Triple-negative breast cancer: A run-through of features,classification and current therapies

Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12–20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.     

Systemic treatment for triple negative breast cancer in older patients: A Young International Society of Geriatric Oncology Review Paper

Breast cancer is the most common type of cancer affecting women worldwide and its risk increases with age. Compared with other breast cancer subtypes, triple negative breast cancer (TNBC) behaves more aggressively, with earlier relapses and poorer survival outcomes. Although the incidence of TNBC decreases with age, it still affects about 10% of older women with breast cancer. The management of TNBC in older patients is particularly challenging as chemotherapy is the main treatment choice in both early and advanced diseases and older patients are often prone to increased treatment-related toxicities. This review highlights the specific considerations in this vulnerable group of patients and summarizes the current evidence for TNBC management in older adults from early to late stage of disease.     

Epidemiology of ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is a relatively common diagnosis among women undergoing screening mammography. The greatest increases in DCIS incidence have been in non-comedo subtypes of DCIS that are not associated with subsequent invasive cancer. After a 500% increase in DCIS from 1983 to 2003, the incidence of DCIS declined in women aged 50 years and older, whereas the incidence in women younger than age 50 continues to increase. Having undergone mammography is one of the strongest and most prevalent risk factors associated with a diagnosis of DCIS. Other risk factors for DCIS are similar to that for invasive cancer including increasing age, family history of breast cancer, high mammographic breast density, and postmenopausal hormone therapy use. Treatment for DCIS is relatively aggressive with the use of both surgery and radiation therapy and most recently adjuvant hormonal therapy. Breast cancer mortality is low and similar with all types of treatment. New information regarding incidence of DCIS and subtypes of DCIS according to frequency of mammography and risk factors could lead to insights into the biology of DCIS.     

Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways

Breast cancer is the most prevalent cancer in women worldwide. About 15–20% of all breast cancers are triple negative breast cancer (TNBC) and are often highly aggressive when compared to other subtypes of breast cancers. To better characterize the biology that underlies the TNBC phenotype, we profiled the phosphotyrosine proteome of a panel of twenty-six TNBC cell lines using quantitative high resolution Fourier transform mass spectrometry. A heterogeneous pattern of tyrosine kinase activation was observed based on 1,789 tyrosine-phosphorylated peptides identified from 969 proteins. One of the tyrosine kinases, AXL, was found to be activated in a majority of aggressive TNBC cell lines and was accompanied by a higher level of AXL expression. High levels of AXL expression are correlated with a significant decrease in patient survival. Treatment of cells bearing activated AXL with a humanized AXL antibody inhibited cell proliferation and migration in vitro, and tumor growth in mice. Overall, our global phosphoproteomic analysis provided new insights into the heterogeneity in the activation status of tyrosine kinase pathways in TNBCs. Our approach presents an effective means of identifying important novel biomarkers and targets for therapy such as AXL in TNBC.     

No evidence for an association of human papillomavirus and breast carcinoma

Breast cancer represents a serious public health problem worldwide, for its high incidence, morbidity, mortality, and its high cost treatment. It is known that breast cancer is a multifactorial disease, possessing various risk factors, among which include hormonal factors, genetic and environmental. The role of viruses in breast carcinogenesis is controversial. This study aims to evaluate the expression of HPV 6, 11, 16, and 18 by polymerase chain reaction (PCR) in invasive ductal breast carcinoma. We analyzed 90 women diagnosed with invasive ductal breast carcinoma, of which the extracted DNA was amplified, quantified and tested for DNA subtypes 6, 11, 16, and 18 by PCR. The research carried out in 79 samples of HPV DNA, proved negative. Our study demonstrates no association between the most prevalent types of HPV and breast cancer.     

