Top

Breast Cancer Research and Treatment

Published in:

06-06-2022 | Biomarkers | Clinical trial

Biomarker profile of invasive lobular carcinoma: pleomorphic versus classic subtypes, clinicopathological characteristics and prognosis analyses

Authors: Yu Zhang, Xiulan Luo, Min Chen, Libo Yang, Ting Lei, Tianjie Pu, Bing Wei, Hong Bu, Zhang Zhang

Published in: Breast Cancer Research and Treatment | Issue 2/2022

Abstract

Purpose

To compare the clinicopathologic features and prognosis of pleomorphic invasive lobular carcinoma (P-ILC) and classic ILC (C-ILC) according to the biomarker profile.

Methods

A total of 667 C-ILCs and 133 P-ILCs between 2011 and 2021 were included. Clinicopathologic features and stromal tumor-infiltrating lymphocytes (sTILs) status were evaluated. P-ILCs were divided into subtypes based on ER/PR and HER2 expression. The overall survival and disease-free survival (DFS) of patients were compared among matched P-ILCs, C-ILCs, and invasive ductal carcinomas (IDCs) with biomarker subtypes.

Results

Compared to C-ILCs, P-ILCs had greater tumor sizes and stages, fewer ER-positive, more HER2-positive, triple negative (TN), and Ki-67 > 20% tumors (P < 0.05). P-ILCs were subdivided into ER+ (63.1%), HER2+ (21.1%) and TN (15.8%). ER+ P-ILCs were mainly showed trabecular and solid growth patterns. Apocrine and solid features were more strongly associated with HER2+ P-ILCs and TN-P-ILCs, respectively. The prognosis of each biomarker group (ER+, HER2+ and TN) differed by subtype. The P-ILC biomarker subtypes had worse prognosis than the same subtypes in the IDC group, while there was no difference between the P-ILC and the C-ILC counterparts. Solid variants of P-ILC had the worst prognosis. Bone was the most common metastatic site in ER+ P-ILCs and TN-P-ILCs. HER2+ P-ILCs tended to metastasize to the brain and liver. DFS of HER2+ P-ILCs and TN-P-ILCs were worse than that of ER+ P-ILCs. Lacking lobular carcinoma in situ and sTILs ≤ 10% were associated with worse survival of ER+ P-ILCs and TN-P-ILCs, respectively. For HER2+ P-ILCs, Ki-67 > 20% and sTILs ≤ 10% were significant factors for lower DFS.

Conclusion

P-ILCs is an aggressive subtype of ILCs. Analyzing the prognostic factors of P-ILCs with heterogeneous morphological and biomarker characteristics is helpful for creating an individualized treatment.

Available only for authorised users

Rakha EA, El-Sayed ME, Powe DG et al (2008) Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur J Cancer 44:73–83. https://doi.org/10.1016/j.ejca.2007.10.009CrossRefPubMed

Viale G, Rotmensz N, Maisonneuve P et al (2009) Lack of prognostic significance of “classic” lobular breast carcinoma: a matched, single institution series. Breast Cancer Res Treat 117:211–214. https://doi.org/10.1007/s10549-008-0112-4CrossRefPubMed

Rakha EA, El-Sayed ME, Menon S, Green AR, Lee AH, Ellis IO (2008) Histologic grading is an independent prognostic factor in invasive lobular carcinoma of the breast. Breast Cancer Res Treat 111:121–127. https://doi.org/10.1007/s10549-007-9768-4CrossRefPubMed

Orvieto E, Maiorano E, Bottiglieri L et al (2008) Clinicopathologic characteristics of invasive lobular carcinoma of the breast: results of an analysis of 530 cases from a single institution. Cancer 113:1511–1520. https://doi.org/10.1002/cncr.23811CrossRefPubMed

Talman ML, Jensen MB, Rank F (2007) Invasive lobular breast cancer. Prognostic significance of histological malignancy grading. Acta Oncol 46:803–809. https://doi.org/10.1080/02841860601137397CrossRefPubMed

Eusebi V, Magalhaes F, Azzopardi JG (1992) Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol 23:655–662. https://doi.org/10.1016/0046-8177(92)90321-sCrossRefPubMed

