To evaluate and validate the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in breast cancer.
Data sources
A literature search from January 2015 to March 2022 was performed using the key terms breast cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, predictive and/or prognostic biomarkers, and targeted therapies.
Study selection and data extraction
Relevant clinical trials, meta-analyses, seminal articles, and published evidence- and consensus-based clinical practice guidelines in the English language were identified, reviewed and evaluated.
Data synthesis
Breast cancer is a biologically heterogeneous disease, leading to wide variability in treatment responses and survival outcomes. Biomarkers for breast cancer are evolving from traditional biomarkers in immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor type 2 (HER2) to genetic biomarkers with therapeutic implications (e.g. breast cancer susceptibility gene 1/2 [BRCA1/2], estrogen receptor α [ESR1] gene mutation, HER2 gene mutation, microsatellite instability [MSI], phosphatidylinositol 3-kinase catalytic subunit 3Cα [PIK3CA] gene mutation, neurotrophic tyrosine receptor kinase [NTRK] gene mutation). In addition, current data are most robust for biomarkers in immunotherapy (e.g. programmed cell death receptor ligand-1 [PD-L1], microsatellite instability-high [MSI-H] or deficient mismatch repair [dMMR]). Oncotype DX assay remains the best validated gene expression assay that is both predictive and prognostic whereas MammaPrint is prognostic for genomic risk.
Conclusions
Biomarker-driven therapies have the potential to confer greater therapeutic advantages than standard-of-care therapies. The purported survival benefits associated with biomarker-driven therapies should be weighed against their potential harms.
ChungCChristiansonM. Predictive and prognostic biomarkers with therapeutic targets in breast, colorectal, and non-small cell lung cancers: a systemic review of current development, evidence, and recommendation. J Oncol Pharm Pract2014; 20: 11–28.
3.
MasudaSNittaHKellyBD, et al.Intratumoral estrogen receptor heterogeneity of expression in human epidermal growth factor receptor 2-positive breast cancer as evaluated by a brightfield multiplex assay. J Histochem Cytochem2019; 67: 563–574.
4.
JosephCPapadakiAAlthobitiM, et al.Breast cancer intratumour heterogeneity: current status and clinical implications. Histopathology2018; 73: 717–731.
5.
HammondMEHayesDFDowsettM, 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 Med2010; 134: 907–922.
6.
YiMHuoLKoenigKB, et al.Which threshold for ER positivity? A retrospective study based on 9639 patients. Ann Oncol2014; 25: 1004–1011.
7.
OsborneCKYochmowitzMGKnightWA3rd, et al.The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer1980; 46: 2884–2888.
8.
WalkerRAJonesJLChappellS, et al.Molecular pathology of breast cancer and its application to clinical management. Cancer Metastasis Rev1997; 16: 5–27.
9.
AllredDCHarveyJMBerardoM, et al.Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol1998; 11: 155–168.
10.
HarveyJMClarkGMOsborneCK, et al.Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol1999; 17: 1474–1481.
11.
MoscettiL. Are all patients truly hormone receptor negative?J Clin Oncol2017; 35: 1627.
12.
ReganMMPaganiOFrancisPA, et al.Predictive value and clinical utility of centrally assessed ER, PgR, and ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials. Breast Cancer Res Treat.2015; 154: 275–286.
13.
PrabhuJSKorlimarlaADesaiK, et al.A Majority of low (1-10%) ER positive breast cancers behave like hormone receptor negative tumors. J Cancer2014; 5: 156–165.
14.
AllisonKHHammondMEHDowsettM, et al.Estrogen and progesterone receptor testing in breast cancer: american society of clinical oncology/college of American pathologists guideline update. Arch Pathol Lab Med2020; 144: 545–563.
15.
HeldringNPikeAAnderssonS, et al.Estrogen receptors: how do they signal and what are their targets. Physiol Rev2007; 87: 905–931.
16.
KimCTangGPogue-GeileKL, et al.Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol2011; 29: 4160–4167.
17.
PujolPDauresJPThezenasS, et al.Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause. Cancer1998; 83: 698–705.
18.
SoderqvistGvon SchoultzBSkoogTE. Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol1993; 168: 874–879.
19.
AlimontiAFerrettiGCognettiF. Can the reliance of hormone receptor assays of surgical specimens be explained by the fluctuation of estrogen receptor, progesterone receptor, and HER-2 protein expression in tumor samples of premenopausal breast cancer patients?J Clin Oncol2005; 23: 8918.