Ethnic differences in the incidence of cancer in Norway

Traditionally there have been differences in cancer incidence across geographic regions. When immigrants have moved from low‐income to high‐income countries, their incidence have changed as they have adapted to the lifestyle in the new host country. Given worldwide changes in lifestyle factors over time, we decided to examine cancer incidence in immigrant groups in Norway, a country with a recent immigration history, complete cancer registration and universal public health care. We linked immigration history for the complete population to information on cancer diagnosis from the Cancer Registry of Norway for the period 1990–2012. Age‐standardized (world) overall and site‐specific cancer incidence were estimated for different immigrant groups and compared to incidence among individuals born in Norway. Among 850,008 immigrants, 9,158 men and 10,334 women developed cancer, and among 5,508,429 Norwegian‐born, 263,316 men and 235,020 women developed cancer. While incidence of breast and colorectal cancer were highest among individuals born in Norway and other high‐income countries, other cancer types were higher in immigrants from low‐income countries. Lung cancer incidence was highest in Eastern European men, and men and women from Eastern Europe had high incidence of stomach cancer. Incidence of liver cancer was substantially higher in immigrants from low‐income countries than in individuals born in Norway and other high‐income countries. Our results mirror known cancer challenges across the world. Although cancer incidence overall is lower in immigrants from low‐income countries, certain cancers, such as lung, liver and stomach cancer, represent major challenges in specific immigrant groups.     

Epidemiology of Breast Cancer

All over the world, the most common malignancy in women is breast cancer. Breast cancer is also a significant factor of death in women. In 2020, approximately 2.3 million cases of breast cancer were newly diagnosed in women globally, and approximately 685,000 people died. Breast cancer incidence varies by region around the world, but it is all increasing. According to the current morbidity and mortality trend of breast cancer, it is estimated that by 2030, the number of incidence and deaths of breast cancer will reach 2.64 million and 1.7 million, respectively. The age-standardized incidence rate was 66.4/100,000 in developed countries and 27.3/100,000 in developing countries. The incidence of breast cancer in the world is increasing rapidly, and the incidence rate has increased by 57.8% in the past 30 years, and the rate of increase is 0.5% per year. The incidence and mortality of breast cancer among Chinese women rank first in the world, and in recent years, the incidence and mortality of breast cancer among Chinese women have also been on the rise. Breast cancer is a disease caused by a variety of factors, such as genetics, estrogen levels, environment, and behavior and lifestyle. The purpose of this review is to explore the global epidemiology, associated risk factors and molecular types of breast cancer to understand breast cancer prevalence, mortality, and to help with its prevention, early detection, treatment and improvement of prognosis.     

Proteomics approaches: New Technologies and Clinical Applications in Breast Carcinomas

Breast cancer is the most diagnosed cancer in women, accounting for approximately 40,000 deaths annually in the USA. In Tunisia, the incidence of breast cancer is approximately 19 new cases per 100,000 women per year. Significant advances have been made in the areas of detection and treatment, but a significant number of breast cancers are detected late. The advent of proteomics provides the hope of discovering novel biological markers that can be used for early detection, prognosis, diagnosis, and therapy. Several proteomics technologies have been used to uncover molecular mechanisms associated with breast. Introduction: Breast cancer is a major health problem and one of the leading causes of death among women worldwide. Its incidence is steadily rising in developing countries. In Tunisia, the incidence of breast cancer is approximately 19 new cases per 100,000 women per year(1). Invasive carcinomas represent 70-80% of all breast cancer and among these, infiltrating ductal carcinomas (IDCA) are the most aggressive forms and have a poor prognosis(2). Histopathologically identical breast cancers show a different biological behavior in terms of aggressiveness, progression, and response to therapy. Thus, there is a great need for new breast cancer biomarkers that might help detect this cancer at an earlier stage, to uncover prognostically distinct subclasses, and to provide best individual treatment(2). Currently, the search for specific cancer-related alterations are largely carcinoma at the global level to discover protein patterns that distinguish disease and disease-free states with high sensitivity and specificity. Two dimensional gel electrophoresis coupled with mass spectrometry constitute a new proteomicsbased paradigm for detecting disease in pathology specimens and monitoring disease response to therapy. This review describes these proteomics technologies and their application in the analysis of breast carcinoma Keywords: Breast cancer, Proteomics, Markers, 2-DE, MALDI-TOF.     

