https://orcid.org/0009-0005-2844-2374
Figures
Abstract
Background
Evidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis.
Methods
This was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis.
Results
In total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04–2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94–2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10–3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53–4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42–3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ.
Citation: Piedra-Delgado L, Chambergo-Michilot D, Morante Z, Fairen C, Jerves-Coello F, Luque-Benavides R, et al. (2024) Survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience. PLoS ONE 19(2): e0293833. https://doi.org/10.1371/journal.pone.0293833
Editor: Divijendra Natha Reddy Sirigiri, BMSCE: BMS College of Engineering, INDIA
Received: May 15, 2023; Accepted: October 19, 2023; Published: February 1, 2024
Copyright: © 2024 Piedra-Delgado et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Among the phenotypes of breast cancer, triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors [1]. TNBC is frequent in African American and Hispanic women [2], and accounts for 15–20% of all breast cancers [3].
This phenotype is well known for its aggressiveness, high heterogeneity, high percentage of metastasis to solid organs, and high relapse rates compared to other phenotypes. For instance, one quarter of patients with mild local disease present relapse with distant metastasis within the first three years after diagnosis [4]. Due to these characteristics in addition to the lack of targeted therapy, TNBC has a poor prognosis with a worse overall survival and breast cancer cause specific-survival [5].
It is estimated that 20–30% of early cases of breast cancer will develop metastasis and the site of distant recurrence is associated with the breast cancer subtype [6]. TNBC has a higher rate of metastasis in lung, bone and brain, as well as multiple metastasis [7, 8]. Although the literature has shown that TNBC generally has a lower OS and relapse-free survival (RFS) than other phenotypes, data on survival according to the site of distant metastasis is still limited.
Hence, our aim was to analyze the OS and distant relapse free survival (DRFS) according to the site of metastasis in women with TNBC. Moreover, as a secondary objective, we analyzed the survival since the diagnosis of the relapse (MS) in TNBC patients.
Materials and methods
Study design and patient population
This was retrospective cohort study. We included and reviewed medical records from TNBC patients diagnosed and treated at the “Instituto Nacional de Enfermedades Neoplasicas” (Lima, Peru) from 2000 to 2014. The follow-up was until February 2020. The data were collected from December 2017 to March 2020. Inclusion criteria were as follows: age 18 years and older, breast cancer patients with confirmed a triple negative phenotype, stages I-III at diagnosis, and patients with distant relapse. The study included all the patients who met the inclusion and exclusion criteria. Cases lost to follow-up were excluded.
TNBC were identified by immunohistochemistry as estrogen receptor negative or <1%, progesterone receptor negative or <1%, and HER-2 negative or <1%. Patients with inconclusive staining for HER2 underwent fluorescence in situ hybridization; negativity was considered with a result < 2. Tumor stage was classified according to the 8th edition of the American Joint Committee on Cancer (AJCC) [9]. The body mass index was classified as underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2) and, obese (≥30 kg/m2).
The type of metastasis was classified as visceral, central nervous system (CNS), bone, and multiple sites. Visceral metastasis was defined as the spread of cancer cells to adjacent or distant organ sites inside the thorax or abdominal cavity; whereas CNS metastasis included dura, brain parenchyma, and leptomeninges; while, bone metastasis referred to disease extension to bone. Multiple metastasis involved disease extension to multiple sites, such as bone and one solid organ or multiple solid organs. Later metastases were not considered in the initial classification.
Follow-up
OS was considered as from diagnosis of the primary tumor until death or the end of the study. DRFS was considered as from the date of the beginning of any type of treatment until the diagnosis of the first distant metastasis, death, or the end of the study. MS was considered from the diagnosis of distant metastasis to the death or the end of study.
Distant relapse of breast cancer was identified by computed tomography, magnetic resonance imaging, bone scintigraphy, or positron emission tomography.
Statistical analysis
For quantitative variables we used means and standard deviation (SD) or median with the interquartile range according to the distribution of data, while frequencies and percentages were estimated for qualitative variables. For univariate analysis, the Student’s t or Mann-Whitney U test (according to the distribution) was used for quantitative variables, while the chi-square test was used for qualitative variables. Survival rates were calculated using the Kaplan-Meier method, while differences between types of metastases were assessed by the Log rank test. Missing data were reported but were not included in the statistical analysis. Prognostic factors and their hazard ratios (HR) were estimated with multivariate Cox regression analysis. To address any potential sources of bias, we included all the population available in our analyses. All the analysis had a 95% of confidence interval (95% CI), and a p value <0.05 was considered statistically significant. All the analyses were performed with the Statistical Package for the Social Sciences (SPSS) v.24 and Stata 17 (College Station, TX: StataCorp LLC).