20.
BardouVJArpinoGElledgeRM, et al.Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol2003; 21: 1973–1979.
21.
DeSombreERSmithSBlockGE, et al.Prediction of breast cancer response to endocrine therapy. Cancer Chemother Rep1974; 58: 513–519.
22.
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. Lancet2005; 365: 1687–1717.
23.
ReganMMPaganiOFlemingGF, et al.Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials. Breast2013; 22: 1094–1100.
24.
TurnerNCSlamonDJRoJ, et al.Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med2018; 379: 1926–1936.
25.
SledgeGWJrToiMNevenP, et al.Abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol2017; 35: 2875–2884.
26.
RoyceMOsgoodCMulkeyF, et al.FDA Approval summary: abemaciclib with endocrine therapy for high-risk early breast cancer. J Clin Oncol2022; JCO2102742.
27.
SlamonDJNevenPChiaS, et al.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 Oncol2018; 36: 2465–2472.
28.
SlamonDJNevenPChiaS, et al.Overall Survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med2020; 382: 514–524.
29.
KreidiehFSadekRFZhangLF, et al.Validity of 1% hormonal receptor positivity cutoff by the ASCO/college of American pathologists guidelines at the Georgia cancer center. JCO Precis Oncol2022; 6: e2100201.
30.
BenefieldHCAllottEHReeder-HayesKE, et al.Borderline estrogen receptor-positive breast cancers in black and white women. J Natl Cancer Inst2020; 112: 728–736.
31.
VillegasSLNekljudovaVPfarrN, et al.Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors - an analysis of 2765 patients from neoadjuvant clinical trials. Eur J Cancer2021; 148: 159–170.
32.
ChenTZhangNMoranMS, et al.Borderline ER-positive primary breast cancer gains no significant survival benefit from endocrine therapy: a systematic review and meta-analysis. Clin Breast Cancer2018; 18: 1–8.
33.
CaiYWShaoZMYuKD. De-escalation of five-year adjuvant endocrine therapy in patients with estrogen receptor-low positive (immunohistochemistry staining 1%-10%) breast cancer: propensity-matched analysis from a prospectively maintained cohort. Cancer2022; Feb 25. [Epub ahead of print].
34.
García-BecerraRSantosNDíaz, et al.Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci2013; 14: 108–145.
35.
OsborneCKBardouVHoppTA, et al.Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst2003; 95: 353–361.
36.
OsborneCKSchiffR. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med2011; 62: 233–247.
37.
EllmannSStichtHThielF, et al.Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell Mol Life Sci2009; 66: 2405–2426.
38.
JeselsohnRYelenskyRBuchwalterG, et al.Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res2014; 20: 1757–1767.
39.
SchiavonGHrebienSGarcia-MurillasI, et al.Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med2015; 7: 313ra182.
40.
HerzogSKFuquaSAW. ESR1 Mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges. Br J Cancer2022; 126: 174–186.
41.
BidardFCHardy-BessardACBachelotT, et al.Fulvestrant-palbociclib vs continuing AI-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2-metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS3-05. Presented December 9, 2021.
42.
BardiaAKaklamaniVWilksS, et al.Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2–negative advanced breast cancer. J Clin Oncol2021; 39: 1360–1370.
43.
SiehWKöbelMLongacreTA, et al.Hormone-receptor expression and ovarian cancer survival: an ovarian tumor tissue analysis consortium study. Lancet Oncol2013; 14: 853–862.
CardosoFKyriakidesSOhnoS, et al.Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol2019; 30: 1194–1220.
46.
GennariAAndréFBarriosCH, et al.ESMO Clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol2021; 32: 1475–1495.
47.
BursteinHJSomerfieldMRBartonDL, et al.Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol2021; 39: 3959–3977.
48.
MoyBRumbleRBComeSE, et al.Chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative: ASCO guideline update. J Clin Oncol2021; 39: 3938–3958.
49.
AndreFIsmailaNAllisonKH, et al.Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update. J Clin Oncol2022; JCO2200069.
50.
RavdinPMGreenSDorrTM, et al.Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: results of a prospective southwest oncology group study. J Clin Oncol1992; 10: 1284–1291.
51.