Mukhtar RA, Krings G, Chen YY et al (2020) Mitotic score and pleomorphic histology in invasive lobular carcinoma of the breast: impact on disease-free survival. Breast Cancer Res Treat 181:23–29. https://doi.org/10.1007/s10549-020-05606-5CrossRefPubMed

Palacios J, Sarrió D, García-Macias MC, Bryant B, Sobel ME, Merino MJ (2003) Frequent E-cadherin gene inactivation by loss of heterozygosity in pleomorphic lobular carcinoma of the breast. Mod Pathol 16:674–678. https://doi.org/10.1097/01.MP.0000073974.42583.F7CrossRefPubMed

Desmedt C, Zoppoli G, Gundem G et al (2016) Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol 34:1872–1881. https://doi.org/10.1200/JCO.2015.64.0334CrossRefPubMed

10.

Reis-Filho JS, Simpson PT, Jones C et al (2005) Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 207:1–13. https://doi.org/10.1002/path.1806CrossRefPubMed

11.

Simpson PT, Reis-Filho JS, Lambros MB et al (2008) Molecular profiling pleomorphic lobular carcinomas of the breast: evidence for a common molecular genetic pathway with classic lobular carcinomas. J Pathol 215:231–244. https://doi.org/10.1002/path.2358CrossRefPubMed

12.

Allison KH, Brogi E, Ellis IO et al (2019) WHO classification of tumours editorial board. Breast Tumours. International Agency for Research on Cancer, Lyon, pp 116–117

13.

Buchanan CL, Flynn LW, Murray MP et al (2008) Is pleomorphic lobular carcinoma really a distinct clinical entity? J Surg Oncol 98:314–317. https://doi.org/10.1002/jso.21121CrossRefPubMed

14.

Butler D, Rosa M (2013) Pleomorphic lobular carcinoma of the breast: a morphologically and clinically distinct variant of lobular carcinoma. Arch Pathol Lab Med 137:1688–1692. https://doi.org/10.5858/arpa.2012-0603-RSCrossRefPubMed

15.

Liu YL, Choi C, Lee SM et al (2018) Invasive lobular breast carcinoma: pleomorphic versus classical subtype, associations and prognosis. Clin Breast Cancer 18:114–120. https://doi.org/10.1016/j.clbc.2017.06.006CrossRefPubMed

16.

Haque W, Arms A, Verma V, Hatch S, Brian Butler E, Teh BS (2019) Outcomes of pleomorphic lobular carcinoma versus invasive lobular carcinoma. Breast 43:67–73. https://doi.org/10.1016/j.breast.2018.11.007CrossRefPubMed

17.

Narendra S, Jenkins SM, Khoor A, Nassar A (2015) Clinical outcome in pleomorphic lobular carcinoma: a case-control study with comparison to classic invasive lobular carcinoma. Ann Diagn Pathol 19:64–69. https://doi.org/10.1016/j.anndiagpath.2015.01.005CrossRefPubMedPubMedCentral

18.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: breast cancer. https://www.nccn.org/patients/guidelines/content/PDF/breast-invasive-patient.pdf. Accessed 26 June 2021

19.

Iorfida M, Maiorano E, Orvieto E et al (2012) Invasive lobular breast cancer: subtypes and outcome. Breast Cancer Res Treat 133:713–723. https://doi.org/10.1007/s10549-012-2002-zCrossRefPubMed

20.

Ohashi R, Matsubara M, Watarai Y et al (2017) Pleomorphic lobular carcinoma of the breast: a comparison of cytopathological features with other lobular carcinoma variants. Cytopathology 28:122–130. https://doi.org/10.1111/cyt.12362CrossRefPubMed

21.

Tille JC, Vieira AF, Saint-Martin C et al (2020) Tumor-infiltrating lymphocytes are associated with poor prognosis in invasive lobular breast carcinoma. Mod Pathol 33:2198–2207. https://doi.org/10.1038/s41379-020-0561-9CrossRefPubMed

22.

