Genomic assays for lobular breast carcinoma
Background: One of the current challenges in breast cancer is the appropriate treatment of invasive lobular breast cancer (ILC) and defining the high-risk group within ILC. The biological character of ILC typically translates to a good prognosis, however several studies have indicated that the long-term prognosis is worse than for patients diagnosed with the more commonly invasive ductal carcinoma (IDC). Many genomic tests are now available to determine whether those patients are at high-risk (HR) and enable tailored treatment. Unfortunately, most of the studies in which these genomic tests have been evaluated entail retrospective analysis of a prospective trial.
Aim: This review focuses on the validation of the available genomic assays based on trials performed in ILC patients, where in some instances the various subtypes of ILC (classical, pleomorphic, non-classic type) were taken into account.
Results: Using Oncotype DX in retrospective studies, only 1.3% to 8% of ILC tumors were categorized as HR tumors. For MammaPrint, 24% of patients were classified as HR, which was associated with poor outcome. In a recent sub-analysis of the Mindact study comprising 487 ILC patients, 16.2% were high genomic risk. Endopredict, Prosigna Breast Cancer Prognostic Gene Signature Assay, and the Breast Cancer Index have been validated in patients receiving only endocrine treatment.
Conclusion: Although ILC accounts for the second most common breast cancer subtype in women, none of these tests encompass tumor morphology in their algorithms. Prospective studies on ILC with genomic assays are warranted given the various subtypes of and treatment options for this underestimated, but frequently occurring cancer.
Relevance for patients: Genomic assays can be employed in ILC patients to predict the risk of recurrence and identify those patients who might benefit from chemotherapy in addition to their standard treatment regimen.
[1] Li CI, Anderson BO, Daling JR, Moe RE. Trends in Incidence Rates of Invasive Lobular and Ductal Breast Carcinoma. JAMA 2003;289:1421-4.
[2] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin 2019;69:7-34.
[3] Biglia N, Maggiorotto F, Liberale V, Bounous VE, Sgro LG, Pecchio S, et al. Clinical-pathologic Features, Long Termoutcome and Surgical Treatment in a Large Series of Patients with Invasive Lobular Carcinoma (ILC) and Invasive Ductal Carcinoma (IDC). Eur J Surg Oncol 2013;39:455-60.
[4] Rakha EA, Van Deurzen CH, Paish EC, MacMillan RD, Ellis IO, Lee AH. Pleomorphic Lobular Carcinoma of the Breast: Is it a Prognostically Significant Pathological Subtype Independent of Histological Grade? Mod Pathol 2013;26:496-501.
[5] Marmor S, Hui JY, Huang JL, Kizy S, Beckwith H, BlaesAH, et al. Relative Effectiveness of Adjuvant Chemotherapy for Invasive Lobular Compared with Invasive Ductal Carcinoma of the Breast. Cancer 2017;123:3015-21.
[6] Loibl S, Volz C, Mau C, Blohmer JU, Costa SD, Eidtmann H, et al. Response and Prognosis After Neoadjuvant Chemotherapy in 1,051 Patients with Infiltrating Lobular Breast Carcinoma. Breast Cancer Res Treat 2014;144:153-62.
[7] Reed AE, Kalinowski L, Simpson PT, Lakhani SR. Invasive Lobular Carcinoma of the Breast: The Increasing Importance of this Special Subtype. Breast Cancer Res 2021;23:6.
[8] Iorfida M, Maiorano E, Orvieto E, Maisonneuve P, Bottiglieri L, Rotmensz N, et al. Invasive Lobular Breast Cancer: Subtypes and Outcome. Breast Cancer Res Treat 2012;133:713-23.
[9] Simpson PT, Reis-Filho JS, Lambros MB, Jones C, Steele D, Mackay A, et al. Molecular Profiling Pleomorphic Lobular Carcinomas of the Breast: Evidence for a Common Molecular Genetic Pathway with Classic Lobular Carcinomas. J Pathol 2008;215:231-44.
[10] Narendra S, Jenkins SM, Khoor A, Nassar A. Clinical Outcome in Pleomorphic Lobular Carcinoma: A Casecontrol Study with Comparison to Classic Invasive Lobular Carcinoma. Ann Diagn Pathol 2015;19:64-9.
[11] Dos Reis FJ, Wishart GC, Dicks EM, Greenberg D, Rashbass J, Schmidt MK, et al. An Updated PREDICT Breast Cancer Prognostication and Treatment Benefit Prediction Model with Independent Validation. Breast Cancer Res 2017;19:58.