AlbertJMGonzalez-AnguloAMGurayM, et al.Patients with only 1 positive hormone receptor have increased locoregional recurrence compared with patients with estrogen receptor-positive progesterone receptor-positive disease in very early stage breast cancer. Cancer2011; 117: 1595–1601.
52.
PratACheangMCMartínM, et al.Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol2013; 31: 203–209.
53.
DaviesCGodwinJGrayR, et al.Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet2011; 378: 771–784.
54.
FoleyNMCollJMLoweryAJ, et al.Re-appraisal of estrogen receptor negative/progesterone receptor positive (ER−/PR+) breast cancer phenotype: true subtype or technical artefact?Pathol Oncol Res2018; 24: 881–884.
55.
SparanoJAGrayRJMakowerDF, et al.Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med2018; 379: 111–121.
56.
CardosoFvan’t VeerLJBogaertsJ, et al.70-gene Signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med2016; 375: 717–729.
57.
KropIIsmailaNAndreF, et al.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 focused update. J Clin Oncol2017; 35: 2838–2847.
58.
PaikSShakSTangG, et al.A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med2004; 351: 2817–2826.
59.
TangGShakSPaikS, et al.Comparison of the prognostic and predictive utilities of the 21-gene recurrence score assay and adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat2011; 127: 133–142.
60.
PaikSTangGShakS, et al.Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol2006; 24: 3726–3734.
61.
KalinskyKBarlowWEGralowJR, et al.21-gene Assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med2021; 385: 2336–2347.
62.
GaoJJSwainSM. Luminal A breast cancer and molecular assays: a review. Oncologist2018; 23: 556–565.
63.
TeschMESpeersCDioceeRM, et al.Impact of TAILORx on chemotherapy prescribing and 21-gene recurrence score-guided treatment costs in a population-based cohort of patients with breast cancer. Cancer2022; 128: 665–674.
64.
McVeighTPKerinMJ. Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer. Breast Cancer(Dove Med Press)2017; 29: 393–400.
65.
CortazarPZhangLUntchM, et al.Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet2014; 384: 164–172.
66.
KaufmannMvon MinckwitzGSmithR, et al.International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations. J Clin Oncol2003; 21: 2600–2608.
67.
VilaJMittendorfEAFaranteG, et al.Nomograms for predicting axillary response to neoadjuvant chemotherapy in clinically node-positive patients with breast cancer. Ann Surg Oncol2016; 23: 3501–3509.
68.
Morales MurilloSGasol CudosAVeas RodriguezJ, et al.Selection of neoadjuvant treatment based on the 21-gene test results in luminal breast cancer. Breast2021; 56: 35–41.
69.
PeaseAMRibaLAGrunerRA, et al.Oncotype DX® Recurrence score as a predictor of response to neoadjuvant chemotherapy. Ann Surg Oncol2019; 26: 366–371.
70.
BearHDWanWRobidouxA, et al.Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: a multicenter trial. J Surg Oncol2017; 115: 917–923.
71.
NamGSinghKLoprestiML, et al.How does invasive breast cancer oncotype Dx recurrence score on core needle biopsies influence neoadjuvant treatment decision? A descriptive study. Technol Cancer Res Treat2021; 20: 15330338211035037.
72.
PratAPinedaEAdamoB, et al.Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast2015; 24: S26–S35.
73.
GoldhirschAWinerEPCoatesAS, et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol2013; 24: 2206–2223.
74.
CoatesASWinerEPGoldhirschA, et al.Tailoring therapies--improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol2015; 26: 1533–1546.
75.
LehmannBDBauerJAChenX, et al.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest2011; 121: 2750–2767.
76.
ZhaoSMaDXiaoY, et al.Molecular subtyping of triple-negative breast cancers by immunohistochemistry: molecular basis and clinical relevance. Oncologist2020; 25: e1481–e1491.
77.
GerratanaLBasileDBuonoG, et al.Androgen receptor in triple negative breast cancer: a potential target for the targetless subtype. Cancer Treat Rev2018; 68: 102–110.
78.
RavdinPMSiminoffLADavisGJ, et al.Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol2001; 19: 980–991.
79.
PiccartMvan ‘t VeerLJPoncetC, et al.70–gene Signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol2021; 22: 476–488.
80.
LiCIUribeDJDalingJR. Clinical characteristics of different histologic types of breast cancer. Br J Cancer2005; 93: 1046–1105.
81.
JenkinsJAMarmorSHuiJYC, et al.The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer. Breast Cancer Res Treat2022; 191: 401–407.
