022. https://doi.org/10.18632/oncotarget.12010

    Article  PubMed  PubMed Central  Google Scholar 

  • Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, and Diaz LA, Jr. (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1–10. https://doi.org/10.1200/JCO.19.02105.

  • Martinez-Saez O, Prat A (2021) Current and future management of HER2-positive metastatic breast cancer. JCO Oncol Pract 17:594–604. https://doi.org/10.1200/OP.21.00172

    Article  PubMed  Google Scholar 

  • Mateo J, Lord CJ, Serra V, Tutt A, Balmana J, Castroviejo-Bermejo M, Cruz C, Oaknin A, Kaye SB, De Bono JS (2019) A decade of clinical development of PARP inhibitors in perspective. Ann Oncol 30:1437–1447. https://doi.org/10.1093/annonc/mdz192

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mayer IA, Prat A, Egle D, Blau S, JaP F, Gnant M, Fasching PA, Colleoni M, Wolff AC, Winer EP, Singer CF, Hurvitz S, Estevez LG, Van Dam PA, Kummel S, Mundhenke C, Holmes F, Babbar N, Charbonnier L, Diaz-Padilla I, Vogl FD, Sellami D, Arteaga CL (2019) A phase II randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (NEO-ORB). Clin Cancer Res 25:2975–2987. https://doi.org/10.1158/1078-0432.CCR-18-3160

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mccabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, Giavara S, O’connor MJ, Tutt AN, Zdzienicka MZ, Smith GC, Ashworth A (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–8115. https://doi.org/10.1158/0008-5472.CAN-06-0140

    Article  PubMed  CAS  Google Scholar 

  • Miglietta F, Griguolo G, Guarneri V, Dieci MV (2019) Programmed cell death ligand 1 in breast cancer: technical aspects, prognostic implications, and predictive value. Oncologist 24:e1055–e1069. https://doi.org/10.1634/theoncologist.2019-0197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, Dowsett M, Jiang A, Smith RA, Maira SM, Manning HC, Gonzalez-Angulo AM, Mills GB, Higham C, Chanthaphaychith S, Kuba MG, Miller WR, Shyr Y, Arteaga CL (2011) ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 1:338–351. https://doi.org/10.1158/2159-8290.CD-11-0101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396:1090–1100. https://doi.org/10.1016/S0140-6736(20)31953-X

    Article  PubMed  CAS  Google Scholar 

  • Modi S, Park H, Murthy RK, Iwata H, Tamura K, Tsurutani J, Moreno-Aspitia A, Doi T, Sagara Y, Redfern C, Krop IE, Lee C, Fujisaki Y, Sugihara M, Zhang L, Shahidi J, Takahashi S (2020a) Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol 38:1887–1896. https://doi.org/10.1200/JCO.19.02318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I, Investigators DE-B (2020b) Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610–621. https://doi.org/10.1056/NEJMoa1914510

    Article  PubMed  CAS  Google Scholar 

  • Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA (2022) Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa2203690

    Article  PubMed  Google Scholar 

  • Morice PM, Coquan E, Weiswald LB, Lambert B, Vaur D, Poulain L (2021) Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays. Br J Cancer 125:7–14. https://doi.org/10.1038/s41416-021-01295-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moynahan ME, Chen D, He W, Sung P, Samoila A, You D, Bhatt T, Patel P, Ringeisen F, Hortobagyi GN, Baselga J, Chandarlapaty S (2017) Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR(+), HER2(-) advanced breast cancer: results from BOLERO-2. Br J Cancer 116:726–730. https://doi.org/10.1038/bjc.2017.25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murai J, Feng Y, Yu GK, Ru Y, Tang SW, Shen Y, Pommier Y (2016) Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 7:76534–76550. https://doi.org/10.18632/oncotarget.12266

    Article  PubMed  PubMed Central  Google Scholar 

  • Murthy RK, Loi S, Okines A, Paplomata E, Hamilton E, Hurvitz SA, Lin NU, Borges V, Abramson V, Anders C, Bedard PL, Oliveira M, Jakobsen E, Bachelot T, Shachar SS, Muller V, Braga S, Duhoux FP, Greil R, Cameron D, Carey LA, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pegram M, Slamon D, Palanca-Wessels MC, Walker L, Feng W, Winer EP (2020) Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 382:597–609. https://doi.org/10.1056/NEJMoa1914609

    Article  PubMed  CAS  Google Scholar 

  • Myriad Genetics (2022) BRACAnalysis CDx® FDA-approved targeted therapies. https://myriad.com/managed-care/bracanalysis-cdx/. Accessed 27 June 2022