Results
Ot he 534 TNBC patients presenting recurrence, 390 with distant metastasis (73.03%) were included in the study. The mean age was 48.3 years (SD: 11.9), 98 (25.2%) patients were obese and half were premenopausal (51.0%). The majority of patients had stage III TNBC at diagnosis (78.7%), followed by women with stage II (19.0%), and there were 7 cases of bilateral breast cancer (Table 1). The majority of patients (82.2%) underwent surgery, 58.5% received neoadjuvant chemotherapy (NAC), 41.5% received adjuvant chemotherapy (ACT), and 64.4% received radiotherapy.
The lung was the most frequent first site of metastasis (33.3%), followed by multiple metastasis (29.2%), brain (18.5%), bone (9.7%), liver (6.7%), and leptomeningeal metastasis (1.5%). Regarding the type of metastasis, visceral metastasis accounted for 41% (Table 2).
Compared to visceral, CNS, or multiple metastasis; bone metastasis was more frequent in patients with a family history of breast or ovarian cancer (P = 0.02). N staging significantly differed among the four groups, with patients with multiple metastasis sites presenting similar lymph node involvement to that of patients with visceral and CNS metastasis, while patients with bone metastasis had a higher number of affected lymph nodes (P = 0.02). Finally, death was more frequent in the group with multiple metastasis sites (97.4%) compared to the groups of CNS (88.5%),visceral (85.6), and bone metastasis (81.6%) (P<0.01) (Table 3).
The study population was followed for a median of 10.2 years. The DRFS at 3 and 5 years was 30% and 10%, respectively (Fig 1), while the OS was 44% and 26%, respectively (Fig 1).
Relapse free survival (A), overall survival (B), and survival since diagnosis of first metastasis (C) of patients with triple negative breast cancer with distant metastasis.
There were no differences when DRFS was assessed according to the type of metastasis (p = 0.08). Similarly, there were no differences when comparing the survival of patients with metastasis with lung, brain, or liver (p = 0.17) (Figs 2 and 3). However, the OS and MS rates were lower in patients with multiple sites of metastasis, followed by visceral, CNS, and bone metastasis at 3 years (34%, 44%, 62%, and 47%) and at 6 months (33%, 48%, 45%, and 61%), respectively (Fig 4).
Comparison of relapse-free survival of patients with triple negative breast cancer from the time of diagnosis of primary cancer to relapse according to the type of metastasis (A) and solid organs (B).
Comparison of overall survival of patients with triple negative breast cancer with distant relapse (A) and metastasis survival since the diagnosis of first metastasis (B) according to solid organ metastasis.
Comparison of overall survival of patients with triple negative breast cancer with distant relapse according to the type of metastasis of the primary cancer (A) and metastasis survival since the diagnosis of first metastasis (B).
Cox regression multivariate analysis showed the predictors of a worse OS: N staging (N2-N3 vs. N0, HR: 1.49; 95% CI: 1.04–2.14), metastasis to CNS (vs. bone; HR: 1.88; 95% CI: 1.10–3.22), and multiple metastases (vs. bone; HR: 2.55; 95% CI: 1.53–4.24) (Table 4). Moreover, the only predictor of a worse MS was the presence of multiple metastasis (HR: 2.30; 95% CI:1.42–3.72) (Table 5).
Discussion
We evaluated the association between the site of metastasis site and clinical outcomes in patients with TNBC. The results showed that N staging, CNS metastasis to and multiple metastasis were significant prognostic factors for a worse OS, and multiple metastasis was the only predictor of a worse MS in patients with TNBC and distant metastases.
With regards to the demographic characteristics of TNBC patients, our results are consistent with previous literature. The mean age of our patients was 48 years old, being similar to previous studies describing the diagnosis of TNBC in patients no older than 50 years old. Indeed, TNBC is more frequent in younger women compared to other phenotypes of breast cancer [10, 11]. Hence, TNBC is mainly presented in pre-menopausal women, although this factor has not been associated with an impact on survival outcomes [12, 13].
The majority of our patients were diagnosed in stage III (78.7%). TNBC patients are less likely to be diagnosed in a screening mammography, leading to diagnosis being made at a more advance stage [11, 14]. Moreover, In Latin America most cases are diagnosed in advanced stages due to the serious problem of limited access to breast cancer screenings in these countries [15, 16] Asad et al. found that the stage at diagnosis was the most significant factor for the rapid development of relapse of TNBC; with 55% of patients with stage III TNBC at diagnosis developing relapse, demonstrating a 15-fold higher probability of relapse compared to women with stage I [17]. The majority of our patients (78.1%) have a histologic grade III. In fact, almost all TNBC tumours are grade III invasive ductal adenocarcinomas [18, 19]. Cheung et al. reported a correlation between histological grade and the expression of the snail2 protein, which is linked to transformation of tumor cells to the mesenchymal phenotype, thereby enabling metastasis and suggesting an association between histological grade and TNBC metastasis [20].