82.
HynesNEMacDonaldG. Erbb receptors and signaling pathways in cancer. Curr Opin Cell Biol2009; 21: 177–184.
83.
WolffACHammondMEHAllisonKH, 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 Med2018; 142: 1364–1382.
84.
von MinckwitzGProcterMde AzambujaE, et al.Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med2017; 377: 122–131.
85.
SlamonDEiermannWRobertN, et al.Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med2011; 365: 1273–1283.
86.
RomondEHPerezEABryantJ, et al.Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med2005; 353: 1673–1684.
87.
SchneeweissAChiaSHickishT, et al.Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol2013; 24: 2278–2284.
88.
MadarnasYTrudeauMFranekJA, et al.Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu overexpressing breast cancer: a systematic review. Cancer Treat Rev2008; 34: 539–557.
89.
ChanADelalogeSHolmesFA, et al.Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol2016; 17: 367–377.
90.
MartinMHolmesFAEjlertsenB, et al.Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol2017; 18: 1688–1700.
91.
von MinckwitzGHuangCSManoMS, et al.Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med2019; 380: 617–628.
92.
BaselgaJCortésJKimSB, et al.Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med2012; 366: 109–119.
93.
PerezEASumanVJRowlandKM, et al.Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer2005; 6: 425–432.
94.
KaufmanBMackeyJRClemensMR, et al.Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol2009; 27: 5529–5537.
95.
VermaSMilesDGianniL, et al.Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med2012; 367: 1783–1791.
96.
ModiSSauraCYamashitaT, et al.Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med2020; 382: 610–621.
97.
RugoHSImSACardosoF, et al.Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol2021; 7: 573–584.
98.
GeyerCEForsterJLindquistD, et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med2006; 355: 2733–2743.
99.
MurthyRKLoiSOkinesA, et al.Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med2020; 382: 597–609.
100.
BallardMJalikisFKringsG, et al.‘Non-classical’ HER2 FISH results in breast cancer: a multi-institutional study. Mod Pathol2017; 30: 227–235.
101.
LinLSirohiDColemanJF, et al.American Society of clinical oncology/college of American pathologists 2018 focused update of breast cancer HER2 FISH testing guidelines results from a national reference laboratory. Am J Clin Pathol2019; 152: 479–485.
102.
SorscherS. Clinical consequences of altering the definition of HER2-positive breast cancer to exclude group 2, HER2–negative disease. J Natl Compr Canc Netw2021; 19: xxii.
103.
IsolaJTannerMForsythA, et al.Interlaboratory comparison of HER-2 oncogene amplification as detected by chromogenic and fluorescence in situ hybridization. Clin Cancer Res2004; 10: 4793–4798.
104.
MarchiòCLambrosMBGugliottaP, et al.Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray-based CGH analysis. J Pathol2009; 219: 16–24.
105.
GriffinBBPincusJLSiziopikouKP, et al.Double-equivocal HER2 invasive breast carcinomas: institutional experience and review of literature. Arch Pathol Lab Med2018; 142: 1511–1516.
106.
SchalperKAKumarSHuiP, et al.A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American society of clinical oncology/college of American pathologists criteria. Arch Pathol Lab Med2014; 138: 213–219.
107.
SchettiniFChicNBrasó-MaristanyF, et al.Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer2021; 7: 1.
108.
RossiVSarottoIMaggiorottoF, et al.Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist2012; 17: 1418–1425.
109.
BanerjiUvan HerpenCMLSauraC, et al.Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol2019; 20: 1124–1135.
110.
van der LeeMMGroothuisPG, et al.The preclinical profile of the duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. Mol Cancer Ther2015; 14: 692–703.
111.
TarantinoPHamiltonETolaneySM. HER2-low Breast cancer: pathological and clinical landscape. J Clin Oncol2020; 38: 1951–1962.
112.
FehrenbacherLCecchiniRSGeyerCEJr, et al.NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2. J Clin Oncol2020; 38: 444–453.
113.
DoiTShitaraKNaitoY, et al.Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol2017; 18: 1512–1522.
114.
FernandezAILiuMBellizziA, et al.Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol2022: e217239.
PetrelliFTomaselloGBarniS, et al.Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature. Breast Cancer Res Treat2017; 166: 339–349.
117.
ConnellCMDohertyGJ. Activating HER2 mutations as emerging targets in multiple solid cancers. ESMO Open2017; 2: e000279.