Unique sphingolipid signature identifies luminal and triple-negative breast cancer subtypes

Breast cancer (luminal and triple-negative breast cancer [TNBC]) is the most common cancer among women in India and worldwide. Altered sphingolipid levels have emerged as a common phenomenon during cancer progression. However, these alterations are yet to be translated into robust diagnostic and prognostic markers for cancer. Here, we present the quantified sphingolipids of tumor and adjacent-normal tissues from patients of luminal (n = 70) and TNBC (n = 42) subtype from an Indian cohort using targeted liquid chromatography mass spectrometry. We recorded unique sphingolipid profiles that distinguished luminal and TNBC tumors in comparison to adjacent normal tissue by six-sphingolipid signatures. Moreover, systematic comparison of the profiles of luminal and TNBC tumors provided a unique five-sphingolipid signature distinguishing the two subtypes. We further identified key sphingolipids that can stratify grade II and grade III tumors of luminal and TNBC subtype as well as their lymphovascular invasion status. Therefore, we provide the right evidence to develop these candidate sphingolipids as widely acceptable marker/s capable of diagnosing luminal vs TNBC subtype of breast cancer, and predicting the disease severity by identifying the tumor grade.     

Female breast cancer in Vietnam: a comparison across Asian specific regions

Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer death of women over the world. A large number of females with breast cancer in Vietnam and other Southeast Asian (SEA) countries present at an early age with more aggressive tumors compared with women in Australia. Despite experiencing a low incidence rate, the increasing incidence rate among SEA countries exceeds that of the Westernized world. Changes in reproductive factors, environmental exposures, and lifestyle are the possible causes of this trend. However, limited evidence shows that these factors are associated with breast cancer in the Vietnamese population. Breast cancer incidence rates within Vietnam are not uniform and appear to be dependent on geographic location. Findings from this review have important implications for breast cancer control and treatment in Vietnam. A good understanding of the morphology of the breast and the type and nature of breast cancers presenting in Vietnam is required to facilitate the introduction of an effective national breast screening program.KEYWORDS : Breast cancer, Vietnam, Southeast Asia (SEA), Australia     

nab-Paclitaxel for the Treatment of Aggressive Metastatic Breast Cancer

Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple-negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis.     

Potential Risk Factors for Breast Cancer in Pakistani Women

Background: Breast cancer is the most common female malignancy worldwide and its incidence is on the rise in Pakistan. The aim of this case-control study was to quantify the association of various risk factors with breast cancer risk among Pakistani women. Materials and Methods: A total of 2,246 women were studied, including 1,238 women with histologically confirmed breast cancer patients and age matched control subjects (N1008) without breast cancer and other chronic diseases. Subjects were interviewed using a specifically designed questionnaire. Unconditional logistic regression was applied. Subsequent disease-specific mortality was also measured. Results: In this study, majority of the breast cancer patients (69.59%) were in age ranges of 40s and 50s. BMI greater than 25kg/m2 (OR1.57; 95%CI, 1.26-1.90 and OR1.60; 95%CI, 1.26-2.03), marital status of unmarried (OR2.03; 95%CI, 1.69-2.44), lack of breast feeding, smoking (current or ever), lack of physical activity and post-menopausal status were found to have significant positive associations with breast cancer. It was also observed that increased parity reduced the disease risk. A larger number of cases (58.1%) had their right breast affected while 22.8% had other complications as well. Conclusions: This exploratory analysis indicated a number of risk factors to be associated with increased risk of breast cancer. It was also observed that mean age at diagnosis is a decade earlier than in western countries. It is hoped that our findings will facilitate establishment of adequate evidence-based awareness and preventive measures for Pakistani women.     

Factors that influence the incidence of breast cancer in Arica, Chile (Review)

Breast cancer is a common disease estimated to occur in 1 in 9 women over their lifetime. Epidemiological research has identified a number of risk factors for breast cancer. Racial and ethnic differences in breast cancer mortality rates have been difficult to ascertain. The present review reports that there was an increase in the incidence of breast cancer in Arica, Chile, from 1997 to 2007, particularly in 2005, reaching 55.1% per 100,000 women, while the percentage decreased in 2006 and 2007. A greater percentage of breast cancer was found in individuals between 46 and 65 years of age when the population was distributed by age. The Indian population, Aymara, had only a 13.9% incidence of the disease. The incidence for breast cancer for patients with no family background reached approximately 88%, with or without Indian ethnicity, and 98.4% of these women did not have prior hormonal therapy. When the stage of the disease and the number of pregnancies were considered, results showed that there was an increase in the progression of the disease from stage I to stage III in women that had 1-3 pregnancies. Results also showed that 20.9 and 33.2% who received prior tamoxifen treatment were in stages I and IIA, respectively. The breast cancer incidence reached 42.4% when patients had a sister with the disease. It can be concluded that important differences in the risk factors of breast cancer should be identified in the future for a comparison with other biological factors, such as genetic and molecular factors. This may provide greater insight into breast cancer aetiology in different populations.     