In spite of the fact that all the patients included in this study received either NAC, ACT, and/or radiotherapy, all of them developed relapse. In accordance with a prior cohort study about recurrence of TNBC; results showed that despite the majority of patients after undergoing adjuvant therapy, a dramatically high rate of recurrence was still observed [21]. A possible explanation of this outcome may be found in the study by Kim et al., which showed that breast cancer cells can develop resistance or even have pre-existing resistance to chemotherapy [22]. However, a meta-analysis by Yang et al. found that adjuvant chemotherapy reduced the rate of recurrence for T1a/bN0 TNBC [23]. Albeit promising, these results cannot be extrapolated to our investigation as the patients in the aforementioned study were all T1 whereas more than the 95% of our patients were T2 and above. Although the current NCCN guidelines are well established for each tumour size and lymph node invasion [24], information on the efficacy of chemotherapy and reduction of recurrence in advanced TNBC stages is still limited, and therefore additional studies are needed to elucidate the true role of the chemotherapy in TNBC relapse.
Predominant distant metastasis is a documented finding in TNBC, Dent et al. found that women with TNBC had an increased likelihood of distant recurrence within five years after diagnosis [25]. In fact, research suggests that the high risk and predominance of distant recurrence is in part caused by the excess of visceral and CNS metastases, but diminished bone recurrence seen in patients in the first five years after diagnosis [26, 27]. Some explanations for the tendency of TNBC to present visceral and CNS metastasis include the association between metastasis to certain organs and the expression of specific genes by the tumour [28]. Hicks et al. described that breast cancer patients that developed brain metastasis were likely to express cytokeratin 5 and 6 markers [29]. The expression of cytokeratin 5 is linked to the phenotype of cells undergoing the epithelial-mesenchymal transition, which is used by the tumour to gain migratory and invasive properties, thereby causing metastasis [30–32].
We found that lung metastasis was the most common site of metastasis similar to what other authors described, and was also the most common first site of invasion, followed by multiple metastasis and brain [33–38]. However, it has been proposed that the genes present in TNBC comprise the signature of lung metastasis, being a possible explanation of this phenomenon [35, 38–40]. The signature genes identified include the EGFR ligand epiregulin, COX2 and matrix metalloproteinases 1 and 2 [41]. Expression of these genes is important for motility but also allows angiogenesis, and intravasation of tumor cells into the circulation, which may be a factor of lung extravasation via the lung capillaries [40, 42]. Epiregulin and EGFR are of particular interest with several studies having found a strong correlation with their expression in TNBC [43–48]. The expression of EGFR has been reported as being inversely related to hormone receptor expression [43, 49, 50], suggesting that lung metastasis may be an intrinsic feature of TNBC.
Our results showed that the DRFS was 30% and 10% at three and five years, respectively. Due to the lack of specific targets, treatment with standard agents leaves patients prone to systemic and local relapse [48]. Cho et al. proposed that high expression of EGFR as well mutations of BRCA1 are linked to a worse RFS in TNBC [51]. Further evidence for EGFR as a marker for unfavourable prognosis is that expression of the aforementioned gene is linked to resistance to chemotherapy and radiation treatment, inherently forewarning poor survival [49, 50, 52].
We found no significant difference in disease-free metastasis, regardless of the organ invaded. This might be explained by the overall inefficiency of the available treatments. Treatment options are limited to standard chemotherapy and there is a current lack of targeted therapies. Despite an apparent responsiveness to these agents, the prognosis remains poor due to the higher likelihood of visceral relapse; a phenomenon referred to as the TNBC paradox [53–55]. This statement is demonstrated in the study by Fornier et al. [56]; who reported rapid progression following multiple lines of chemotherapy.
Regarding the stratification of risk factors according to the sites of metastasis, we found that a family history of breast or ovarian cancer was associated with higher rates of metastasis to multiple sites. Family history as a risk factor is mainly due to the association with BRCA1 mutations [57], which have been identified as contributors to the metastatic and aggressive nature of tumor cells [58]. Fasching et al. [57] reported that brain metastasis was frequently seen in patients with BRCA1 mutations whereas Song et al. [59] found that carriers of this mutation frequently experience lung and lymph node metastasis. On the same hand, N1 tumor staging was associated with metastasis to visceral, CNS, and multiple sites. Similar to our results, Lin et al. described that lower lymph node involvement (N1) was associated with a greater risk of metastasis to solid organs such as the brain and lung [60]. Finally, the association between death and metastasis to CNS and multiple sites showed the greatest significance. As shown in Table 3, multiple metastasis was related to death in 97.4% of cases whereas CNS and visceral metastasis to were associated with death in 88.5% and 85.6% of cases, respectively.