118.
BoseRKavuriSMSearlemanAC, et al.Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov2013; 3: 224–237.
119.
ChristgenMBartelsSLuftA, et al.Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer. Virchows Arch2018; 473: 577–582.
120.
VernieriCMilanoMBrambillaM, et al.Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: current knowledge, new research directions and therapeutic perspectives. Crit Rev Oncol Hematol2019; 139: 53–66.
121.
DeyNWilliamsCLeyland-JonesB, et al.A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. Am J Transl Res2015; 7: 733–750.
122.
GoncalvesMDHopkinsBDCantleyLC. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N Engl J Med2018; 379: 2052–2062.
123.
SantarpiaLBottaiGKellyCM, et al.Deciphering and targeting oncogenic mutations and pathways in breast cancer. Oncologist2016; 21: 1063–1078.
124.
ChangDYMaWLLuYS. Role of Alpelisib in the treatment of PIK3CA-mutated breast cancer: patient selection and clinical perspectives. Ther Clin Risk Manag2021; 17: 193–207.
125.
MoseleFStefanovskaBLusqueA, et al.Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol2020; 31: 377–386.
126.
SobhaniNRovielloGCoronaSP, et al.The prognostic value of PI3K mutational status in breast cancer: a meta-analysis. J Cell Biochem2018; 119: 4287–4292.
127.
AndréFCiruelosERubovszkyG, et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med2019; 380: 1929–1940.
128.
NandaRChowLQDeesEC, et al.Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol2016; 34: 2460–2467.
129.
LoiSDrubayDAdamsS, et al.Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol2019; 37: 559–569.
130.
MittendorfEAPhilipsAVMeric-BernstamF, et al.PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res2014; 2: 361–370.
131.
LuenSVirassamyBSavasP, et al.The genomic landscape of breast cancer and its interaction with host immunity. Breast2016; 29: 241–250.
132.
MatikasAZerdesILövrotJ, et al.Prognostic implications of PD-L1 expression in breast cancer: systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data. Clin Cancer Res2019; 25: 5717–5726.
133.
SchmidPRugoHSAdamsS, 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 Oncol2020; 21: 44–59.
134.
YardleyDA. nab-Paclitaxel mechanisms of action and delivery. J Control Release2013; 170: 365–372.
135.
MilesDGligorovJAndréF, et al.Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol2021; 32: 994–1004.
136.
CortesJCesconDWRugoHS, et al.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. Lancet2020; 396: 1817–1828.
137.
SchmidPAdamsSRugoHS, et al.Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med2018; 379: 2108–2121.
138.
DirixLYTakacsIJerusalemG, 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 Treat2018; 167: 671–686.
139.
EmensLACruzCEderJP, 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 Oncol2019; 5: 74–82.
140.
WinerEPLipatovOImSA, et al.Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol2021; 22: 499–511.
141.
HuangXDingQGuoH, et al.Comparison of three FDA-approved diagnostic immunohistochemistry assays of PD-L1 in triple-negative breast carcinoma. Hum Pathol2021; 108: 42–50.
142.
ChaYJKimDBaeSJ, et al.PD-L1 expression evaluated by 22C3 antibody is a better prognostic marker than SP142/SP263 antibodies in breast cancer patients after resection. Sci Rep2021; 11: 19555.
143.
LoiblSUntchMBurchardiN, et al.A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol2019; 30: 1279–1288.
144.
MittendorfEAZhangHBarriosCH, et al.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. Lancet2020; 396: 1090–1100.
145.
SchmidPCortesJPusztaiL, et al.Pembrolizumab for early triple-negative breast cancer. N Engl J Med2020; 382: 810–821. (522).
146.
KeenanTETolaneySM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw2020 Apr; 18: 479–489.
147.
VidulaNEllisenLWBardiaA. Novel agents for metastatic triple-negative breast cancer: finding the positive in the negative. J Natl Compr Canc Netw2020 Oct 15: 1–9.
148.
GalskyMDSaciASzaboPM, et al.Nivolumab in patients with advanced platinum-resistant urothelial carcinoma: efficacy, safety, and biomarker analyses with extended follow-up from CheckMate 275. Clin Cancer Res2020; 26: 5120–5128.
149.
AyersMLuncefordJNebozhynM, et al.IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest2017; 127: 2930–2940.
150.
