Abstract
Background
To provide further information on the clinical and pathological prognostic factors in triple-negative breast cancer (TNBC), for which limited and inconsistent data are available.
Methods
Pathological characteristics and clinical records of 841 TNBCs diagnosed between 1994 and 2015 in four major oncologic centers from Sardinia, Italy, were reviewed. Multivariate hazard ratios (HRs) for mortality and recurrence according to various clinicopathological factors were estimated using Cox proportional hazards models.
Results
After a mean follow-up of 4.3 years, 275 (33.3%) TNBC patients had a progression of the disease and 170 (20.2%) died. After allowance for study center, age at diagnosis, and various clinicopathological factors, all components of the TNM staging system were identified as significant independent prognostic factors for TNBC mortality. The HRs were 3.13, 9.65, and 29.0, for stage II, III and IV, respectively, vs stage I. Necrosis and Ki-67 > 16% were also associated with increased mortality (HR: 1.61 and 1.99, respectively). Patients with tumor histotypes other than ductal invasive/lobular carcinomas had a more favorable prognosis (HR: 0.40 vs ductal invasive carcinoma). No significant associations with mortality were found for histologic grade, tumor infiltrating lymphocytes, and lymphovascular invasion. Among lymph node positive TNBCs, lymph node ratio appeared to be a stronger predictor of mortality than pathological lymph nodes stage (HR: 0.80 for pN3 vs pN1, and 3.05 for >0.65 vs <0.21 lymph node ratio), respectively. Consistent results were observed for cancer recurrence, except for Ki-67 and necrosis that were not found to be significant predictors for recurrence.
Conclusions
This uniquely large study of TNBC patients provides further evidence that, besides tumor stage at diagnosis, lymph node ratio among lymph node positive tumors is an additional relevant predictor of survival and tumor recurrence, while Ki-67 seems to be predictive of mortality, but not of recurrence.
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Background
With an estimated 1.8 million new patients each year, breast cancer is the most common cancer in women worldwide [1]. In Italy, age-standardized (European standard) incidence and mortality rates in 2012 were 118/100,000 and 23/100,000, respectively, i.e., higher than those from other southern European countries [2].
Since 2005, triple-negative breast cancer (TNBC) identifies a specific subtype of breast cancer, characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [3]. TNBCs include a heterogeneous group of diseases which account for about 10–20% of all breast cancers and are more frequent among African American and Hispanic women, and in women with younger age, higher premenopausal body mass index, earlier age at menarche, and higher parity [3,4,5]. Moreover, they have higher expression of the Ki-67 antigen, higher mitotic index, and more frequent BRCA1 mutations. TNBCs are generally more aggressive than other breast neoplasms and have limited therapeutic options; therefore, they have usually a high risk of recurrence or death within 5 years since diagnosis [6].
Data on the clinical and pathological prognostic determinants for TNBC tumors are scanty and inconsistent and they generally derive from small hospital cancer registries including around a few hundreds of patients. TNM stage – including in particular the number of axillary lymph nodes involved – is one of the best-established prognostic factors for breast cancer, but its prognostic value in TNBCs, as in other intrinsic subtypes of breast cancer, is less clear [7, 8]. The ratio of positive lymph nodes on the total number of lymph nodes removed has been proposed as an additional and more accurate prognostic factor than the number of lymph nodes involved, although only a few studies have specifically evaluated its role in TNBC survival [9]. Although histologic grade has been shown to be a good predictor of survival for breast cancer, its prognostic role in TNBCs may be more limited given that most of these tumors are of high grade [10]. Furthermore, the findings on the prognostic value of the proliferation marker Ki-67 in TNBCs have been inconsistent [11]. Scantier data exist on tumor histotypes, tumor infiltrating lymphocytes (TIL), necrosis, and lymphovascular invasion (LVI) and survival from TNBC [12,13,14,12]. Accordingly, we did not find any difference in terms of recurrence and mortality between lobular and invasive ductal carcinomas, whereas other TNBC subtypes (mostly medullary and apocrine carcinomas) showed significantly better outcomes than invasive ductal carcinomas.
Among the best-established prognostic factors for breast cancer there is histologic grade [10]. This notwithstanding, in our large cohort of TNBC patients – as reported in a few other smaller studies [8, 26] – grade had no role in survival outcomes. This may be at least in part due to the high histological grade of TNBC patients [3], which might make it difficult to disentangle the role of grade on TNBC prognosis. Indeed, in our cohort only 1.5% of patients were G1 and over 3 out of 4 patients were G3.
Various large studies recently found that tumor TILs (mainly stromal) – a surrogate marker of adaptive immune response – is associated with a favorable prognosis in TNBC patients [39,40,41,42], although the use of TILs as an additional prognostic factors in TNBCs is not yet recommend giving the lack of standardization and clinical validation of this marker [13]. In our cohort, although death rates were lower among TNBC patients with TILs, no significant association was found between TILs and cancer progression or mortality. However, we had no information on the number/proportion of TILs and we did not specifically measured stromal TILs.