Risk factors for breast cancer among young women in southern Iran

Age standardized incidence rates of breast cancer in developed countries is nearly threefold higher than in developing countries. Iran has had one of the lowest incidence rates for breast cancer in the world, but during the last four decades increasing incidence rates of breast cancer made it the most prevalent cancer in Iranian women. After adjustment for age, Iranian young women are at relatively higher risk of breast cancer than their counterparts in developed countries. The purpose of this study was to investigate some established risk factors of breast cancer in Iranian young women. A hospital-based case control study comprising 521 women with histologically confirmed, incident breast cancer and 521 controls frequency-matched by age and province of residence was conducted. Logistic regression performed to investigate associations of reproductive and anthropometric factors with breast cancer risk. In multivariate analysis, family history [odds ratio (OR): 1.61; 95% confidence interval (CI): 1.07-2.42], oral contraceptives (OC) usage (OR: 1.52; 95% CI: 1.11-2.08), low parity (OR parity ≥ 3 vs. 1-2: 0.33; 95% CI: 0.23-0.49), employment (OR: 1.83; 95% CI: 1.05-3.23) and shorter period of breast feeding (OR ≥ 37 months vs. < 37: 0.61; 95% CI: 0.44-0.84) were related to a higher risk of breast cancer in young women. This was the first study focusing on risk factors of breast cancer in Iranian young women. The trend of decreasing parity and shortened duration of breast feeding along with OC usage might partly explain the rapid rising of breast cancer incidence in Iranian young women.     

Familial risk factors for breast cancer among Arab women in Israel.

The incidence of breast cancer in Arab women is low compared with western populations in other countries. Very few studies on risk factors for breast cancer in Arab women have been reported. The aim of the present study was to evaluate familial risk factors for breast cancer among Arab women in Israel. A case-control study was carried out on 72 Arab women diagnosed with breast cancer and 140 healthy controls. Cases were identified through oncology wards and controls were sampled from community and hospital out-patient clinics. All participants were interviewed and information obtained on family history of breast cancer and other cancers, and other potential risk factors. Eight women with breast cancer and five women without breast cancer had a first-degree relative with breast cancer. The odds ratio for breast cancer for a woman with a first-degree relative with breast cancer was 3.4 (95% confidence interval (CI) 1.06-10.7, P = 0.04). The odds ratio for Muslim women with a first-degree relative with breast cancer was higher than that for Christian women (6.07 and 1.53, respectively). Family history of breast cancer was a risk factor for breast cancer in Arab women. The estimated relative risk associated with an affected first-degree relative was generally higher than that reported from other populations.     

Prevalence of Known Risk Factors in Women Diagnosed with Breast Cancer at Inmol Hospital,Lahore, Punjab

Background: Breast cancer is the most prevalent cancer in women worldwide and its frequency is increasing gradually in many countries. Over the last three decades an increase in the breast cancer has been witnessed in the earlier low-risk Asian countries including Pakistan. Purpose: The objective of the current study was to assess the prevalence of known risk factors like early menarche, late menopause, socio economic, reproductive and demographic factors, among women diagnosed with breast cancer at INMOL hospital, Lahore, Punjab, as little information exists in this regard. Materials and Methods: A survey study was conducted on 200 women diagnosed with breast cancer who were seen at Institute of Nuclear Medicine and Oncology (INMOL) hospital, Lahore. A structured questionnaire was administered to these patients regarding the known risk factors through face to face interviews after obtaining appropriate consent. Results: Regarding non-modifiable risk factors, our study showed that majority of the breast cancer patients were diagnosed at 35-45 years (32.5%) or at older age (≤46) and experienced menarche at 12 years or older (66 %). Likewise, a large number of patients reached menopause at the age of 45 years (60%), had no family and personal history of breast cancer (80%) and hence fell in a low risk category. Regarding modifiable risk factors in women diagnosed with breast cancer, most of the patients fell in low risk strata as the majority were married (98%) at young age, breastfed their children for 12 months or more (88%) and bore two to three children (80%). Considering income criteria, the majority of the patients had a low risk profile as they belonged to middle class (70%), urban area (60%) and were house wives (80%). However, it was noted that a considerable number of women (34%) diagnosed with breast cancer experienced menarche at an early age (<12) and reached menopause after the age of 45 years. This situation is further augmented by environmental changes and dietary habits and places them in a high risk category.     

