Triple negative breast cancer – Understanding the clinical implications of heterogeneity

Main Article Content

Gelmon Karen LeVasseur N

Abstract

Triple negative breast cancers (TNBC) have long been associated with a worse prognosis in contrast to hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) positive breast tumours. However, advances in the classification and molecular categorization of TNBC have led to meaningful advances, highlighting substantial TNBC heterogeneity and distinct histomolecular subtypes. While TNBC has historically been treated with single or combined chemotherapeutic agents, novel targeted therapies are being developed and evaluated. A better understanding of oncogenic drivers and the pathogenicity of germline and somatic mutations has also paved the way to new targeted treatments. More recently, the neoadjuvant space has become increasingly popular to better understand the behaviour of TNBC subtypes, leading to the development of biomarker-driven trials to better select targeted treatments. This has ultimately led to a number of advances and new potential targets for treatment which remain under investigation and will undoubtedly lead to a better understanding and personalized approach for patients diagnosed with TNBC.

Article Details

How to Cite
KAREN, Gelmon; N, LeVasseur. Triple negative breast cancer – Understanding the clinical implications of heterogeneity. Medical Research Archives, [S.l.], v. 8, n. 3, mar. 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2037>. Date accessed: 24 apr. 2024. doi: https://doi.org/10.18103/mra.v8i3.2037.
Section
Articles