Hoda SA, Brogi E, Koerner FC, Rosen PP (2014) Rosen’s breast pathology-fourth edition. Wolters Kluwer Health, Lippincott Williams & Wilkins, Philadelphia, pp 861–866

23.

Wolff AC, Hammond MEH, Allison KH et al (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.2018.77.8738CrossRefPubMed

24.

Loi S, Sirtaine N, Piette F et al (2013) 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 31:860–867. https://doi.org/10.1200/JCO.2011.41.0902CrossRefPubMed

25.

Adams S, Gray RJ, Demaria S et al (2014) 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 32:2959–2966. https://doi.org/10.1200/JCO.2013.55.0491CrossRefPubMedPubMedCentral

26.

Fu L, Tsuchiya S, Matsuyama I, Ishii K (1998) Clinicopathologic features and incidence of invasive lobular carcinoma in Japanese women. Pathol Int 48:348–354. https://doi.org/10.1111/j.1440-1827.1998.tb03917.xCrossRefPubMed

27.

Li S, Yu KD, Fan L, Hou YF, Shao ZM (2011) Predicting breast cancer recurrence following breast-conserving therapy: a single-institution analysis consisting of 764 Chinese breast cancer cases. Ann Surg Oncol 18:2492–2499. https://doi.org/10.1245/s10434-011-1626-2CrossRefPubMed

28.

Kim J, Kim JY, Lee HB et al (2020) Characteristics and prognosis of 17 special histologic subtypes of invasive breast cancers according to World Health Organization classification: comparative analysis to invasive carcinoma of no special type. Breast Cancer Res Treat 184:527–542. https://doi.org/10.1007/s10549-020-05861-6CrossRefPubMed

29.

Al-Baimani K, Bazzarelli A, Clemons M, Robertson SJ, Addison C, Arnaout A (2015) Invasive pleomorphic lobular carcinoma of the breast: pathologic, clinical, and therapeutic considerations. Clin Breast Cancer 15:421–425. https://doi.org/10.1016/j.clbc.2015.06.010CrossRefPubMed

30.

Jung HN, Shin JH, Han BK, Ko EY, Cho EY (2013) Are the imaging features of the pleomorphic variant of invasive lobular carcinoma different from classic ILC of the breast? Breast 22:324–329. https://doi.org/10.1016/j.breast.2012.07.016CrossRefPubMed

31.

Monhollen L, Morrison C, Ademuyiwa FO, Chandrasekhar R, Khoury T (2012) Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type. Histopathology 61:365–377. https://doi.org/10.1111/j.1365-2559.2012.04230.xCrossRefPubMed

32.

Rakha EA, van Deurzen CH, Paish EC, Macmillan RD, Ellis IO, Lee AH (2013) Pleomorphic lobular carcinoma of the breast: is it a prognostically significant pathological subtype independent of histological grade? Mod Pathol 26:496–501. https://doi.org/10.1038/modpathol.2012.197CrossRefPubMed

33.

Lien HC, Chen YL, Juang YL, Jeng YM (2015) Frequent alterations of HER2 through mutation, amplification, or overexpression in pleomorphic lobular carcinoma of the breast. Breast Cancer Res Treat 150:447–455. https://doi.org/10.1007/s10549-015-3336-0CrossRefPubMed

34.

D’Arcy C, Quinn CM (2019) Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast. J Clin Pathol 72:7–11. https://doi.org/10.1136/jclinpath-2018-205485CrossRefPubMed

35.

Saridakis A, Berger ER, Harigopal M et al (2021) Apocrine breast cancer: unique features of a predominantly triple-negative breast cancer. Ann Surg Oncol 28:5610–5616. https://doi.org/10.1245/s10434-021-10518-9CrossRefPubMed

36.

Clinton LK, Plesec T, Goldblum JR, Hajifathalian K, Downs-Kelly E, Patil DT (2020) Specific histopathologic features aid in distinguishing diffuse-type gastric adenocarcinoma from metastatic lobular breast carcinoma. Am J Surg Pathol 44:77–86. https://doi.org/10.1097/PAS.0000000000001341CrossRefPubMed

37.