HendrySSalgadoRGevaertT, et al.Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the international immunooncology biomarkers working group: part 1: assessing the host immune response, TILs in invasive breast carcinoma and ductal carcinoma in situ, metastatic tumor deposits and areas for further research. Adv Anat Pathol2017; 24: 235–251.
151.
WenYHBrogiEZengZ, et al.DNA Mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors. Am J Surg Pathol2012; 36: 1700–1708.
152.
DudleyJCLinMTLeDT, et al.Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res2016; 22: 813–820.
153.
SalemMEPucciniAGrotheyA, et al.Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res2018; 16: 805–812.
154.
HorimotoYThinzar HlaingM, et al.Microsatellite instability and mismatch repair protein expressions in lymphocyte-predominant breast cancer. Cancer Sci2020; 111: 2647–2654.
155.
RenXYSongYWangJ, et al.Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients. Front Oncol2021; 11: 570623.
156.
FuscoNLopezGCortiC, et al.Mismatch repair protein loss as a prognostic and predictive biomarker in breast cancers regardless of microsatellite instability. JNCI Cancer Spectr2018; 2: pky056.
157.
ChumsriSSokolESSoyano-MullerAE, et al.Durable complete response with immune checkpoint Iihibitor in breast cancer with high tumor mutational burden and APOBEC signature. J Natl Compr Canc Netw2020; 18: 517–521.
158.
GradisharWJAndersonBOAbrahamJ, et al.Breast cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw2020; 18: 452–478.
159.
BertonDBanerjeeSCuriglianoG, et al.Antitumor activity of dostarlimab in patients with mismatch repair-deficient (dMMR) tumors: a combined analysis of 2 cohorts in the GARNET study. Presented at American Society for Clinical Oncology Virtual Meeting. June 4-8, 2021. [Abstract 2564].
160.
ChalmersZRConnellyCFFabrizioD, et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med2017; 9: 34.
161.
Barroso-SousaRJainECohenO, et al.Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann Oncol2020; 31: 387–394.
162.
MarcusLLemerySJKeeganP, et al.FDA Approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res2019; 25: 3753–3758.
MarabelleALeDTAsciertoPA, et al.Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer results from the phase II KEYNOTE-158 study. J Clin Oncol2020; 38: 1–10.
165.
RoyRChunJPowellSN. BRCA1 And BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer2011; 12: 68–78.
166.
TuttAAshworthA. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med2002; 8: 571–576.
167.
MaloneKEDalingJRDoodyDR, et al.Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res2006; 66: 8297–8308.
168.
KurianAWGongGDJohnEM, et al.Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the northern California breast cancer family registry. Cancer Epidemiol Biomarkers Prev2009; 18: 1084–1091.
169.
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet. 1997; 349: 1505–10.
170.
KimEKParkSYKimSW. Clinicopathological characteristics of BRCA-associated breast cancer in Asian patients. J Pathol Transl Med2020; 54: 265–275.
171.
BarettaZMocellinSGoldinE, et al.Effect of BRCA germline mutations on breast cancer prognosis: a systematic review and meta-analysis. Medicine (Baltimore)2016 Oct; 95: e4975.
172.
RobsonMImSASenkusE, et al.Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med2017; 377: 523–533.
173.
LittonJKRugoHSEttlJ, et al.Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med2018; 379: 753–763.
174.
TuttANJGarberJEKaufmanB, et al.Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med2021; 384: 2394–2405.
175.
TuttAToveyHCheangMCU, et al.Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med2018; 24: 628–637.
176.
VaishnaviALeATDoebeleRC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov2015; 5: 25–34.
177.
TognonCKnezevichSRHuntsmanD, et al.Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell2002; 2: 367–376.
178.
RossJSChungJElvinJE, et al.NTRK fusions in breast cancer: Clinical, pathologic and genomic findings [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res. 2018; 78:Abstract nr P2-09-15.
179.
CunananKMGonenMShenR, et al.Basket trials in oncology: a trade-off between complexity and efficiency. J Clin Oncol2017; 35: 271–273.
DrilonALaetschTWKummarS, et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med2018; 378: 731–739.
182.
RolfoCDDe BraudFGRobert Charles DoebeleRC, et al.Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: an updated integrated analysis. J Clin Oncol2020; 38: 3605–3605.
183.
SantiIVellekoopSHuygensM, et al.Prognostic value of the NTRK fusion biomarker in the Netherlands. Ann Oncol2021; 32: S382–S406.