References

(1) Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011 Jul;121(7):2750-2767.
(2) Cossetti RJ, Tyldesley SK, Speers CH, Zheng Y, Gelmon KA. Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008. J Clin Oncol 2015 Jan 1;33(1):65-73.
(3) Anderson WF, Chen BE, Jatoi I, Rosenberg PS. Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer. Breast Cancer Res Treat 2006 Nov;100(1):121-126.
(4) Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007 Aug 1;13(15 Pt 1):4429-4434.
(5) Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, et al. Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat 2012 Apr;132(2):523-535.
(6) Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 2008 Nov 15;113(10):2638-2645.
(7) Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 2010 Jun; 134(6):907-922.
(8) Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 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 2013 Nov 1; 31(31):3997-4013.
(9) Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 2018 Nov; 142(11):1364-1382.
(10) Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 1998 May 16; 351(9114):1451-1467.
(11) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005 May 14-20; 365(9472):1687-1717.
(12) Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007 Apr 15;13(8):2329-2334.
(13) Prat A, Fan C, Fernandez A, Hoadley KA, Martinello R, Vidal M, et al. Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med 2015 Dec 18; 13:303-015-0540-z.
(14) Colleoni M, Cole BF, Viale G, Regan MM, Price KN, Maiorano E, et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Clin Oncol 2010 Jun 20;28(18):2966-2973.
(15) Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000 Aug 17; 406(6797):747-752.
(16) Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009 May 20; 101(10):736-750.
(17) Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999 May; 17(5):1474-1481.
(18) Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Unabridged Version). Archives of Pathology & Laboratory Medicine 2010; 134(7):e48-e72.
(19) McCullough AE, Dell'orto P, Reinholz MM, Gelber RD, Dueck AC, Russo L, et al. Central pathology laboratory review of HER2 and ER in early breast cancer: an ALTTO trial [BIG 2-06/NCCTG N063D (Alliance)] ring study. Breast Cancer Res Treat 2014 Feb; 143(3):485-492.
(20) Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001 Sep 11; 98(19):10869-10874.
(21) Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003 Jul 8; 100(14):8418-8423.
(22) Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 2009 Dec 24; 462(7276):1005-1010.
(23) Russnes HG, Navin N, Hicks J, Borresen-Dale AL. Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 2011 Oct; 121(10):3810-3818.
(24) Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist 2011; 16 Suppl 1:61-70.
(25) Gelmon K, Dent R, Mackey JR, Laing K, McLeod D, Verma S. Targeting triple-negative breast cancer: optimising therapeutic outcomes. Ann Oncol 2012 Sep; 23(9):2223-2234.
(26) Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 2016 Jun 16; 11(6):e0157368.
(27) Triple negative breast cancer: Biology and heterogeneity. . 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016 .
(28) Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012 Oct 4; 490(7418):61-70.
(29) Garrido-Castro AC, Lin NU, Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov 2019 Feb; 9(2):176-198.
(30) Chan JJ, Tan TJY, Dent RA. Are There Any Clinically Relevant Subgroups of Triple-Negative Breast Cancer in 2018? J Oncol Pract 2018 May; 14(5):281-289.
(31) Picornell AC, Echavarria I, Alvarez E, Lopez-Tarruella S, Jerez Y, Hoadley K, et al. Breast cancer PAM50 signature: correlation and concordance between RNA-Seq and digital multiplexed gene expression technologies in a triple negative breast cancer series. BMC Genomics 2019 Jun 3; 20(1):452-019-5849-0.
(32) Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014 Jul 12; 384(9938):164-172.
(33) Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008 Feb 10; 26(5):778-785.
(34) von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012 May 20; 30(15):1796-1804.
(35) Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017 Jun 1; 376(22):2147-2159.
(36) Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol 2017 Apr 1; 35(10):1049-1060.
(37) Hatzis C, Symmans WF, Zhang Y, Gould RE, Moulder SL, Hunt KK, et al. Relationship between Complete Pathologic Response to Neoadjuvant Chemotherapy and Survival in Triple-Negative Breast Cancer. Clin Cancer Res 2016 Jan 1; 22(1):26-33.
(38) Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res 2013 Oct 1; 19(19):5533-5540.
(39) Santonja A, Sanchez-Munoz A, Lluch A, Chica-Parrado MR, Albanell J, Chacon JI, et al. Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy. Oncotarget 2018 May 29; 9(41):26406-26416.
(40) Levasseur N, Clemons M, Hilton J, Addison C, Robertson S, Ibrahim M, et al. Neoadjuvant endocrine therapy and window of opportunity trials: new standards in the treatment of breast cancer? Minerva Chir 2015 Jun; 70(3):181-193.
(41) von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 2014 Jun; 15(7):747-756.
(42) Loibl S, Weber KE, Timms KM, Elkin EP, Hahnen E, Fasching PA, et al. Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto. Ann Oncol 2018 Dec 1; 29(12):2341-2347.
(43) Echavarria I, Lopez-Tarruella S, Picornell A, Garcia-Saenz JA, Jerez Y, Hoadley K, et al. Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification. Clin Cancer Res 2018 Apr 15; 24(8):1845-1852.
(44) Prado-Vazquez G, Gamez-Pozo A, Trilla-Fuertes L, Arevalillo JM, Zapater-Moros A, Ferrer-Gomez M, et al. A novel approach to triple-negative breast cancer molecular classification reveals a luminal immune-positive subgroup with good prognoses. Sci Rep 2019 Feb 7;9(1):1538-018-38364-y.
(45) Zapater-Moros A, Gamez-Pozo A, Prado-Vazquez G, Trilla-Fuertes L, Arevalillo JM, Diaz-Almiron M, et al. Probabilistic graphical models relate immune status with response to neoadjuvant chemotherapy in breast cancer. Oncotarget 2018 Jun 12; 9(45):27586-27594.