The average OS in the present study was lower than that described in a previous study (26% at 5 years) [61]. It has been reported, that the outcomes of Latin American breast cancer patients are worse compared to patients from developed countries. These poor outcomes are mainly associated with socioeconomic factors that not only limit access to screening, favoring late diagnosis, but also cause deficient access to specialised cancer care [15, 16]. This should be one of the major priorities for intervention in our setting to achieve better short and long term outcomes in our population.
When comparing the different sites of metastases, the lowest OS rates were found in patients with multiple metastases, followed by CNS, visceral, and bone. Supporting the latter, Wang et al. and other authors found that patients with metastasis to visceral, CNS and multiple sites had a lower OS, whilst those with bone metastasis had the highest OS amongst [61–63]. This last finding, together with the fact that TNBC tends to invade visceral sites more frequently than bone [64], is a framework to establish that worse prognosis and unfavorable OS in metastatic TNBC, are related to the excess risk and high incidence of visceral metastasis [27]. Therefore, the invasion of multiple viscera burdens carries the worst prognosis due to life threatening and life diminishing clinical presentations [63, 65].
We found that metastasis to CNS, N staging and multiple metastasis were prognostic factors for OS in TNBC. It was expected that a well-documented prognostic factor such as lymph node status [66–68], would be significant in multivariate analysis. In a study conducted using the SEER database, Gao et al. found that TNBC patients with distant metastasis have worse OS if they were IV stage, uninsured, did not undergo surgery and chemotherapy, and had metastasis in brain and liver [69]. However, to our knowledge this is the first instance in which multiple metastasis has been identified as such a significant prognostic factor for OS and MS in metastatic TNBC.
Limitations
This was a retrospective study and thus, the associations among the factors analysed can be assured but not causation. Some patients were lost during follow-up, and were thereby excluded from the study, limiting maximum data collection and analysis. Moreover, test results for BRCA gene mutation was not available in the majority of our patients due to non-coverage by national insurance. In addition, although we included neoadjuvant and adjuvant chemotherapy, and radiotherapy in our analyses, we did not have further therapeutic information such as the chemotherapy regimen This information should be included in future studies due to the possible effects on the outcomes of this specific population.
Although the data used belonged to the main Peruvian Cancer Institute, patients from private centres might have different outcomes. Therefore, future investigations should include the collection of data from multiple centres in order to limit potential selection bias and achieve true randomization as well as being more applicable to other populations.
Conclusions
In conclusion, patients with multiple sites of metastasis have a 2.5-fold higher risk of death compared to those with bone metastasis in terms of OS and MS. Moreover, CNS metastasis is also a predictor of a worse OS compared to bone metastasis. There was no difference in DRFS regarding the different solid organs or according to type of metastasis. Further prospective randomized controlled studies are needed in TNBC patients presenting metastasis to assess different therapeutic modalities and molecular biomarkers.
Supporting information
S1 Checklist. STROBE statement—checklist of items that should be included in reports of observational studies.
https://doi.org/10.1371/journal.pone.0293833.s001
(DOCX)
S1 Data. Data set- survival according to the site of metastasis in triple-negative breast cancer patients: The Peruvian experience.
https://doi.org/10.1371/journal.pone.0293833.s002
(XLSX)
Acknowledgments
The authors thank the Universidad Cientifica del Sur for their support in the publication of this research/project.
References
- 1. Griffiths CL, Olin JL. Triple negative breast cancer: a brief review of its characteristics and treatment options. J Pharm Pract [Internet]. 2012 [cited 2023 Apr 12];25(3):319–23. Available from: https://pubmed.ncbi.nlm.nih.gov/22551559/ pmid:22551559