LVI – which refers to the invasion of lymphatic spaces and blood vessels – has long been considered a relevant prognostic marker of breast cancer, although it has not been incorporated in most internationally recognized staging system as the AJCC/TMN one [14, 21]. A few small studies which have investigated the relationship between LVI and DFS or OS in patients with TNBC showed that LVI is an independent predictor of poor outcome [14, 26, 43]. In our large cohort we found that LVI presence has a negative impact on both tumor recurrence and mortality when taking into account only study center and age at diagnosis. However, after allowance for other clinicopathological characteristics, the association between LVI and mortality was no more significant, thus do not supporting a relevant prognostic role of this marker.
Scanty data are available on the role of necrosis on prognostic outcomes in TNBC patients. In a study on 154 TBNCs from China, tumor necrosis was found to be a significant prognostic factor, although only results from univariate analyses were provided [15]. In our large cohort, necrosis at baseline was significantly associated to survival outcomes, even after allowance for other clinicopathological factors.
The results of this study should be interpreted after taking into consideration various limitations, mainly inherent to its retrospective design. Thus, we could not retrieve information on vital status at follow-up for 311 out of 1152 TNBC patients (about 27%) and we had to exclude them from the present analyses. Moreover, for some patients important clinical and pathological data were missing because not originally included in the medical records, and those missing information may have to some extent influenced the associations evaluated. Furthermore, some misclassification of patients may have resulted from the classification of tumors in different laboratories across hospital centers, where clinical and pathological testing practices can vary. However, pathology materials were reviewed centrally by three pathologists following the same national/international breast cancer guidelines in order to uniformely classify TNBCs across hospital centers and standardize ER, PgR and HER2 immunohistochemical results for TNBC samples, according to the ASCO/CAP recommendations [17].
The strengths of our study include its uniquely large sample size – including from one third up to half of all new Sardinian TNBC patients over the study period, the comprehensive and standardized nature of the registry database with patients’ characteristics, pathological tumor features, cancer treatments, and the complete ascertainment of patient status at regular follow-up intervals. This also allowed us to derive multivariate HR estimates for OS and DFS after allowance for a number of potential confounders.
Conclusions
In this uniquely large cohort, we provide further evidence that, besides tumor stage at diagnosis, lymph node ratio among lymph node positive tumors is an additional relevant predictor of mortality and recurrence in TNBCs, while Ki-67 seems to be predictive of mortality, but not of recurrence.
Abbreviations
- AJCC:
-
American Joint Committee on Cancer criteria
- CI:
-
confidence interval
- DFS:
-
Disease-free survival
- ER:
-
estrogen receptor
- HER2:
-
human epidermal growth factor receptor 2
- HR:
-
hazard ratio
- LVI:
-
lymphovascular invasion
- M:
-
metastasis
- OS:
-
Overall survival
- pN:
-
pathological N stage
- PR:
-
progesterone receptor
- SD:
-
standard deviation
- T:
-
tumor stage
- TIL:
-
tumor infiltrating lymphocytes
- TNBC:
-
triple-negative breast cancer
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Acknowledgements
Authors wish to thank Prof. Andrea Piga ("A. Businco" Oncological Hospital, Caglari, Italy), Università degli Studi di Sassari, for the initial concept of this study, Dr. Eliana Rulli (IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy) for the development of the SAS macro for the Kaplan-Meier curve, and Mrs. Ivana Garimoldi (IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy) for editorial assistance.
Funding
The study was supported by the Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N. 7, “Promozione della Ricerca Scientifica e dell'Innovazione Tecnologica in Sardegna”). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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The dataset analyzed during the current study is available from the corresponding author on reasonable request.
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AB, MRD, PCR, SAMU and SO had the original study idea; EV, FA, CC, GS, MG, AMu, AMA, VM, DO, SC, MCS, LC provided materials and/or patients; ES, DP, RM, SAMU, FS, GP, AMa, MF,TM collected and assembled data; SG conducted the statistical analysis; SAMU and SG wrote the manuscript; CB, EV, MDI, MRD, PCR and SO contributed in drafting the manuscript; all authors gave substantial contributions in the conception, design and interpretation of data and approved the final version of the manuscript.
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The study protocol was approved by the local research ethics committee of Sardinia Region (File number 224/CE/12). Informed consent was waived from the local research ethics committee since patients’ information was collected during the routine clinical practice and patients were identified by anonymized investigator-generated code not linkable to their personal data.
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Additional files
Additional file 1: Table S1.
Hazard ratios (HRs) of recurrence, and corresponding 95% confidence intervals (CIs), according to selected clinical and pathological characteristics, among 825 triple-negative breast cancers (TNBCs). Sardinia, Italy 1994-2015. Table S2. Hazard ratios (HRs) of recurrence, and corresponding 95% confidence intervals (CIs), according to pathological lymph nodes and lymph node ratio among 311 triple-negative breast cancers (TNBCs) with positive lymph nodes. Sardinia, Italy 1994-2015. Figure S1. Kaplan-Meir curves for disease-free survival according to tumor stage among 825 triple-negative breast cancer patients. Sardinia, Italy 1994–2005. Figure S2. Kaplan-Meir curves for disease-free survival according to pathological lymph nodes stage (a) and lymph node ratio (b) among 311 triple-negative breast cancer patients with positive lymph nodes. Sardinia, Italy 1994–2005 (DOC 658 kb)
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Urru, S.A.M., Gallus, S., Bosetti, C. et al. Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients. BMC Cancer 18, 56 (2018). https://doi.org/10.1186/s12885-017-3969-y
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DOI: https://doi.org/10.1186/s12885-017-3969-y