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Triple negative breast cancer in Moroccan women: A study
– Reported, June 11, 2013
Patients with local disease had received corresponding local treatments (surgery plus radiotherapy) and systemic treatments (mainly adjuvant and/or neoadjuvant chemotherapy). The main surgical operations included radical mastectomy (Patey type mastectomy) and breast conserving surgery when permitted by tumor size according to the judgment of the multidisciplinary care team. Patients how had metastatic disease at diagnosis received mono or poly chemotherapy based on the characteristics of the tumors and the aggressiveness of the disease. These patients have received palliative radiotherapy if indicated.
Of nine hundred eighty breast cancer patients, diagnosed between 2007 and 2008, with available immunostaining data, 16,5% were assessed as TNBC. In the US, approximately 15-20% of breast cancers are TNBC. However, some studies have suggested that its prevalence differs between races with a higher prevalence reported among African-American women and Hispanic.
TNBC are associated with a younger age at presentation, having a mean age of 53 years old, compared to 58 years old for other subgroups in a study. However, until now, there is still no final conclusion about whether age is a risk factor of TNBC, and there are still inconsistent findings in previous clinical studies. In our study population, the median age at diagnosis (46 years) was younger than the average age mostly reported in the United States but may be comparable to the median age in Hispanic triple negative breast cancer patients . Additionally, thirty two (17, 7%) patients had an age = 35 years old suggesting that there might be factors that may predispose them to development of this disease. Given that the early age at onset is generally considered an indicator of genetic susceptibility to breast cancer and the fact that triple negative entity most often presents at a young age, an important part of future progress will be the identification of subgroups who may have a higher personal or familial risk of developing TNBC.
From an epidemiologic perspective, the known risk factors for triple-negative disease are modest, suggesting few clear interventions. Race appears to be a risk factor, as TNBC is more frequent in premenopausal patients of African-American heritage. There is also some suggestion that TNBC are more prevalent among women who reside at a lower socioeconomic level and/or lack access to healthcare. In the current study, no racial or socioeconomic specificity have been identified.
What is less well known is whether anthropometrics, demographics, and reproductive history are independently associated with TNBC. Previous population-based work has observed that younger age at menarche or younger age at first pregnancy, higher parity, shorter duration of breast feeding, higher body mass index (BMI) or higher waist to-hip ratio (WHR) were all associated with basal-like tumors versus luminal A tumors (tumors characterized by positive ER and PR and negative HER2) . Oral contraceptive use for more than one year was associated with a 2.5-fold increase in the incidence of TNBC. It has been proposed that the mechanism through which oral contraceptives use impacts the risk of breast cancer among young women is that estrogen promotes the growth of breast cancer-enhancing angiogenesis and stromal cell recruitment. In the current series, oral contraception was found in 23% of our patients.
Recently, the association between BRCA1 mutations and the development of TNBC is well established. In a recent report, Gonzalez Angulo and al found a 19.5% incidence of BRCA mutations. Review of the spectrum of breast cancer tumor subtypes, which include basal-like, triple-negative and BRCA1-positive tumors, suggest that they have overlapping clinical, pathologic and molecular features, which are different from endocrine responsive breast cancers. Gene-profiling studies of this heterogeneous subset have lead to a better understanding of the molecular pathology of these aggressive tumors and the identification of possible therapeutic targets. More recently, poly (ADP-ribose) polymerase PARP inhibitors appear to take advantage of the concept of synergic lethality, or dual pathway inhibition, in attacking triple-negative and BRCA-associated tumors. The current study found less than 10% of family history of breast cancer. Unfortunately, the research of a BRCA1/2 gene mutation was not performed due to its non availability in the time of study period.
Triple negative breast cancer in the studied patients was more frequently diagnosed at advanced stage. Consequently, the majority of patients received radical mastectomy. Only 23% of our patients with local disease received conservative surgery. Haftty et all demonstrates in a previous report that there was no evidence that TNBC patients are at higher risk for local relapse after conservative surgery and radiation although triple negative have a poor prognosis.
The pattern of distant recurrence was strikingly different between cancer subgroups. In patients with triple negative breast cancer, the risk of any recurrence rose sharply from date of diagnosis, peaked 1 to 3 years, and dropped quickly thereafter. The patients outcomes (OS and DFS) in our series are in accordance with other previous reports.
