Índice
Incluido en la revista Ocronos. Vol. VI. Nº 11–Noviembre 2023. Pág. Inicial: Vol. VI; nº 11: 413
Autor principal (primer firmante): Gloria Nataly Pérez Serrano
Fecha recepción: 02/11/2023
Fecha aceptación: 28/11/2023
Ref.: Ocronos. 2023;6(11): 413
Autores: Gloria Nataly Perez Serrano. 1 Martinez Belmonte Haydee Alejandra. 2 Lilia Gabriela Castañeda Ramirez. 3
1,2,3. Hospital General Regional INSTITUTO MEXICANO DEL SEGURO SOCIAL 58
Palabras clave: Triple-negative breast cancer, mamary carcinoma,
Triple-negative breast cancer (TNBC) is a diverse form of breast cancer that accounts for approximately 15-20% of all cases of invasive breast cancer. It is more common in younger patients and its incidence varies by race and ethnicity. It tends to have a naturally aggressive course and there is a significant risk of recurrence, so the prognosis is poor.
To know the epidemiological, histopathological and pathophysiological relationship that triple negative breast cancer has with the prognosis in terms of recurrence and survival of the patient and the aggressiveness of this neoplasm.
Triple negative breast cancer presents a series of important alterations that contribute to its pathogenesis such as gene activation and suppression facilitated by miRNA chains, alterations of the BRCA1 and BRCA2 genes, TP53, PIK30A, among others. It also presents histopathological and immunological processes of relevance.
There are important associations between the pathophysiological characteristics of this subtype of mammary carcinoma and the long-term prognosis in affected women. Triple-negative carcinoma, which predominates in the Hispanic race, shows greater aggressiveness when associated with other biological, molecular and genetic factors in neoplastic cells.
Introduction
Breast cancer is a malignant neoplasm of epithelial cells lining the lobules of the breast. It represents about 33% of malignant tumors in women, being the most important cause of cancer deaths in women. Currently, in developed countries and due to the care in detection and timely treatment, mortality from breast cancer has been reduced significantly, however, in developing countries this mortality has increased by 10.9% (1,2).
This malignant proliferation is considered a clonal disease, because an individual cell, as a result of somatic mutations, has reached the capacity to express its malignant potential. Breast cancer can be found as a non-invasive or non-metastatic invasive neoplasm (1,2).
Breast malignancies are classified into five intrinsic subtypes based on gene expression: 1) luminal A, increased expression at HER2 and ER receptors; 2) luminal B, HER2 negative or HER2 positive; 3) healthy mass-like; 4) HER2 overexpression; 5) basal: tumors without estrogen/progestagen receptors and without HER2, called triple negative. (1,2)
Breast cancer in general is a heterogeneous disease. It is also said that triple negative breast cancer (TNBC) is also an entity of heterogeneous nature, since it can be divided into 4 different intrinsic subtypes given by the gene expression profile; basal cell-like, luminal A, luminal B and HER2-enriched. There is also another classification of TNBC subtypes: basal cell-like 1, basal cell-like 2, mesenchymal, and luminal androgen receptor. (3)
TNBC comprises 15-20% of all invasive breast cancers (corresponding to 170,000 cases of TNBC globally). It is more common in younger patients and varies depending on race and ethnicity. The literature reports that it is more common in African-American women (26% prevalence compared to 16% in the non-African-American population), as well as a high prevalence in Mexican women, and interestingly in both it occurs at a young age at the time of diagnosis or at premenopausal age. (3)
Normally, TNBC has an aggressive natural course characterized by a rapid development of resistance to chemotherapy, with higher recurrence rates and poor outcomes. They are at increased risk of distant recurrence during the first 3-5 years after diagnosis. The high risk of distal metastasis and recurrence in addition to a shorter disease-free survival and overall survival compared to other types of breast cancer make the prognosis poor. (5) The most common sites of metastasis are in the lungs and central nervous system. (3). Theoretical framework
Pattern of breast cancer now and over time
Breast cancer is the most common neoplasm among women worldwide. (1) It is the leading cause of death in Latina women and women living in the USA. In this population the overall incidence was 91.9 and mortality was 14.0 per 100,000 in 2015. Mortality in Mexico is estimated at 18.78%. (7)
The 5-year survival rate of breast cancer in Latin America barely exceeds 70%, this is related to late diagnosis, 30 – 40% of patients are diagnosed in stages III and IV of the disease.(7)
Epidemiology
Notably, the incidence of triple negative breast cancer subtype (TNBC), one of the most clinically aggressive subtypes of cancer, varies by ethnicity, occurring more frequently in African American (24-42%) and Latina (15-33%) women compared to non-Hispanic white women (11-28%). (7)
Similar to African-American women, Latina women with TNBC are diagnosed at a younger age, at more advanced stages and are more likely to develop metastases (7).