[12] Green AR, Soria D, Stephen J, Powe DG, Nolan CC, KunklerI, et al. Nottingham Prognostic Index Plus: Validation of a Clinical Decision Making Tool in Breast Cancer in an Independent Series. J Pathol Clin Res 2016;2:32-40.
[13] Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018;379:111-21.
[14] Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016;375:717-29.
[15] Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, et al. Gene Expression Profi ling in Breast Cancer:Understanding the Molecular Basis of Histologic Grade To Improve Prognosis. J Natl Cancer Inst 2006;98:262-72.
[16] Bastien RR, Ebbert MT, Boucher KM, Kelly CM, Wang B, Iwamoto T, et al. Using the PAM50 Breast Cancer Intrinsic Classifier to Assess Risk in ER+ Breast Cancers: A Direct Comparison to Onco type DX. J Clin Oncol 2011;29:503.
[17] Dubsky P, Brase JC, Jakesz R, Rudas M, Singer CF, Greil R, et al. The EndoPredict Score Provides Prognostic Information on Late Distant Metastases in ER+/HER2− Breast Cancer Patients. Br J Cancer 2013;109:2959-64.
[18] Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, et al. Prediction of Late Distant Recurrence in Patients with Oestrogen-Receptor-Positive Breast Cancer: A Prospective Comparison of the Breast-Cancer Index (BCI) Assay, 21-Gene Recurrence Score, and IHC4 in the TransATAC study Population. Lancet Oncol 2013;14:1067-76.
[19] Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A Multigene Assay to Predict Recurrence of TamoxifenTreated, Node-Negative Breast Cancer. N Engl J Med 2004;351:2817-26.
[20] Mamounas EP, Russell CA, Lau A, Turner MP, Albain KS. Clinical Relevance of the 21-Gene Recurrence Score® assay in treatment Decisions for Patients with Node-Positive Breast Cancer in the Genomic Era. NPJ Breast Cancer 2018;4:27.
[21] Albain KS, Barlow WE, Hayes DF, Allred GW, Davidson NE, Gralow JR, et al. Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in a Randomized Trial of Chemotherapy for Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer NIH Public Access. Lancet Oncol 2010;11:55-65.
[22] Gluz O, Nitz U, Christgen M, Kates R, Clemens M, NudingB, Shak S, et al. Five-year Results of the Prospective Phase III WSG PlanB Trial Confirm Prognostic Impact of 21-Gene Recurrence Score in high-risk HR+/HER2-Early Breast Cancer (EBC) Patients with 1-3 Involved Lymph Nodes. Breast 2017;32:S93.
[23] Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene Expression and Benefit of Chemotherapy in Women with Node-negative, Estrogen Receptor-positive Breast Cancer. J Clin Oncol 2006;24:3726-34.
[24] Sparano JA, Gray RJ, Ravdin PM, Makower DF, Pritchard KI, Albain KS, et al. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. N Engl J Med 2019;380:2395-405.
[25] Kalinsky K, Barlow WE, Gralow JR, MericBernstam F, Albain KS, Hayes DF, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med 2021;385:2336-4.
[26] Conlon N, Ross DS, Howard J, Catalano JP, Dickler MN, Tan LK. Is there a Role for Oncotype Dx Testing in Invasive Lobular Carcinoma? Breast J 2015;21:514-9.
[27] Felts JL, Zhu J, Han B, Smith SJ, Truica CI. An Analysis of Oncotype DX Recurrence Scores and Clinicopathologic Characteristics in Invasive Lobular Breast Cancer. Breast J 2017;23:677-86.
[28] Tsai ML, Lillemoe TJ, Finkelstein MJ, Money JE, Susnik B, Grimm E, et al. Utility of Oncotype DX Risk Assessment in Patients With Invasive Lobular Carcinoma. Clin Breast Cancer 2016;16:45-50.
[29] Kizy S, Huang JL, Marmor S, Tuttle TM, Hui JY. Impact of the 21-Gene Recurrence Score on Outcome in Patients with Invasive Lobular Carcinoma of the Breast. Breast Cancer Res Treat 2017;165:757-63.
[30] Weiser R, Polychronopoulou E, Hatch SS, Haque W, Ghani HA, He J, et al. Adjuvant Chemotherapy in Patients with Invasive Lobular Carcinoma and use of the 21-Gene Recurrence Score: A National Cancer Database analysis. Cancer 2022;128:1738-47.