(46) Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 2012 Apr 4; 486(7403):395-399.
(47) Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 2016 Nov; 13(11):674-690.
(48) den Brok WD, Gelmon KA. Targeting triple-negative breast cancer: optimizing therapeutic outcomes – UPDATE. Medical Research Archives 2016; 4(6).
(49) Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011 Mar 1; 17(5):1082-1089.
(50) Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer 2012 Jun 1; 118(11):2787-2795.
(51) Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015 Feb 1; 33(4):304-311.
(52) Grindedal EM, Heramb C, Karsrud I, Ariansen SL, Maehle L, Undlien DE, et al. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC Cancer 2017 Jun 21; 17(1):438-017-3422-2.
(53) Zhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. Clin Cancer Res 2017 Dec 15;23(24):7521-7530.
(54) Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012 Jul 20; 30(21):2615-2623.
(55) Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 2018 May; 24(5):628-637.
(56) Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010 Jul 24;376(9737):235-244.
(57) Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017 Aug 10; 377(6):523-533.
(58) Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, et al. Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant. J Clin Oncol 2019 Aug 28:JCO1901304.
(59) Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004 Oct;4(10):814-819.
(60) Severson TM, Peeters J, Majewski I, Michaut M, Bosma A, Schouten PC, et al. BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential. Mol Oncol 2015 Oct; 9(8):1528-1538.
(61) Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, et al. 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 2017 Aug 25; 19(1):99-017-0861-2.
(62) Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016 Dec 1; 375(22):2154-2164.
(63) Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clin Cancer Res 2016 Aug 1; 22(15):3764-3773.
(64) Buys SS, Sandbach JF, Gammon A, Patel G, Kidd J, Brown KL, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017 May 15; 123(10):1721-1730.
(65) Shimelis H, LaDuca H, Hu C, Hart SN, Na J, Thomas A, et al. Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing. J Natl Cancer Inst 2018 Aug 1; 110(8):855-862.
(66) Santarpia L, Qi Y, Stemke-Hale K, Wang B, Young EJ, Booser DJ, et al. Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. Breast Cancer Res Treat 2012 Jul; 134(1):333-343.
(67) Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, et al. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J Clin Invest 2016 Oct 3; 126(10):3739-3757.
(68) Shi Y, Yang F, Sun Z, Zhang W, Gu J, Guan X. Differential microRNA expression is associated with androgen receptor expression in breast cancer. Mol Med Rep 2017 Jan; 15(1):29-36.
(69) Rodon J, Soria JC, Berger R, Miller WH, Rubin E, Kugel A, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med 2019 May; 25(5):751-758.
(70) Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res 2013 Oct 1; 19(19):5505-5512.
(71) Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, et al. Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer. J Clin Oncol 2018 Mar 20; 36(9):884-890.
(72) Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol 2016 May; 27(5):812-818.
(73) Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 2014 Aug 8; 16(4):406-014-0406-x.
(74) Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, et al. Single-Cell Dynamics Determines Response to CDK4/6 Inhibition in Triple-Negative Breast Cancer. Clin Cancer Res 2017 Sep 15; 23(18):5561-5572.
(75) Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006 Dec 1 ;24(34):5373-5380.
(76) Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014 Sep 20; 32(27):2959-2966.
(77) Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 2013 Mar 1; 31(7):860-867.
(78) Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers. J Clin Oncol 2019 Mar 1;37(7):559-569.
(79) Park JH, Jonas SF, Bataillon G, Criscitiello C, Salgado R, Loi S, et al. Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann Oncol 2019 Dec 1;30(12):1941-1949.
(80) Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, et al. Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study. JAMA Oncol 2019 Jan 1;5(1):74-82.
(81) Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, et al. PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol 2015 Jul; 26(7):1488-1493.
(82) Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol 2016 Jul 20; 34(21):2460-2467.
(83) Adams S, Diamond JR, Hamilton E, Pohlmann PR, Tolaney SM, Chang CW, et al. Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial. JAMA Oncol 2019 Mar 1; 5(3):334-342.
(84) Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat 2018 Feb; 167(3):671-686.
(85) Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. 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 2019 Nov 27.
(86) Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC). Annals of Oncology 2019; 30(suppl_5):v851-v934.
(87) Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; Philadelphia (PA): AACR; Cancer Res 2018; 78(4 Suppl):Abstract nr PD6-13.; 2017.
(88) KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro. ESMO 2019 Congress; September 29, 2019; Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394.; 2019.
(89) Taylor NA, Vick SC, Iglesia MD, Brickey WJ, Midkiff BR, McKinnon KP, et al. Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer. J Clin Invest 2017 Sep 1; 127(9):3472-3483.
(90) Marra A, Viale G, Curigliano G. Recent advances in triple negative breast cancer: the immunotherapy era. BMC Med 2019 May 9; 17(1):90-019-1326-5.
(91) Tray N, Adams S, Esteva FJ. Antibody-drug conjugates in triple negative breast cancer. Future Oncol. 2018 Oct; 14(25):2651-2661.