The role of genetic alterations as prognostic markers has been evaluated in several studies, among them are alterations in BRCA1 and BRCA2, these genes are among the most precisely defined and have the highest clinical significance. The BRCA1 gene is identified at chromosomal locus 17q21; it encodes a zinc-finger protein and the protein product acts as a transcription factor and is involved in gene repair. On average, 20% of women with triple-negative breast cancers will have the deleterious and pathologic germline BRCA1 SNP.
The BRCA2 gene, located on chromosome 13q12, is also linked to an increased incidence of breast cancer in women, but they are more likely to be estrogen receptor positive. (1)
In Mexico, testing for BRCA genes is not widely available; it is performed in the private sector through laboratories outside the country. The «HISPANEL» is a genetic screening of 115 recurrent mutations in Hispanic women with TNBC. In the study by Villarreal-Garza J et al, «HISPANEL» was defined as having a sensitivity of 68% to identify BRCA1 and BRCA2 mutations in Mexican women specifically.
Of a total of 109 patients with TNBC, they found a mutation in 44 patients (23.2%) and of these there were 11 different mutations.
The most relevant was the BRCA1 ex9-12del mutation in 18 patients, which is the most common founder mutation in Mexico and has not been reported in other Latin American countries. Other mutations found with lower incidence in these patients were: BRCA1 943ins10, BRCA1 R71G, BRCA1 2925del1, BRCA1 185delAG, BRCA1 R1443X, BRCA1 387delTA, among others.
Evidence has been reported on the benefit of knowing which patients are carriers of genetic mutations prior to initiating treatment in TNBC, a more personalized approach is performed and another benefit of genetic screening is to be able to offer it to women in the patient’s unaffected family. (10)
Triple-negative breast cancer genome sequencing (TNBC)
Next-Generation Sequencing (NGS) is a method to visualise the genomic landscape in tumours and to reveal tumour heterogeneity by deletion of genetic variants. It is used to sequence cancer-related genes (6).
TNBC represents a subtype of breast cancer with adverse clinical outcomes and inconsistent responses to current therapy, and the spectrum of genetic mutations is diverse in each patient and differs between racial and ethnic groups. Ethnicity may play an important role in genomic discrepancy and diversity in TNBC patients (4).
In a study published in Mexico during 2019 by Oncology Letters: «Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico» where genetic alterations of TNBC were characterised in tissue biopsies through NGS and found between 18-26 genetic variants, including ATM, GNA11, GNAQ, NRAS, PIK3CA, PTEN, RB1, SMAD4, SRC and TP53 (6).
NGS has shown that CMTN presents TP53 alterations in up to 80% of cases, followed by genes with lower frequency such as PIK30A, followed by the most frequently mutated gene in CMTN, and FLT3, where it presented a variant (rs2491231) that had not previously been reported in CMTN (6).