TNBC clearly represents an important clinical challenge. This is due to poor disease-free intervals in the adjuvant and neoadjuvant setting, shortened progression-free survival associated to a more aggressive clinical course in the metastatic setting, and the lack of targeted therapy. Most recent studies in triple-negative disease are directed to better identify effective treatment options and improve outcomes in these patients. Chemotherapy is known to be effective in triple-negative disease, and advances in chemotherapy have particularly benefited this patient group. However, there is not a clear, proven effective single agent that targets a driving vulnerability in triple-negative breast cancer.
Although response to chemotherapy is high in the neoadjuvant setting, the overall prognosis of this subset of tumors remains poor. Liedtke and al demonstrates in a previous report that patients with TNBC have increased pathologic complete response (pCR) rates compared with non-TNBC, and also had better survival compared to TNBC patients who dont achieve pCR.
However, a poorer prognosis was seen in the triple-negative subgroup with residual disease (RD) after completing neoadjuvant chemotherapy, particularly in the first 3 years. The systemic effect of neoadjuvant chemotherapy on the immune system deserves to be accurately investigated. Several researchers have dedicated their attention to cancer immune response in order to identify prognostic factors and immunological targets. In a recent study, Denkert and al reported that it is possible to identify a subgroup of breast carcinomas that is characterized by a lymphocytic infiltrate In the tumor tissue and a particularly strong response to chemotherapy .In our series, 28% of patients receiving neoadjuvant chemotherapy achieved pCR, which is in accordance with the literature.
Most approaches in triple-negative disease consist of more targeted chemotherapy, growth factor pathway approaches, and BRCA1-driven approaches. Many antiangiogenic treatments have been introduced or are currently under development, and may hold promise for patients with triple-negative breast cancer. Bevacizumab has the most data in breast cancer. In a recent report from Von Minckwitz and al, the addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome.
In metastatic setting, three randomised clinical trials (E2100, AVADO and RIBBON I) has proven the efficacy of Bevacizumab combined with chemotherapy, especially with taxanes, as the first line treatment of metastatic breast cancer. The combination improved patient progression-free survival in all trials with no impact on the known toxic effects of taxanes. This may be a potent treatment option particularly for patients with triple negative breast cancer .
As mentioned previously, PARP inhibition may be another therapeutically valuable mechanism in patients with triple negative disease. Some clinical data are available to support this approach. In one phase II study of olaparib, an oral PARP inhibitor was conducted in pretreated BRCA1 or BRCA2 mutation carriers, 41% exhibited response to this therapy. Another PARP inhibitor, Iniparib, is an i.v. agent studied first in a randomized phase II of patients with metastatic triple-negative disease. Patients were randomized to receive gemcitabine plus carboplatin either alone or with the addition of Iniparib. This trial, suggested that the addition of iniparib to chemotherapy improved the clinical benefit and survival of patients with metastatic triple-negative breast cancer without significantly increased toxic effects. However, this result was not confirmed by the phase III trial presented at the 2011 ASCO Annual Meeting. The selection of patients who may benefit from these agents is essential, for instance, these agents may prove to be effective only in patients with BRCA1 or BRCA2 mutations.
The majority of triple-negative breast cancer tumors overexpress the EGFR(epidermal growth factor receptor). EGFR has been considered as a sensible target in basal-like and triple negative breast cancer. Cetuximab, which is an anti-EGFR monoclonal antibody, was added to carboplatin therapy in a pretreated triple-negative cohort, with a modest response rate of 17%. Meanwhile, in a subset of the U.S. Oncology 225200 trial, the addition of cetuximab to carboplatin and irinotecan led to a higher response rate, 49% versus 30%, but did not improve the PFS interval. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.
In summary, this report documents the clinical experience of TNBC at our institution. This study is limited by our unfortunate inability to determine the exact incidence of TNBC and to do the comparative study with other breast cancer subtype. In addition, the lack of cytogenetic investigation of BRCA gene mutation due to the low socioeconomic level of these patients and the lake of Her-2 gene amplification test in the half of breast cancer patients diagnosed in our institution are two major limitations.
CREDITS.
Ghizlane Rais, Soundouss Raissouni, Meryem Aitelhaj, Fadoi Rais, Sara Naciri, Siham Khoyaali, Halima Abahssain, Youssef Bensouda, Basma Khannoussi, Hind Mrabti and Hassan Errihani
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