Breast cancer-specific survival by clinical subtype after 7 years follow-up of young and elderly women in a nationwide cohort

Age and tumor subtype are prognostic factors for breast cancer survival, but it is unclear which matters the most. We used population-based data to address this question. We identified 21,384 women diagnosed with breast cancer at ages 20–89 between 2005 and 2015 in the Cancer Registry of Norway. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A-like (ER+PR+HER2-), luminal B-like HER2-negative (ER+PR-HER2-), luminal B-like HER2-positive (ER+PR+/-HER2+), HER2-positive (ER-PR-HER2+) and triple-negative (TNBC) (ER-PR-HER2-). Cox regression estimated hazard ratios (HR) for breast cancer-specific 7-year survival by age and subtype, while adjusting for year, grade, TNM stage and treatment. Young women more often had HER2-positive and TNBC tumors, while elderly women (70–89) more often had luminal A-like tumors. Compared to age 50–59, young women had doubled breast cancer-specific mortality rate (HR = 2.26, 95% CI 1.81–2.82), while elderly had two to five times higher mortality rate (70–79: HR = 2.25, 1.87–2.71; 80–89: HR = 5.19, 4.21–6.41). After adjustments, the association was non-significant among young women but remained high among elderly. Young age was associated with increased breast cancer-specific mortality among luminal A-like subtype, while old age was associated with increased mortality in all subtypes. Age and subtype were strong independent prognostic factors. The elderly always did worse, also after adjustment for subtype. Tumor-associated factors (subtype, grade and stage) largely explained the higher breast cancer-specific mortality among young. Future studies should address why luminal A-like subtype is associated with a higher mortality rate in young women.     

Risk factors for breast cancer among women in Bhopal urban agglomerate: a case-control study

Background: Breast cancer is the most common cancer in females worldwide, and the second leading cause of cancer deaths in women. The incidence is on the rise in India, and breast cancer is the second most common malignancy in Indian women. Objective: To assess the risk factors for breast cancer patients living in Bhopal. Study Design and Method: This case-control study was conducted in Bhopal urban agglomerate for a period of a year from October 2008 to August 2009. Demographic data and reproductive risk factor related information was collected using a structured questionnaire with analyses by Epi-info and SPSS 16. Results: A history of oral contraceptive pill use (OR=2.77, 95% CI: 1.15-6.65), history of not having breastfeeding (OR=3.49, 95% CI:1.22-9.97), over weight (OR=0.11, 95%CI:0.02-0.49), obese women ( OR=0.24, 95%CI: 0.06-0.88) and family history of breast cancer (OR=3.89, 95% CI: 1.01-14.92) were associated significantly with the occurrence of breast cancer on multivariate analysis. Conclusions: The findings of the present study suggests that positive family history of breast cancer and history of using OCP may be the epigenetic factors promoting the occurrence of breast cancer while breastfeeding reduces the possibility of acquiring breast cancer.     

三阴性乳腺癌易患因素的研究进展

三阴性乳腺癌（Triple negative breast cancer,TNBC）是乳腺癌的一种特殊亚型,包括基底样型乳腺癌和未分类型乳腺癌。自从2005年被定义,TNBC在生物学特性上与其他亚型的差异、不良的预后情况就一直是流行病学家,病理学家及临床医生研究的重点与热点。 TNBC的易患因素包括种族、肥胖、年龄、女性生殖期口服避孕药、体育锻炼、流产史、家族史和社会经济因素等。本文主要就种族、肥胖、女性生殖期口服避孕药和年龄对三阴性乳腺癌的影响的最新研究成果进行综述,旨在加强健康女性对三阴性乳腺癌的认识与自我保健,提示临床医生将TNBC生物学特点与流行病学特点结合进行指导预防,为研究人员对TNBC的病因学进一步的研究提供更多的理论依据。