In the study by Philipovskiy et al, the predominant mutation found in all Hispanic-Latino women with TNBC was TP53, mostly a nonsense mutation. The second most common genetic alteration was in the NOTCH signalling pathway (44%). Other common alterations found were MAP3K1 (28%) and AKT1/AKT2 (28%) pathway alterations, and finally to a lesser extent mutations were found: EGFR and PIK3CA (20%).
An interesting finding in this study was that alterations in AKT, MAP3K and EGFR were significantly higher in these Hispanic-Latino women compared to populations from other databases. It was also concluded that the presence of NOTCH and PIK3CA mutations, alone or in combination, were associated with worse prognosis in this population (4).
Spectrum of different prognostic factors in TNBC
The TNBC form is characterised by a clinically aggressive, poor prognosis compared to other breast cancer subtypes, this form is virtually incurable (6).
Approximately 1/3 of TNBC patients will have distant recurrence within the first 8 years of diagnosis. (9) When the tumour stage is high at diagnosis (large tumour size, pathological lymph nodes and the presence of metastases), the prognosis is based especially on the ability for cancer progression and resulting in high mortality.
The number of axillary lymph nodes involved is one of the best studied prognostic factors for breast cancer, but its prognostic value in TNBC has not been elucidated. Both tumour size and lymph node (TN) involvement were independently associated with recurrence and overall mortality. Grade played no role in survival outcomes in TNBC. Invasion of lymphatic spaces and blood vessels has been considered a relevant prognostic marker of breast cancer in the same way (8).
Localised treatment with radiotherapy and chemotherapy (or the combination of both) showed benefit in terms of recurrence compared to surgical treatment. (9)
Role of histological subtypes in the prognosis of TNBC
Tumors are classified based on their histopathological subtype, which can range from common tumors such as invasive lobular carcinoma to extremely rare types such as glycogen-rich clear cell tumors. The reason why estrogen, progesterone and HER2 receptors are assessed in all breast tumors is because they offer prognostic and predictive value in determining patient management (9).
Triple negative breast cancer (TNBC) shows a more aggressive pattern of invasion (distant recurrence within the first 8 years after diagnosis with a median survival of 13 months in the presence of metastases) and is associated with specific histological subtypes of carcinoma.
Patients with special histological subtypes of carcinomas tend to have an increased risk of recurrence. Tumors with a special histological pattern were associated with worse relapse-free survival (RFS) and worse overall survival (OS) compared to tumours without a special type (9).
In addition, it has recently been investigated that invasive TNBC lobular carcinoma and metaplastic carcinoma are associated with a relatively worse SFR and OS relative to invasive carcinoma of no special type (NST). It has been shown how TNBC tumors of special histological subtypes exhibit a favorable prognosis when compared to invasive NST carcinoma.
Exceptions to the poor prognostic pattern of TNBC are the subtypes adenoid cystic carcinoma and secretory carcinoma, which are atypical entities of the triple-negative spectrum because they are associated with a more favorable prognosis than traditional triple-negative breast tumours (9).
Biomarkers in survival
At present, there are no specific markers to determine the risk of recurrence of TNBC. Much of the current research is focused on uncovering the molecular characteristics of TNBC to obtain prognostic and predictive starting points for optimized patient care. (9) Considering the poor prognosis due to the lack of early detection in TNBC, there is an urgent need to develop new prognostic biomarkers and therapeutic targets (5).
MicroRNAs (miRNAs) are endogenous non-coding RNA molecules that have been identified to precipitate a role in breast tumorigenesis. MicroRNA expression shows different patterns depending on the molecular subtype of breast cancer. In TNBC, these different microRNAs mediate cellular processes associated with aggressive genotypes that promote metastatic development as well as resistance to treatment (7).
Recently, some miRNAs have been identified and associated with TNBC, explaining the aggressive phenotype of this carcinoma, and, remarkably, establishing the possibility that this may serve as a prognostic biomarker and contribute to cancer management strategies (5).