[31] Tadros AB, Wen HY, Morrow M. Breast Cancers of Special Histologic Subtypes are Biologically Diverse. Ann Surg Oncol 2018;25:3158-64.
[32] Christgen M, Gluz O, Harbeck N, Kates RE, Raap M, Christgen H, et al. Differential Impact of Prognostic Parameters in Hormone Receptor-positive Lobular Breast Cancer. Cancer 2020;126:4847-58.
[33] Makower D, Qin J, Lin J, Xue X, Sparano JA. The 21- Gene Recurrence Score in Early non-ductal Breast Cancer: A National Cancer Database analysis. NPJ Breast Cancer 2022;8:4.
[34] Van’t Veer LJ, Dai H, Van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene Expression Profiling Predicts Clinical Outcome of Breast Cancer. Nature 2002;415:530-6.
[35] Mook S, Schmidt MK, Viale G, Pruneri G, Eekhout I, Floore A, et al. The 70-gene Prognosis-signature Predicts Disease Outcome in Breast Cancer Patients with 1-3 Positive Lymph Nodes in an Independent Validation Study. Breast Cancer Res Treat 2009;116:295-302.
[36] Kok M, Koornstra RH, Mook S, Hauptmann M, Fles R, Jansen MP, et al. Additional Value of the 70-Gene Signature and Levels of ER and PR for the Prediction of Outcome in Tamoxifen-treated ER-Positive Breast Cancer. Breast 2012;21:769-78.
[37] Buyse M, Loi S, van’t Veer L, Viale G, Delorenzi M, GlasAM, d’Assignies MS, et al. Validation and Clinical Utility of a 70- Gene Prognostic Signature for Women with Node-negative Breast Cancer. J Natl Cancer Inst 2006;98:1183-92.
[38] Cardoso F, van ’t Veer L, Poncet C, Cardozo J, Delaloge S, Pierga JY, et al. MINDACT: Long-term Results of the Large Prospective Trial Testing the 70-Gene Signature Mammaprint as Guidance for Adjuvant Chemotherapy in Breast Cancer Patients. J Clin Oncol 2020;38:506.
[39] Beumer IJ, Persoon M, Witteveen A, Dreezen C, Chin SF, Sammut SJ, et al. Prognostic Value of MammaPrint® in Invasive lobular breast cancer. Biomark Insights 2016;11:139-46.
[40] Metzger O, Cardoso F, Poncet C, Desmedt C, Linn S, Wesseling J, et al. Clinical utility of MammaPrint testing in Invasive Lobular Carcinoma: Results from the MINDACT Phase III trial. Eur J Cancer 2020;138:S5-6.
[41] Jenkins JA, Marmor S, Yuet J, Hui C, Heather B, Blaes AH, et al. The 70-Gene Signature Test as a Prognostic and Predictive Biomarker in Patients with Invasive Lobular Breast Cancer. Breast Cancer Res Treat 2022;191:401-7.
[42] Almstedt K, Mendoza S, Otto M, Battista MJ, Steetskamp J, Heimes AS, et al. EndoPredict® in Early Hormone Receptor-positive, HER2-Negative Breast Cancer. Breast Cancer Res Treat 2020;182:137-46.
[43] Sestak I, Filipits M, Buus R, Rudas M, Balic M, Knauer M, et al. Prognostic Value of EndoPredict in Women with Hormone Receptor–Positive, HER2-Negative Invasive Lobular Breast Cancer. Clin Cancer Res 2020;26:4682-7.
[44] Laenkholm AV, Jensen MB, Eriksen JO, Buckingham W, Ferree S, Nielsen TO, et al. The Ability of PAM50 Risk of Recurrence Score to Predict 10-year Distant Recurrence in Hormone Receptor-positive Postmenopausal Women with Special Histological Subtypes. Acta Oncol (Madr) 2018;57:44-50.
[45] Laenkholm AV, Jensen MB, Eriksen JO, Roslind A, Buckingham W, Ferree S, et al. Population-based Study of Prosigna-PAM50 and Outcome Among Postmenopausal Women With Estrogen Receptor-positive and HER2- negative Operable Invasive Lobular or Ductal Breast Cancer. Clin Breast Cancer 2020;20:423-55.