- 2. Lund MJ, Trivers KF, Porter PL, Coates RJ, Leyland-Jones B, Brawley OW, et al. Race and triple negative threats to breast cancer survival: A population-based study in Atlanta, GA. Breast Cancer Res Treat. 2009 Jan 7;113(2):357–70. pmid:18324472
- 3. Dass SA, Tan KL, Rajan RS, Mokhtar NF, Adzmi ERM, Rahman WFWA, et al. Triple Negative Breast Cancer: A Review of Present and Future Diagnostic Modalities. Medicina (B Aires). 2021 Jan 1;57(1):1–18. pmid:33445543
- 4. O’Reilly D, Sendi M Al, Kelly CM. Overview of recent advances in metastatic triple negative breast cancer. World J Clin Oncol. 2021 Mar 3;12(3):164. pmid:33767972
- 5. Li X, Yang J, Peng L, Sahin AA, Huo L, Ward KC, et al. Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res Treat. 2017 Jan 1;161(2):279–87. pmid:27888421
- 6. Lobbezoo DJA, Van Kampen RJW, Voogd AC, Dercksen MW, Van Den Berkmortel F, Smilde TJ, et al. Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer [Internet]. 2015 Apr 28 [cited 2023 Apr 17];112(9):1445–51. Available from: https://pubmed.ncbi.nlm.nih.gov/25880008/ pmid:25880008
- 7. Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, et al. Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis [Internet]. 2015 Feb 6 [cited 2023 Apr 17];32(2):125–33. Available from: https://pubmed.ncbi.nlm.nih.gov/25630269/ pmid:25630269
- 8. Kast K, Link T, Friedrich K, Petzold A, Niedostatek A, Schoffer O, et al. Impact of breast cancer subtypes and patterns of metastasis on outcome. Breast Cancer Res Treat [Internet]. 2015 Apr 1 [cited 2023 Apr 17];150(3):621–9. Available from: https://pubmed.ncbi.nlm.nih.gov/25783184/ pmid:25783184
- 9. Giuliano AE, Edge SB, Hortobagyi GN. Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer. Ann Surg Oncol. 2018 Jul 1;25(7):1783–5. pmid:29671136
- 10. Boyle P. Triple-negative breast cancer: Epidemiological considerations and recommendations. Annals of Oncology. 2012 Aug 1;23(SUPPL. 6):vi7–12. pmid:23012306
- 11. Amirikia KC, Mills P, Bush J, Newman LA. Higher population-based incidence rates of triple-negative breast cancer among young African-American women. Cancer [Internet]. 2011 Jun 15 [cited 2023 Apr 17];117(12):2747–53. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.25862
- 12. Tian XS, Cong MH, Zhou WH, Zhu J, Chen YZ, Liu Q. Clinicopathologic and Prognostic Characteristics of Triple-Negative Breast Cancer. Oncol Res Treat [Internet]. 2008 Nov [cited 2023 Apr 17];31(11):610–4. Available from: https://www.karger.com/Article/FullText/162288 pmid:19145094
- 13. Zhang J, Wang Y, Yin Q, Zhang W, Zhang T, Niu Y. An associated classification of triple negative breast cancer: the risk of relapse and the response to chemotherapy. Int J Clin Exp Pathol [Internet]. 2013 [cited 2023 Apr 17];6(7):1380. Available from: /pmc/articles/PMC3693204/ pmid:23826420
- 14. Chen Y, Susick L, Davis M, Bensenhaver J, Nathanson SD, Burns J, et al. Evaluation of Triple-Negative Breast Cancer Early Detection via Mammography Screening and Outcomes in African American and White American Patients. JAMA Surg [Internet]. 2020 May 1 [cited 2023 Apr 17];155(5):440. Available from: /pmc/articles/PMC7042930/ pmid:32074266
- 15. Ayala N, Barchuk S, Inurrigarro G, Celano C, Soriano-García JL, Bolaños P, et al. Status of breast cancer in Latin American: Results of the breast cancer revealed initiative. Crit Rev Oncol Hematol [Internet]. 2023 Jan 1 [cited 2023 Sep 19];181. Available from: https://pubmed.ncbi.nlm.nih.gov/36462594/ pmid:36462594
- 16. Pinto JA, Pinillos L, Villarreal-Garza C, Morante Z, Villarán M V., Mejía G, et al. Barriers in Latin America for the management of locally advanced breast cancer. Ecancermedicalscience [Internet]. 2019 Jan 22 [cited 2022 May 31];13. Available from: /pmc/articles/PMC6372299/ pmid:30792814
- 17. Asad S, Barcenas CH, Bleicher RJ, Cohen AL, Javid SH, Levine EG, et al. Sociodemographic Factors Associated With Rapid Relapse in Triple-Negative Breast Cancer: A Multi-Institution Study. J Natl Compr Canc Netw [Internet]. 2021 Mar 3 [cited 2023 Apr 17];19(7):797. Available from: /pmc/articles/PMC8564718/ pmid:33691275
- 18. Fulford LG, Easton DF, Reis-Filho JS, Sofronis A, Gillett CE, Lakhani SR, et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology [Internet]. 2006 Jul [cited 2023 Apr 17];49(1):22–34. Available from: https://pubmed.ncbi.nlm.nih.gov/16842243/ pmid:16842243