Gamble LA, Rossi A, Fasaye GA et al (2022) Association between hereditary lobular breast cancer due to CDH1 variants and gastric cancer risk. JAMA Surg 157:18–22. https://doi.org/10.1001/jamasurg.2021.5118CrossRefPubMed

38.

Bergeron A, MacGrogan G, Bertaut A et al (2021) Triple-negative breast lobular carcinoma: a luminal androgen receptor carcinoma with specific ESRRA mutations. Mod Pathol 34:1282–1296. https://doi.org/10.1038/s41379-021-00742-9CrossRefPubMedPubMedCentral

39.

Zhong E, Solomon JP, Cheng E, Baum J, Song W, Hoda SA (2020) Apocrine variant of pleomorphic lobular carcinoma in situ: further clinical, histopathologic, immunohistochemical, and molecular characterization of an emerging entity. Am J Surg Pathol 44:1092–1103. https://doi.org/10.1097/PAS.0000000000001493CrossRefPubMed

40.

Ai D, Yao J, Yang F et al (2021) TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer. Mod Pathol 34:710–719. https://doi.org/10.1038/s41379-020-00692-8CrossRefPubMed

41.

Tozbikian GH, Zynger DL (2019) A combination of GATA3 and SOX10 is useful for the diagnosis of metastatic triple-negative breast cancer. Hum Pathol 85:221–227. https://doi.org/10.1016/j.humpath.2018.11.005CrossRefPubMed

42.

Hasebe T, Tsuda H, Tsubono Y, Imoto S, Mukai K (1997) Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumor recurrence and tumor death within three years after the initial operation. Jpn J Cancer Res 88:590–599. https://doi.org/10.1111/j.1349-7006.1997.tb00423.xCrossRefPubMedPubMedCentral

43.

Loi S, Michiels S, Salgado R et al (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/mdu112CrossRefPubMed

44.

Loi S, Drubay D, Adams S et al (2019) Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 37:559–569. https://doi.org/10.1200/JCO.18.01010CrossRefPubMedPubMedCentral

45.

Desmedt C, Salgado R, Fornili M et al (2018) Immune infiltration in invasive lobular breast cancer. J Natl Cancer Inst 110:768–776. https://doi.org/10.1093/jnci/djx268CrossRefPubMedPubMedCentral

46.

Salgado R, Denkert C, Campbell C et al (2015) 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.2015.0830CrossRefPubMedPubMedCentral

47.

He H, Gonzalez A, Robinson E, Yang WT (2014) Distant metastatic disease manifestations in infiltrating lobular carcinoma of the breast. AJR Am J Roentgenol 202:1140–1148. https://doi.org/10.2214/AJR.13.11156CrossRefPubMed

48.

Montagna E, Pirola S, Maisonneuve P et al (2018) Lobular metastatic breast cancer patients with gastrointestinal involvement: features and outcomes. Clin Breast Cancer 18:e401–e405. https://doi.org/10.1016/j.clbc.2017.07.003CrossRefPubMed

49.

Kurozumi S, Alsaleem M, Monteiro CJ et al (2020) Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets. Breast Cancer Res 22:85. https://doi.org/10.1186/s13058-020-01324-4CrossRefPubMedPubMedCentral

50.

Riedlinger GM, Joshi S, Hirshfield KM, Barnard N, Ganesan S (2021) Targetable alterations in invasive pleomorphic lobular carcinoma of the breast. Breast Cancer Res 23:7. https://doi.org/10.1186/s13058-020-01385-5CrossRefPubMedPubMedCentral

51.

Rosa-Rosa JM, Caniego-Casas T, Leskela S et al (2019) High frequency of ERBB2 activating mutations in invasive lobular breast carcinoma with pleomorphic features. Cancers (Basel) 11:74. https://doi.org/10.3390/cancers11010074CrossRef

52.

Zhu S, Ward BM, Yu J et al (2018) IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma. JCI Insight 3:e97398. https://doi.org/10.1172/jci.insight.97398CrossRefPubMedCentral

53.