  • Nicolini A, Ferrari P, Duffy MJ (2018) Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol 52:56–73. https://doi.org/10.1016/j.semcancer.2017.08.010

    Article  PubMed  CAS  Google Scholar 

  • Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, Denkert C, Ellis MJ, Fineberg S, Flowers M, Kreipe HH, Laenkholm AV, Pan H, Penault-Llorca FM, Polley MY, Salgado R, Smith IE, Sugie T, Bartlett JMS, Mcshane LM, Dowsett M, Hayes DF (2021) Assessment of Ki67 in breast cancer: updated recommendations from the international Ki67 in breast cancer working group. J Natl Cancer Inst 113:808–819. https://doi.org/10.1093/jnci/djaa201

    Article  PubMed  CAS  Google Scholar 

  • O’leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, Andre F, Loibl S, Loi S, Garcia-Murillas I, Cristofanilli M, Huang Bartlett C, Turner NC (2018a) The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov 8:1390–1403. https://doi.org/10.1158/2159-8290.CD-18-0264

    Article  PubMed  Google Scholar 

  • O’leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X, Liu Y, Bartlett CH, Koehler M, Cristofanilli M, Garcia-Murillas I, Bliss JM, Turner NC (2018b) Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun 9:896. https://doi.org/10.1038/s41467-018-03215-x

    Article  PubMed  CAS  Google Scholar 

  • O’meara TA, Tolaney SM (2021) Tumor mutational burden as a predictor of immunotherapy response in breast cancer. Oncotarget 12:394–400. https://doi.org/10.18632/oncotarget.27877

    Article  PubMed  Google Scholar 

  • Pan H, Gray R, Braybrooke J, Davies C, Taylor C, Mcgale P, Peto R, Pritchard KI, Bergh J, Dowsett M, Hayes DF, Ebctcg (2017) 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med 377:1836–1846. https://doi.org/10.1056/NEJMoa1701830

    Article  PubMed  PubMed Central  Google Scholar 

  • Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, Beeram M, Rasco DW, Hilton JF, Nasir A, Beckmann RP, Schade AE, Fulford AD, Nguyen TS, Martinez R, Kulanthaivel P, Li LQ, Frenzel M, Cronier DM, Chan EM, Flaherty KT, Wen PY, Shapiro GI (2016) Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 6:740–753. https://doi.org/10.1158/2159-8290.CD-16-0095

    Article  PubMed  CAS  Google Scholar 

  • Pilie PG, Gay CM, Byers LA, O’connor MJ, Yap TA (2019a) PARP inhibitors: extending benefit beyond BRCA-mutant cancers. Clin Cancer Res 25:3759–3771. https://doi.org/10.1158/1078-0432.CCR-18-0968

    Article  PubMed  CAS  Google Scholar 

  • Pilie PG, Tang C, Mills GB, Yap TA (2019b) State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol 16:81–104. https://doi.org/10.1038/s41571-018-0114-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pogue-Geile KL, Song N, Jeong JH, Gavin PG, Kim SR, Blackmon NL, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP, Swain SM, Wickerham DL, Geyer CE Jr, Costantino JP, Wolmark N, Paik S (2015) Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol 33:1340–1347. https://doi.org/10.1200/JCO.2014.56.2439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Poh A (2017) First tissue-agnostic drug approval issued. Cancer Discov 7:656. https://doi.org/10.1158/2159-8290.CD-NB2017-078

    Article  Google Scholar 

  • Powles T, Assaf ZJ, Davarpanah N, Banchereau R, Szabados BE, Yuen KC, Grivas P, Hussain M, Oudard S, Gschwend JE, Albers P, Castellano D, Nishiyama H, Daneshmand S, Sharma S, Zimmermann BG, Sethi H, Aleshin A, Perdicchio M, Zhang J, Shames DS, Degaonkar V, Shen X, Carter C, Bais C, Bellmunt J, Mariathasan S (2021) ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595:432–437. https://doi.org/10.1038/s41586-021-03642-9

    Article  PubMed  CAS  Google Scholar 

  • Prat A, Carey LA, Adamo B, Vidal M, Tabernero J, Cortes J, Parker JS, Perou CM, Baselga J (2014) Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/dju152

    Article  PubMed  PubMed Central  Google Scholar 

  • Prat A, Pascual T, De Angelis C, Gutierrez C, Llombart-Cussac A, Wang T, Cortes J, Rexer B, Pare L, Forero A, Wolff AC, Morales S, Adamo B, Braso-Maristany F, Vidal M, Veeraraghavan J, Krop I, Galvan P, Pavlick AC, Bermejo B, Izquierdo M, Rodrik-Outmezguine V, Reis-Filho JS, Hilsenbeck SG, Oliveira M, Dieci MV, Griguolo G, Fasani R, Nuciforo P, Parker JS, Conte P, Schiff R, Guarneri V, Osborne CK, Rimawi MF (2020) HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst 112:46–54. https://doi.org/10.1093/jnci/djz042