- 19. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol [Internet]. 2006 Feb [cited 2023 Apr 17];19(2):264–71. Available from: https://pubmed.ncbi.nlm.nih.gov/16341146/ pmid:16341146
- 20. Cheung SY, Boey YJY, Koh VCY, Thike AA, Lim JCT, Iqbal J, et al. Role of epithelial–mesenchymal transition markers in triple-negative breast cancer. Breast Cancer Res Treat [Internet]. 2015 Aug 31 [cited 2023 Apr 17];152(3):489–98. Available from: https://link.springer.com/article/10.1007/s10549-015-3485-1 pmid:26123543
- 21. Kaplan HG, Malmgren JA, Atwood M. T1N0 Triple Negative Breast Cancer: Risk of Recurrence and Adjuvant Chemotherapy. Breast J [Internet]. 2009 Sep 1 [cited 2023 Apr 17];15(5):454–60. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1524-4741.2009.00789.x pmid:19671105
- 22. Kim C, Gao R, Sei E, Brandt R, Hartman J, Hatschek T, et al. Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing. Cell [Internet]. 2018 May 3 [cited 2023 Apr 17];173(4):879–893.e13. Available from: http://www.cell.com/article/S0092867418303659/fulltext pmid:29681456
- 23. Yang Z, Chen Y, Liu X, Cui J, Hu Y, Wei W. Effects of adjuvant chemotherapy on recurrence rate in T1abN0M0 triple-negative breast cancer: A meta-analysis. Cancer Treat Res Commun [Internet]. 2020 Jan 1 [cited 2023 Apr 17];25. Available from: https://pubmed.ncbi.nlm.nih.gov/33113437/ pmid:33113437
- 24. Gradishar WJ, Moran MS, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw [Internet]. 2022 Jun 1 [cited 2023 Apr 17];20(6):691–722. Available from: https://pubmed.ncbi.nlm.nih.gov/35714673/ pmid:35714673
- 25. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence. Clinical Cancer Research [Internet]. 2007 Aug 1 [cited 2023 Apr 17];13(15):4429–34. Available from: https://aacrjournals.org/clincancerres/article/13/15/4429/194334/Triple-Negative-Breast-Cancer-Clinical-Features pmid:17671126
- 26. Rodríguez-Pinilla SM, Sarrío D, Honrado E, Hardisson D, Calero F, Benitez J, et al. Prognostic Significance of Basal-Like Phenotype and Fascin Expression in Node-Negative Invasive Breast Carcinomas. Clinical Cancer Research [Internet]. 2006 Mar 1 [cited 2023 Apr 17];12(5):1533–9. Available from: https://aacrjournals.org/clincancerres/article/12/5/1533/203569/Prognostic-Significance-of-Basal-Like-Phenotype pmid:16533778
- 27. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat [Internet]. 2009 May 10 [cited 2023 Apr 17];115(2):423–8. Available from: https://link.springer.com/article/10.1007/s10549-008-0086-2 pmid:18543098
- 28. Dogu GG, Ozkan M, Ozturk F, Dikilitas M, Er O, Ozturk A. Triple-negative breast cancer: immunohistochemical correlation with basaloid markers and prognostic value of survivin. Med Oncol [Internet]. 2010 Mar [cited 2023 Apr 17];27(1):34–9. Available from: https://pubmed.ncbi.nlm.nih.gov/19156550/ pmid:19156550
- 29. Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol [Internet]. 2006 Sep [cited 2023 Apr 17];30(9):1097–104. Available from: https://pubmed.ncbi.nlm.nih.gov/16931954/ pmid:16931954
- 30. Wang Y, Zhou BP. Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer [Internet]. 2011 [cited 2023 Apr 17];30(9):603. Available from: /pmc/articles/PMC3702729/ pmid:21880181
- 31. Chu PG, Weiss LM. Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases. Mod Pathol [Internet]. 2002 [cited 2023 Apr 17];15(1):6–10. Available from: https://pubmed.ncbi.nlm.nih.gov/11796835/ pmid:11796835
- 32. Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Annals of Oncology [Internet]. 2010 Oct [cited 2023 Apr 17];21 Suppl 7(SUPPL. 7):vii89. Available from: /pmc/articles/PMC3379967/ pmid:20943648
- 33. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer. Cancer [Internet]. 2008 Nov 15 [cited 2023 Apr 17];113(10):2638–45. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.23930
- 34. Soni A, Ren Z, Hameed O, Chanda D, Morgan CJ, Siegal GP, et al. Breast Cancer Subtypes Predispose the Site of Distant Metastases. Am J Clin Pathol [Internet]. 2015 Apr 1 [cited 2023 Apr 17];143(4):471–8. Available from: https://academic.oup.com/ajcp/article/143/4/471/1760581 pmid:25779997
- 35. Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. Journal of Clinical Oncology. 2010 Jul 10;28(20):3271–7. pmid:20498394