The pattern of microRNA expression varies with race and ethnicity. And these miRNA expression patterns as well as gene expression patterns discriminate between the main breast cancer subtypes. (7)
A group of researchers in China conducted a study collecting miRNA expression data from 749 histopathological tumour samples, in which 2238 miRNAs were found, however, upon data analysis, 96 miRNAs unique to TNBC were isolated and related to disease progression, recurrence rate and overall survival rate, it was concluded that high expression of miR-135b-5p, miR-9-3p and miR-135b-3p showed good prognosis, while high expression of miR-455-5p showed poor prognosis of TNBC patients in the database studied. (5)
In turn, in a study published in Oncotarget during 2019 by Bruna M, Sugita, genome-wide miRNA profiling was performed in TNBC subtypes of patients from Latin America and Brazil to detect copy number alterations and miRNA expression.
Five up-regulated expressed miRNAs (miR-135b-5p, miR-944, miR-1275, miR-129-2-3p and miR-634) were found and were previously reported with altered expression in breast cancer studies. (7) Proliferation and migration of TNBC cell lines are inhibited by miR-135b-5p, miR-9-3p and miR-135b-3p, while miR-455-5p promotes them. (5)
A direct relationship was found between these miRNAs and the genes FOXC1, FAM171A1 (which are direct targets of miR-9-3p) and RGMA (which is a direct target of miR-135b-3p), so it is suspected that therapy may be directed towards them. The importance of these genes is based on the fact that the FOXC1 and FAM171A1 genes are responsible for suppressing the proliferation and migration of TNBC cells. Interestingly, FOXC1, FAM171A1 and RGMA genes are involved in brain development and tumorigenesis, which may explain why TNBC tends to metastasize to the brain more frequently (5).
Several studies have shown that some miRNAs of the miR-34a family symbolise a worse prognosis for overall survival. In particular, miR-34a has been identified to act as a tumour suppressor, inducing cycle arrest, apoptosis and senescence in multiple cancer cell lines. The authors have investigated its potential to be used as a target for therapy and, recently, a liposomal miR-34a mimic formulation called MRX34 has been evaluated in patients with advanced solid tumors (11).
It is important to consider that although miRNAs are smaller than mRNAs, they are also more stable, making them an ideal marker for prognostic assessment of disease (5).
In a study conducted in China, 26 sets of immune genes were studied, including 15 immune cell types and functions in the triple-negative subtype, other breast cancer subtypes and in normal tissue. The findings were compared and the results were as follows: 1) Triple negative breast cancer has higher levels of expression of immune cell types and functional marker genes than normal tissues and other breast cancer subtypes; 2) Triple negative has higher levels of expression of inflammation-promoting genes than non-TNBC, this translates to a higher number of cytokines; 3) there is a higher degree of immune cell infiltration than in other subtypes. (12)
Elevated expression of the 11 gene sets such as B cells, CD8+ T cells, macrophages, neutrophils, NK cells, pDC, MHC class I, T cell co-stimulation, T cell co-inhibition, IFN type II response and cytolytic activity was consistently associated with a better prognosis of disease-free survival in the triple-negative type. Authors Liu Z and Li M suggest that these results indicate that triple-negative breast cancer has stronger immunogenicity compared to non-TNSCLC.
This could be an advantage for therapeutic issues as most cancer immunotherapy agents currently used in the clinic or in clinical trials or in pre-clinical development may be more effective against TNBC than other BC subtypes, and may be good candidates for clinical trials of immunotherapy against TNBC. (12)
Author Tapia-Salas, in his study conducted at the Médica Sur hospital, mentions that triple-negative tumors overexpress vascular endothelial growth factor (VEFG), and also states that although there is no FDA-approved target therapy for the triple-negative subtype, these tumors overexpress vascular endothelial growth factor (VEFG), these tumors overexpress vascular endothelial growth factor (VEFG), and because of this, the effects of some anti-VEFG monoclonal antibodies have been tested, such as Bevacizumab, which has been shown, in addition to Paclitaxel, to increase progression-free survival from 5.9 to 11.8 months in this type of patient. (13)
Conclusion
After conducting the present investigation, we fulfilled our objective, as well as our research question, and concluded that there are important associations between the pathophysiological features of this breast carcinoma subtype and long-term prognosis in affected women.