    Article  PubMed  CAS  Google Scholar 

  • Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM (2013) Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res 19:6173–6182. https://doi.org/10.1158/1078-0432.CCR-13-1675

    Article  PubMed  CAS  Google Scholar 

  • Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC (2013) Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726–1731. https://doi.org/10.1200/JCO.2012.44.8027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rimawi MF, Schiff R, Osborne CK (2015) Targeting HER2 for the treatment of breast cancer. Annu Rev Med 66:111–128. https://doi.org/10.1146/annurev-med-042513-015127

    Article  PubMed  CAS  Google Scholar 

  • Rimawi MF, Niravath P, Wang T, Rexer BN, Forero A, Wolff AC, Nanda R, Storniolo AM, Krop I, Goetz MP, Nangia JR, Jiralerspong S, Pavlick A, Veeraraghavan J, De Angelis C, Gutierrez C, Schiff R, Hilsenbeck SG, Osborne CK, and Translational Breast Cancer Research C (2020) TBCRC023: a randomized phase II neoadjuvant trial of lapatinib plus trastuzumab without chemotherapy for 12 versus 24 weeks in patients with HER2-positive breast cancer. Clin Cancer Res 26:821–827. https://doi.org/10.1158/1078-0432.CCR-19-0851

    Article  Google Scholar 

  • Ripani E, Sacchetti A, Corda D, Alberti S (1998) Human Trop-2 is a tumor-associated calcium signal transducer. Int J Cancer 76:671–676. https://doi.org/10.1002/(sici)1097-0215(19980529)76:5%3c671::aid-ijc10%3e3.0.co;2-7

    Article  PubMed  CAS  Google Scholar 

  • Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523–533. https://doi.org/10.1056/NEJMoa1706450

    Article  PubMed  CAS  Google Scholar 

  • Ross JS, Gay LM, Wang K, Ali SM, Chumsri S, Elvin JA, Bose R, Vergilio JA, Suh J, Yelensky R, Lipson D, Chmielecki J, Waintraub S, Leyland-Jones B, Miller VA, Stephens PJ (2016) Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: an emerging opportunity for anti-HER2 targeted therapies. Cancer 122:2654–2662. https://doi.org/10.1002/cncr.30102

    Article  PubMed  CAS  Google Scholar 

  • Royce M, Bachelot T, Villanueva C, Ozguroglu M, Azevedo SJ, Cruz FM, Debled M, Hegg R, Toyama T, Falkson C, Jeong J, Srimuninnimit V, Gradishar WJ, Arce C, Ridolfi A, Lin C, Cardoso F (2018) Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: a clinical trial. JAMA Oncol 4:977–984. https://doi.org/10.1001/jamaoncol.2018.0060

    Article  PubMed  PubMed Central  Google Scholar 

  • Rugo HS, Olopade OI, Demichele A, Yau C, Van ’T Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ, and Investigators IS (2016) Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med 375:23–34. https://doi.org/10.1056/NEJMoa1513749

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rugo HS, Loi S, Adams S, Schmid P, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Winer EP, Kockx MM, Peeters D, Chui SY, Lin JC, Duc AN, Viale G, Molinero L, Emens LA (2021a) PD-L1 immunohistochemistry assay comparison in atezolizumab plus nab-paclitaxel-treated advanced triple-negative breast cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djab108

    Article  PubMed  PubMed Central  Google Scholar 

  • Rugo HS, Im SA, Cardoso F, Cortes J, Curigliano G, Musolino A, Pegram MD, Wright GS, Saura C, Escriva-De-Romani S, De Laurentiis M, Levy C, Brown-Glaberman U, Ferrero JM, De Boer M, Kim SB, Petrakova K, Yardley DA, Freedman O, Jakobsen EH, Kaufman B, Yerushalmi R, Fasching PA, Nordstrom JL, Bonvini E, Koenig S, Edlich S, Hong S, Rock EP, Gradishar WJ, and Group SS (2021b) Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol 7:573–584. https://doi.org/10.1001/jamaoncol.2020.7932

    Article  Google Scholar 

  • Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, De Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S (2015a) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol 1:448–454. https://doi.org/10.1001/jamaoncol.2015.0830

    Article  PubMed  PubMed Central  Google Scholar 

  • Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van Den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S, and International TWG (2015b) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271. https://doi.org/10.1093/annonc/mdu450