- 36. Bartmann C, Wischnewsky M, Stüber T, Stein R, Krockenberger M, Häusler S, et al. Pattern of metastatic spread and subcategories of breast cancer. Arch Gynecol Obstet [Internet]. 2017 Jan 1 [cited 2023 Apr 17];295(1):211–23. Available from: https://link.springer.com/article/10.1007/s00404-016-4225-4 pmid:27832352
- 37. Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metastasis: Molecular biology and therapeutic implications. [Internet]. 2018 Oct 3 [cited 2023 Apr 17];19(10):858–68. Available from: https://www.tandfonline.com/doi/abs/10.1080/15384047.2018.1456599 pmid:29580128
- 38. Wu Q, Li J, Zhu S, Wu J, Chen C, Liu Q, et al. Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study. Oncotarget [Internet]. 2017 Mar 2 [cited 2023 Apr 17];8(17):27990–6. Available from: https://www.oncotarget.com/article/15856/text/ pmid:28427196
- 39. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature [Internet]. 2005 Jul 7 [cited 2023 Apr 17];436(7050):518. Available from: /pmc/articles/PMC1283098/ pmid:16049480
- 40. Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, et al. Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A [Internet]. 2007 Apr 4 [cited 2023 Apr 17];104(16):6740. Available from: /pmc/articles/PMC1871856/ pmid:17420468
- 41. Sihto H, Lundin J, Lundin M, Lehtimäki T, Ristimäki A, Holli K, et al. Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study. Breast Cancer Res [Internet]. 2011 Sep 13 [cited 2023 Apr 17];13(5):R87. Available from: /pmc/articles/PMC3262199/ pmid:21914172
- 42. Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 2006 446:7137 [Internet]. 2007 Apr 12 [cited 2023 Apr 17];446(7137):765–70. Available from: https://www.nature.com/articles/nature05760 pmid:17429393
- 43. Changavi AA, Shashikala A, Ramji AS. Epidermal Growth Factor Receptor Expression in Triple Negative and Nontriple Negative Breast Carcinomas. J Lab Physicians [Internet]. 2015 Jul [cited 2023 Apr 17];7(2):79. Available from: /pmc/articles/PMC4559633/ pmid:26417156
- 44. Ueno NT, Zhang D. Targeting EGFR in Triple Negative Breast Cancer. J Cancer [Internet]. 2011 [cited 2023 Apr 17];2(1):324. Available from: /pmc/articles/PMC3119395/ pmid:21716849
- 45. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer—current status and future directions. Ann Oncol [Internet]. 2009 [cited 2023 Apr 17];20(12):1913–27. Available from: https://pubmed.ncbi.nlm.nih.gov/19901010/ pmid:19901010
- 46. Rodríguez-Pinilla SM, Sarrió D, Honrado E, Moreno-Bueno G, Hardisson D, Calero F, et al. Vimentin and laminin expression is associated with basal‐like phenotype in both sporadic and BRCA1‐associated breast carcinomas. J Clin Pathol [Internet]. 2007 Sep [cited 2023 Apr 17];60(9):1006. Available from: /pmc/articles/PMC1972443/ pmid:17105822
- 47. Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res [Internet]. 2008 Feb 15 [cited 2023 Apr 17];68(4):989–97. Available from: https://pubmed.ncbi.nlm.nih.gov/18281472/ pmid:18281472
- 48. Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol [Internet]. 2007 Mar [cited 2023 Apr 17];8(3):235–44. Available from: https://pubmed.ncbi.nlm.nih.gov/17329194/ pmid:17329194
- 49. Sukumar J, Gast K, Quiroga D, Lustberg M, Williams N. Triple-negative breast cancer: promising prognostic biomarkers currently in development. Expert Rev Anticancer Ther [Internet]. 2021 [cited 2023 Apr 17];21(2):135–48. Available from: https://pubmed.ncbi.nlm.nih.gov/33198517/ pmid:33198517
- 50. Rimawi MF, Shetty PB, Weiss HL, Schiff R, Osborne CK, Chamness GC, et al. Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes. Cancer [Internet]. 2010 Mar 1 [cited 2023 Apr 17];116(5):1234–42. Available from: https://pubmed.ncbi.nlm.nih.gov/20082448/ pmid:20082448
- 51. Cho EY, Chang MH, Choi Y La, Lee JE, Nam SJ, Yang JH, et al. Potential candidate biomarkers for heterogeneity in triple-negative breast cancer (TNBC). Cancer Chemother Pharmacol [Internet]. 2011 Sep [cited 2023 Apr 17];68(3):753–61. Available from: https://pubmed.ncbi.nlm.nih.gov/21170648/ pmid:21170648
- 52. Meche A, Cǐmpean AM, Raica M. Immunohistochemical expression and significance of epidermal growth factor receptor (EGFR) in breast cancer. Rom J Morphol Embryol [Internet]. 2009 [cited 2023 Apr 17];50(2):217–21. Available from: https://pubmed.ncbi.nlm.nih.gov/19434314/ pmid:19434314
- 53. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol [Internet]. 2016 Nov 1 [cited 2023 Apr 17];13(11):674. Available from: /pmc/articles/PMC5461122/ pmid:27184417
