Histologic subtyping affecting outcome of triple negative breast cancer: a large Sardinian population-based analysis

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Abstract

Background

Triple Negative breast cancer (TNBC) includes a heterogeneous group of tumors with different clinico-pathological features, molecular alterations and treatment responsivity. Our aim was to evaluate the clinico-pathological heterogeneity and prognostic significance of TNBC histologic variants, comparing “ special types” to high-grade invasive breast carcinomas of no special type (IBC-NST).

Methods

This study was performed on data obtained from TNBC Database, including pathological features and clinical records of 1009 TNBCs patients diagnosed between 1994 and 2015 in the four most important Oncology Units located in different hospitals in Sardinia, Italy. Kaplan-Meier analysis, log-rank test and multivariate Cox proportional-hazards regression were applied for overall survival (OS) and disease free survival (DFS) according to TNBC histologic types.

Results

TNBC “ special types” showed significant differences for several clinico-pathological features when compared to IBC-NST. We observed that in apocrine carcinomas as tumor size increased, the number of metastatic lymph nodes manifestly increased. Adenoid cystic carcinoma showed the smallest tumor size relative to IBC-NST. At five-year follow-up, OS was 92.1, 100.0, and 94.5% for patients with apocrine, adenoid cystic and medullary carcinoma, respectively; patients with lobular and metaplastic carcinoma showed the worst OS, with 79.7 and 84.3%, respectively. At ten-years, patients with adenoid cystic (100.0%) and medullary (94.5%) carcinoma showed a favourable prognosis, whereas patients with lobular carcinoma showed the worst prognosis (73.8%). TNBC medullary type was an independent prognostic factor for DFS compared to IBC-NST.

Conclusions

Our study confirms that an accurate and reliable histopathologic definition of TNBC subtypes has a significant clinical utility and is effective in the therapeutic decision-making process, with the aim to develop innovative and personalized treatments.

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Most cited references 43

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Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

Carsten Denkert, Sibylle Loibl, Aurelia Noske … (2010)

PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.

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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.

Sylvia Adams, Robert J. Gray, Sandra Demaria … (2014)

Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

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Triple negative tumours: a critical review.

J S Reis-Filho, A Tutt (2008)

Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types.

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Author and article information

Contributors

Paolo Cossu-Rocca: rocco@uniss.it

Maria Rosaria De Miglio: demiglio@uniss.it

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 2 June 2020

Publication date PMC-release: 2 June 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 491

Affiliations

[1 ]GRID grid.11450.31, ISNI 0000 0001 2097 9138, Department of Biomedical Sciences, , University of Sassari, ; Sassari, Italy

[2 ]GRID grid.426317.5, ISNI 0000 0004 0646 6602, Biomedicine Sector, Center for Advanced Studies, Research and Development in Sardinia Technology Park Polaris, ; Cagliari, Italy

[3 ]GRID grid.11450.31, ISNI 0000 0001 2097 9138, Department of Medical, Surgical and Experimental Sciences, , University of Sassari, ; Via P. Manzella, 4, 07100 Sassari, Italy

[4 ]Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, Olbia, Italy

[5 ]GRID grid.11450.31, ISNI 0000 0001 2097 9138, School of Hospital Pharmacy, , University of Sassari, ; Sassari, Italy

[6 ]GRID grid.4527.4, ISNI 0000000106678902, Department of Environmental Health Sciences, , Istituto di Ricerche Farmacologiche Mario Negri IRCCS, ; Milan, Italy

[7 ]GRID grid.4527.4, ISNI 0000000106678902, Department of Oncology, , Istituto di Ricerche Farmacologiche Mario Negri IRCCS, ; Milan, Italy

[8 ]GRID grid.488385.a, ISNI 0000000417686942, Department of Pathology, , AOU Sassari, ; Sassari, Italy

[9 ]Department of Pathology, “A. Businco” Oncologic Hospital, ASL Cagliari, Cagliari, Italy

[10 ]Department of Medical Oncology, “A. Businco” Oncologic Hospital, ASL Cagliari, Cagliari, Italy

[11 ]Medical Oncology Unit, AOU, Cagliari, Italy

[12 ]Department of Pathology, ASSL Nuoro, Nuoro, Italy

[13 ]Department of Medical Oncology, ASSL Nuoro, Nuoro, Italy

[14 ]Department of Pathology, Brotzu Hospital, Cagliari, Italy

Article

Publisher ID: 6998

DOI: 10.1186/s12885-020-06998-9

PMC ID: 7268380

PubMed ID: 32487046

SO-VID: b9fcf54b-f81a-42b1-b9c5-5525c678649e

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 17 December 2019

Date accepted : 24 May 2020

Funding

Funded by: Fondazione Banco di Sardegna, Italy

Funded by: FundRef http://dx.doi.org/10.13039/501100009873, Regione Autonoma della Sardegna;

Award ID: Anno 2012, Legge Regionale 7 agosto 2007, n.7: "Promozione della Ricerca Scientifica e dell'Innovazione Tecnologica in Sardegna"

Funded by: Fondo dell'Ateneo di Sassari per la ricerca 2019

Award ID: 2019

Award Recipient : Paolo Cossu-Rocca

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: triple negative breast cancer,clinico-pathological features,prognosis,histologic special type,tumor size,metastatic lymph node

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: triple negative breast cancer, clinico-pathological features, prognosis, histologic special type, tumor size, metastatic lymph node

Histologic subtyping affecting outcome of triple negative breast cancer: a large Sardinian population-based analysis

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Abstract

Background

Methods

Results

Conclusions

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Karger: Oncology

Most cited references 43

Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

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.

Triple negative tumours: a critical review.

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