    Article  Google Scholar 

  • Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, Investigators IMT (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108–2121. https://doi.org/10.1056/NEJMoa1809615

    Article  PubMed  CAS  Google Scholar 

  • Schmid P, Cortes J, Pusztai L, Mcarthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O’shaughnessy J, Investigators K (2020a) Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810–821. https://doi.org/10.1056/NEJMoa1910549

    Article  PubMed  CAS  Google Scholar 

  • Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Henschel V, Molinero L, Chui SY, Maiya V, Husain A, Winer EP, Loi S, Emens LA, Investigators IM (2020b) Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:44–59. https://doi.org/10.1016/S1470-2045(19)30689-8

    Article  PubMed  CAS  Google Scholar 

  • Schmid P, Cortes J, Dent R, Pusztai L, Mcarthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O’shaughnessy J, Investigators K (2022) Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556–567. https://doi.org/10.1056/NEJMoa2112651

    Article  PubMed  CAS  Google Scholar 

  • Schoninger SF, Blain SW (2020) The ongoing search for biomarkers of CDK4/6 inhibitor responsiveness in breast cancer. Mol Cancer Ther 19:3–12. https://doi.org/10.1158/1535-7163.MCT-19-0253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, Chin SF, Majewski IJ, Michaut M, Bosma A, Pereira B, Bismeijer T, Wessels L, Caldas C, Bernards R, Simon IM, Glas AM, Linn S, Van ’T Veer L (2017) The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res 19:99. https://doi.org/10.1186/s13058-017-0861-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi W, Jiang T, Nuciforo P, Hatzis C, Holmes E, Harbeck N, Sotiriou C, Pena L, Loi S, Rosa DD, Chia S, Wardley A, Ueno T, Rossari J, Eidtmann H, Armour A, Piccart-Gebhart M, Rimm DL, Baselga J, Pusztai L (2017) Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial. Ann Oncol 28:128–135. https://doi.org/10.1093/annonc/mdw434

    Article  PubMed  CAS  Google Scholar 

  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792. https://doi.org/10.1056/NEJM200103153441101

    Article  PubMed  CAS  Google Scholar 

  • Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De La Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G (2018) Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465–2472. https://doi.org/10.1200/JCO.2018.78.9909

    Article  PubMed  CAS  Google Scholar 

  • Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35:2875–2884. https://doi.org/10.1200/JCO.2017.73.7585

    Article  PubMed  CAS  Google Scholar 

  • Stanton SE, Adams S, Disis ML (2016) Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol 2:1354–1360. https://doi.org/10.1001/jamaoncol.2016.1061

    Article  PubMed  Google Scholar 

  • Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J, and Group CS (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734. https://doi.org/10.1056/NEJMoa1413513

    Article  CAS  Google Scholar 

  • Tang SW, Bilke S, Cao L, Murai J, Sousa FG, Yamade M, Rajapakse V, Varma S, Helman LJ, Khan J, Meltzer PS, Pommier Y (2015) SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug response in ewing sarcoma. Clin Cancer Res 21:4184–4193. https://doi.org/10.1158/1078-0432.CCR-14-2112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES (2011) Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 18:333–345. https://doi.org/10.1530/ERC-10-0262

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Thomas A, Murai J, Pommier Y (2018) The evolving landscape of predictive biomarkers of response to PARP inhibitors. J Clin Invest 128:1727–1730. https://doi.org/10.1172/JCI120388

    Article  PubMed  PubMed Central  Google Scholar 

  • Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, Levy C, Legouffe E, Lortholary A, Pujade-Lauraine E, Bourcier AV, Eymard JC, Spaeth D, Bachelot T (2015) Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol 26:120–125. https://doi.org/10.1093/annonc/mdu497

    Article  PubMed  CAS  Google Scholar 

  • Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, Demeo M, Jenkins C, Domchek S, D’andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE (2020) TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 38:4274–4282. https://doi.org/10.1200/JCO.20.02151

    Article  PubMed  CAS  Google Scholar 

  • Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, De Azambuja E, Fielding A, Balmana J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, Mcconnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, Mcfadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr, Olympi ACTSC, Investigators (2021) Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394–2405. https://doi.org/10.1056/NEJMoa2105215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • U.S. Food and Drug Administration (2018a) FDA approves first treatment for breast cancer with a certain inherited genetic mutation. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-breast-cancer-certain-inherited-genetic-mutation. Accessed 12 Jan 2018a

  • U.S. Food and Drug Administration (2018b) FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer. Accessed 14 Dec 2018b