- 54. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes. Clinical Cancer Research [Internet]. 2007 Apr 15 [cited 2023 Apr 17];13(8):2329–34. Available from: https://aacrjournals.org/clincancerres/article/13/8/2329/195724/The-Triple-Negative-Paradox-Primary-Tumor pmid:17438091
- 55. Rakha EA, Ellis IO. Triple-negative/basal-like breast cancer: review. Pathology [Internet]. 2009 [cited 2023 Apr 17];41(1):40–7. Available from: https://pubmed.ncbi.nlm.nih.gov/19089739/ pmid:19089739
- 56. Fornier M, Fumoleau P. The Paradox of Triple Negative Breast Cancer: Novel Approaches to Treatment. Breast J [Internet]. 2012 Jan 1 [cited 2023 Apr 17];18(1):41–51. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1524-4741.2011.01175.x pmid:22098334
- 57. Fasching PA, Yadav S, Hu C, Wunderle M, Häberle L, Hart SN, et al. Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer—Association With Patient and Disease Characteristics and Effect on Prognosis. Journal of Clinical Oncology [Internet]. 2021 May 5 [cited 2023 Apr 17];39(15):1619. Available from: /pmc/articles/PMC8274805/ pmid:33780288
- 58. Krishnan R, Patel PS, Hakem R. BRCA1 and Metastasis: Outcome of Defective DNA Repair. Cancers 2022, Vol 14, Page 108 [Internet]. 2021 Dec 27 [cited 2023 Apr 17];14(1):108. Available from: https://www.mdpi.com/2072-6694/14/1/108/htm pmid:35008272
- 59. Song Y, Barry WT, Seah DS, Tung NM, Garber JE, Lin NU. Patterns of recurrence and metastasis in BRCA1/BRCA2-associated breast cancers. Cancer [Internet]. 2020 Jan 15 [cited 2023 Apr 17];126(2):271–80. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.32540 pmid:31581314
- 60. Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong YN, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer [Internet]. 2012 Nov 15 [cited 2023 Apr 17];118(22):5463–72. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.27581 pmid:22544643
- 61. Tseng LM, Hsu NC, Chen SC, Lu YS, Lin CH, Chang DY, et al. Distant metastasis in triple-negative breast cancer. Neoplasma [Internet]. 2013 [cited 2023 Apr 17];60(3):290–4. Available from: https://pubmed.ncbi.nlm.nih.gov/23373998/ pmid:23373998
- 62. Wang Z, Wang H, Sun X, Fang Y, Lu SS, Ding SN, et al. A Risk Stratification Model for Predicting Overall Survival and Surgical Benefit in Triple-Negative Breast Cancer Patients With de novo Distant Metastasis. Front Oncol. 2020 Jan 24;10:14. pmid:32038988
- 63. Ren Z, Li Y, Hameed O, Siegal GP, Wei S. Prognostic factors in patients with metastatic breast cancer at the time of diagnosis. Pathol Res Pract. 2014 May 1;210(5):301–6. pmid:24635972
- 64. Guo Y, Arciero CA, Jiang R, Behera M, Peng L, Li X. Different Breast Cancer Subtypes Show Different Metastatic Patterns: A Study from A Large Public Database. Asian Pac J Cancer Prev [Internet]. 2020 Dec 1 [cited 2023 Apr 17];21(12):3587. Available from: /pmc/articles/PMC8046324/ pmid:33369456
- 65. Insa A, Lluch A, Prosper F, Marugan I, Martinez-Agullo A, Garcia-Conde J. Prognostic factors predicting survival from first recurrence in patients with metastatic breast cancer: analysis of 439 patients. Breast Cancer Res Treat [Internet]. 1999 [cited 2023 Apr 17];56(1):67–78. Available from: https://pubmed.ncbi.nlm.nih.gov/10517344/ pmid:10517344
- 66. Yuan ZY, Wang S Sen, Gao Y, Su ZY, Luo WB, Guan ZZ. [Clinical characteristics and prognosis of triple-negative breast cancer: a report of 305 cases]. Ai Zheng [Internet]. 2008 Jun 1 [cited 2023 Apr 17];27(6):561–5. Available from: https://europepmc.org/article/med/18570725 pmid:18570725
- 67. Lee JA, Kim K Il, Bae JW, Jung YH, An H, Lee ES. Triple negative breast cancer in Korea-distinct biology with different impact of prognostic factors on survival. Breast Cancer Res Treat [Internet]. 2010 Aug 24 [cited 2023 Apr 17];123(1):177–87. Available from: https://link.springer.com/article/10.1007/s10549-010-0998-5 pmid:20574671
- 68. Ovcaricek T, Frkovic SG, Matos E, Mozina B, Borstnar S. Triple negative breast cancer—Prognostic factors and survival. Radiol Oncol. 2011 Mar 1;45(1):46–52. pmid:22933934
- 69. Gao Y, Chuanzhen Bian |, Kang Gu |, Wang H, Zhuang S, Tang | Xiaowen, et al. Patterns of distant metastases in patients with triple-negative breast cancer—A population-based study. Precision Medical Sciences. 2023 Sep 1;12(3):182–95.