[46] Sanft T, Berkowitz A, Schroeder B, Hatzis C, Schnabel CA, Brufsky A, et al. A Prospective Decision-Impact Study Incorporating Breast Cancer Index into Extended Endocrine Therapy Decision-making. Breast Cancer Manag 2019;8:BMT22.
[47] Jankowitz RC, Cooper K, Erlander MG, Ma XJ, Kesty NC, Li H, et al. Prognostic Utility of the Breast Cancer Index and Comparison to Adjuvant! Online in a Clinical Case Series of Early Breast Cancer. Breast Cancer Res 2011;13:R98.
[48] Bartlett JM, Sgroi DC, Treuner K, Zhang Y, Ahmed I, Piper T, et al. Breast Cancer Index and Prediction of Benefit from Extended Endocrine Therapy in Breast Cancer Patients Treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial. Ann Oncol 2019;30:1776-83.
[49] Sgroi DC, Carney E, Zarrella E, Steffel L, Binns SN, Finkelstein DM, et al. Prediction of late Disease recurrence and Extended Adjuvant Letrozole Benefit by the HOXB13/ il17Br Biomarker. J Natl Cancer Inst 2013;105:1036-42.
[50] Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, et al. Breast Cancer Index Identifies Early-Stage Estrogen Receptor-Positive Breast Cancer Patients at Risk for Early-and late-distant Recurrence. Clin Cancer Res 2013;19:4196-205.
[51] Sella T, Nunes R, Treuner K, Atkinson J, Wong J, Zhang Y, et al. Abstract P3-08-03: Breast Cancer Index and Prognostic Performance in Invasive Lobular Breast Cancer. United States: Cancer Research American Association for Cancer Research (AACR); 2020. p. P3-08-03-P3-08–03.
[52] Nunes R, Salganik M, Liu J, Schnabel CA, Richardson AL. Likelihood of Late Relapse Assessed by the Breast Cancer Index (BCI) in LN-invasive Lobular Compared to Invasive Ductal Carcinoma. J Clin Oncol 2017;35:e12025.
[53] Sinn P, Aulmann S, Wirtz R, Schott S, Marmé F, Varga Z, et al. Multigene Assays for Classification, Prognosis, and Prediction in Breast Cancer: A Critical Review on the Background and Clinical Utility. Geburtshilfe Frauenheilkund 2013;73:932-40.
[54] Metzger-Filho O, Michiels S, Bertucci F, Catteau A, Salgado R, Galant C, et al. Genomic Grade adds Prognostic Value in Invasive Lobular Carcinoma. Ann Oncol 2013;24:377-84.
[55] Fumagalli D, Metzger O, Veys I, Catteau A, Michiels S, Sandy H, et al. Use of Genomic Grade Index to Improve Tumor Grading of Invasive Lobular Breast Carcinoma. J Clin Oncol 2011;29:535.
[56] Reed AE, Lal S, Kutasovic JR, Wockner L, Robertson A, De Luca XM, et al. LobSig is a Multigene Predictor of Outcome in Invasive Lobular Carcinoma. NPJ Breast Cancer 2019;5:18.
[57] Mamtani A, King TA. Lobular Breast Cancer Different Disease, Different Algorithms? Surg Oncol Clin N Am 2018;27:81-94.
[58] Christgen M, Steinemann D, Kühnle E, Länger F, Gluz O, Harbeck N, et al. Pathology-Research and Practice Lobular breast cancer : Clinical, Molecular and Morphological Characteristics. Pathol Res Pract 2016;212:583-97.
[59] Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, Gelber RD, et al. Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol 2008;26:3006-14.
[60] Piccart MJ, Kalinsky K, Gray R, Barlow WE, Poncet C, Cardoso F, et al. Gene Expression Signatures for Tailoring Adjuvant Chemotherapy of Luminal Breast Cancer: Stronger Evidence, Greater Trust. Ann Oncol 2021;32:1077-82.
[61] Trapani D, Gandini S, Corti C, Crimini E, Bellerba F, Minchella I, et al. Benefit of Adjuvant Chemotherapy in Patients with Lobular Breast Cancer: A Systematic Review of the Literature and Metanalysis. Cancer Treat Rev 2021;97:102205.
[62] Chen XH, Zhang WW, Wang J, Sun JY, Li FY, He ZY, et al. 21-Gene Recurrence Score and Adjuvant Chemotherapy Decisions in Patients with Invasive Lobular Breast Cancer. Biomark Med 2018;13:83-93.