  • U.S. Food and Drug Administration (2019) FDA approves first PI3K inhibitor for breast cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer. Accessed 24 May 2019

  • U.S. Food and Drug Administration (2022) FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer. Accessed 5 Aug 2022

  • Varga Z, Sinn P, Seidman AD (2019) Summary of head-to-head comparisons of patient risk classifications by the 21-gene Recurrence Score(R) (RS) assay and other genomic assays for early breast cancer. Int J Cancer 145:882–893. https://doi.org/10.1002/ijc.32139

    Article  PubMed  CAS  Google Scholar 

  • Veeraraghavan J, De Angelis C, Mao R, Wang T, Herrera S, Pavlick AC, Contreras A, Nuciforo P, Mayer IA, Forero A, Nanda R, Goetz MP, Chang JC, Wolff AC, Krop IE, SaW F, Prat A, Hilsenbeck SG, Weigelt B, Reis-Filho JS, Gutierrez C, Osborne CK, Rimawi MF, Schiff R (2019) A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Ann Oncol 30:927–933. https://doi.org/10.1093/annonc/mdz076

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Venkitaraman AR (2014) Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 343:1470–1475. https://doi.org/10.1126/science.1252230

    Article  PubMed  CAS  Google Scholar 

  • Von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, Digiovanna MP, Fasching PA, Crown JP, Wulfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr, Investigators K (2019) Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 380:617–628. https://doi.org/10.1056/NEJMoa1814017

    Article  Google Scholar 

  • Wahby S, Fashoyin-Aje L, Osgood CL, Cheng J, Fiero MH, Zhang L, Tang S, Hamed SS, Song P, Charlab R, Dorff SE, Ricks TK, Barnett-Ringgold K, Dinin J, Goldberg KB, Theoret MR, Pazdur R, Amiri-Kordestani L, Beaver JA (2021) FDA approval summary: accelerated approval of sacituzumab govitecan-hziy for third-line treatment of metastatic triple-negative breast cancer. Clin Cancer Res 27:1850–1854. https://doi.org/10.1158/1078-0432.CCR-20-3119

    Article  PubMed  CAS  Google Scholar 

  • Witkiewicz AK, Cox D, Knudsen ES (2014) CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 5:261–272. https://doi.org/10.18632/genesandcancer.24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wolf DM, Yau C, Sanil A, Glas A, Petricoin E, Wulfkuhle J, Severson TM, Linn S, Brown-Swigart L, Hirst G, Buxton M, Demichele A, Hylton N, Symmans F, Yee D, Paoloni M, Esserman L, Berry D, Rugo H, Olopade O, Van ’T Veer L (2017) DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial. NPJ Breast Cancer 3:31. https://doi.org/10.1038/s41523-017-0025-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wolff AC, Hammond ME, Hicks DG, Dowsett M, Mcshane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF, American Society of Clinical O, and College of American P (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 31:3997–4013. https://doi.org/10.1200/JCO.2013.50.9984

    Article  Google Scholar 

  • Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, Mcshane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36:2105–2122. https://doi.org/10.1200/JCO.2018.77.8738

    Article  PubMed  CAS  Google Scholar 

  • Yan F, Jiang Q, He M, Shen P (2021) PARP inhibitor treatment of advanced breast cancer beyond the BRCA-mutated type: a meta-analysis. Future Oncol 17:2381–2393. https://doi.org/10.2217/fon-2020-1175

    Article  PubMed  CAS  Google Scholar 

  • Yarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377:2500–2501. https://doi.org/10.1056/NEJMc1713444

    Article  PubMed  PubMed Central  Google Scholar 

  • Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS (2013) Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30:870–884. https://doi.org/10.1007/s12325-013-0060-1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, Abdullah SE, Higgs BW, Dennis PA, Van Der Heijden MS, Segal NH, Chaft JE, Hembrough T, Barrett JC, Hellmann MD (2020) Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Discov 10:1842–1853. https://doi.org/10.1158/2159-8290.CD-20-0047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean government (MSIT) (NRF-2020R1A5A2017323 and NRF-2022R1A2C1007293).

Author information

Authors and Affiliations

  1. Vessel-Organ Interaction Research Center, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea

    Mi Jeong Kwon

  2. Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

    Mi Jeong Kwon

Authors
  1. Mi Jeong Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mi Jeong Kwon.

Ethics declarations

Conflict of interest

The author has no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwon, M.J. Predictive biomarkers for molecularly targeted therapies and immunotherapies in breast cancer. Arch. Pharm. Res. 45, 597–617 (2022). https://doi.org/10.1007/s12272-022-01402-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-022-01402-5

Keywords

Search

Navigation