He L, Araj E, Peng Y (2021) HER2 positive and HER2 negative classical type invasive lobular carcinomas: comparison of clinicopathologic features. Curr Oncol 28:1608–1617. https://doi.org/10.3390/curroncol28030150CrossRefPubMedPubMedCentral

54.

LaBoy C, Siziopikou KP, Rosen L, Blanco LZ Jr, Pincus JL (2021) Clinicopathologic features of unexpectedly HER2 positive breast carcinomas: an institutional experience. Pathol Res Pract 222:153441. https://doi.org/10.1016/j.prp.2021.153441CrossRefPubMed

55.

Ercan C, van Diest PJ, van der Ende B et al (2012) p53 mutations in classic and pleomorphic invasive lobular carcinoma of the breast. Cell Oncol (Dordr) 35:111–118. https://doi.org/10.1007/s13402-012-0071-yCrossRef

56.

Zhang Z, Christin JR, Wang C, Ge K, Oktay MH, Guo W (2016) Mammary-stem-cell-based somatic mouse models reveal breast cancer drivers causing cell fate dysregulation. Cell Rep 16:3146–3156. https://doi.org/10.1016/j.celrep.2016.08.048CrossRefPubMedPubMedCentral

57.

Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712. https://doi.org/10.1126/science.2470152CrossRefPubMed

58.

Hirshfield KM, Ganesan S (2014) Triple-negative breast cancer: molecular subtypes and targeted therapy. Curr Opin Obstet Gynecol 26:34–40. https://doi.org/10.1097/GCO.0000000000000038CrossRefPubMed

59.

Segar JM, Pandey R, Farr KJ et al (2020) Clinicopathological and molecular characteristics of pleomorphic invasive lobular carcinoma. Int J Breast Cancer 2020:8816824. https://doi.org/10.1155/2020/8816824CrossRefPubMedPubMedCentral

60.

Viale G, Regan MM, Maiorano E et al (2008) Chemoendocrine compared with endocrine adjuvant therapies for node-negative breast cancer: predictive value of centrally reviewed expression of estrogen and progesterone receptors–International Breast Cancer Study Group. J Clin Oncol 26:1404–1410. https://doi.org/10.1200/JCO.2007.10.6393CrossRefPubMed

61.

Mukhtar RA, Hoskin TL, Habermann EB, Day CN, Boughey JC (2021) Changes in management strategy and impact of neoadjuvant therapy on extent of surgery in invasive lobular carcinoma of the breast: analysis of the National Cancer Database (NCDB). Ann Surg Oncol 28:5867–5877. https://doi.org/10.1245/s10434-021-09715-3CrossRefPubMedPubMedCentral

62.

Swain SM, Tang G, Lucas PC et al (2019) Pathologic complete response and outcomes by intrinsic subtypes in NSABP B-41, a randomized neoadjuvant trial of chemotherapy with trastuzumab, lapatinib, or the combination. Breast Cancer Res Treat 178:389–399. https://doi.org/10.1007/s10549-019-05398-3CrossRefPubMedPubMedCentral

63.

Kwapisz D (2021) Pembrolizumab and atezolizumab in triple-negative breast cancer. Cancer Immunol Immunother 70:607–617. https://doi.org/10.1007/s00262-020-02736-zCrossRefPubMed

Title: Biomarker profile of invasive lobular carcinoma: pleomorphic versus classic subtypes, clinicopathological characteristics and prognosis analyses
Authors: Yu Zhang
Xiulan Luo
Min Chen
Libo Yang
Ting Lei
Tianjie Pu
Bing Wei
Hong Bu
Zhang Zhang
Publication date: 06-06-2022
Publisher: Springer US
Keyword: Biomarkers
Published in: Breast Cancer Research and Treatment / Issue 2/2022
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-022-06627-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2022

Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature

Excision of breast fibroepithelial lesions: when is it still necessary?—A 10-year review of a regional centre

Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study

Identification of tumor biomarkers for pathological complete response to neoadjuvant treatment in locally advanced breast cancer

Abundance of reactive oxygen species (ROS) is associated with tumor aggressiveness, immune response, and worse survival in breast cancer

PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina

Keynote webinar | Spotlight on antibody–drug conjugates in cancer