Triple-negative carcinoma, which predominates in the Hispanic race, shows a distinctive aggressiveness, which may show increased aggressiveness when associated with other biological, molecular and genetic factors in neoplastic cells, making this neoplasm an enormous research challenge due to its high phenotypic and genotypic variability.
It was also determined that further research on this topic is needed to better understand and clarify the pathogenic pathways in the development of this carcinoma and to develop new sensitive and specific therapeutics for the treatment of this pathology.
Bibliography
- Fauci, A. S., Braunwald, E., Kasper, D. L., Hauser, S. L., & Longo, D. L. (2018). Harrison. Principios de Medicina Interna. McGraw Hill Educación.
- García, M. G., & Gómez, Á. H. (2018). Manual de oncología. McGraw-Hill Interamericana.
- Tan, A. R., & Dent, R. (2018). Triple-Negative Breast Cancer. Charlotte, NC USA: Springer International Publishing. https://doi. org/10.1056/NEJMra1001389.
- Philipovskiy, A., Dwivedi, A. K., Gamez, R., McCallum, R., Mukherjee, D., Nahleh, Z.,… & Gaur, S. (2020). Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer. PloS one, 15(9), e0238262.
- Bao, C., Lu, Y., Chen, J., Chen, D., Lou, W., Ding, B.,… & Fan, W. (2019). Exploring specific prognostic biomarkers in triple-negative breast cancer. Cell death & disease, 10(11), 1-14.
- Uscanga‑Perales, G. I., Santuario‑Facio, S. K., Sanchez‑Dominguez, C. N., Cardona‑Huerta, S., Muñoz‑Maldonado, G. E., Ruiz‑Flores, P.,… & Valero‑Gomez, J. (2019). Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico. Oncology letters, 17(3), 3581-3588.
- Sugita, B. M., Pereira, S. R., de Almeida, R. C., Gill, M., Mahajan, A., Duttargi, A.,… & Makambi, K. (2019). Integrated copy number and miRNA expression analysis in triple negative breast cancer of Latin American patients. Oncotarget, 10(58), 6184.
- Urru, S. A. M., Gallus, S., Bosetti, C., Moi, T., Medda, R., Sollai, E.,… & Palmas, D. (2018). Clinical and pathological factors influencing survival in a large cohort of triple-negative breast cancer patients. BMC cancer, 18(1), 56.
- Balkenhol, M. C., Vreuls, W., Wauters, C. A., Mol, S. J., van der Laak, J. A., & Bult, P. (2020). Histological subtypes in triple negative breast cancer are associated with specific information on survival. Annals of Diagnostic Pathology, 151490.
- Villarreal-Garza, C., Weitzel, J. N., Llacuachaqui, M., Sifuentes, E., Magallanes-Hoyos, M. C., Gallardo, L.,… & Akbari, M. (2015). The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer. Breast cancer research and treatment, 150(2), 389-394.
- da Silva, J. L., Nunes, N. C. C., Izetti, P., de Mesquita, G. G., & de Melo, A. C. (2020). Triple negative breast cancer: A thorough review of biomarkers. Critical Reviews in Oncology/Hematology, 145, 102855.
- Liu, Z., Li, M., Jiang, Z., & Wang, X. (2018). A comprehensive immunologic portrait of triple-negative breast cancer. Translational oncology, 11(2), 311-329.
- Tapia-Salas, I., Motola-Kuba, D., Chable-Montero, F., Alvarado-Luna, G., & Arrieta-Rodriguez, Ó. (2017). Poor survival in triple negative breast cancer. Médica Sur, 23(1), 34-37.