Clinical and pathological characteristics of occult breast cancer and review of the literature

Purpose: Occult breast cancer is defined as axillary metastasis without clinically and/or radiologically evident primary tumor. In female patients presenting with isolated axillary nodes with adenocarcinoma, the most likely primary cancer is an invasive breast carcinoma. Herein we present our experience over this issue, together with a brief review of the literature about this clinically challenging condition. Methods: We retrospectively analyzed 1215 consecutive breast cancer patients treated at our clinic between 2004- 2010. Four of these patients presented with axillary nodal metastasis without clinical and radiological evidence of a primary breast tumor. Results: The incidence of occult breast cancer in our clinic was 0.32%. Median follow-up was 8 months. All patients were alive and remained free of disease at the end of the follow-up period. Conclusion: The prognostic factors for occult breast carcinoma are similar to that of its overt counterpart. The number of axillary lymph node involved and the hormone receptor status are considered significant prognostic predictors. Further studies with randomization and longer followup are needed for the establishment of a safe management plan.     

Anti-HER2 vaccines: new prospects for breast cancer therapy

Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-over-expressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti-HER2 passive immunotherapy, these observations allowed to envisage various vaccine strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells, or specific to HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of research concerns the use of anti-idiotypic antibodies mimicking HER2.     

Sequential adjuvant hormone therapy in postmenopausal breast cancer: rationale and clinical results

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer. We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.     

Patterns of post-operative irradiation in breast cancer patients submitted to neoadjuvant chemotherapy

Background/AimPost-operative radiation therapy (PORT) is associated with improvement in loco-regional control and survival rates in early breast cancer. However, the evidence of benefit in patients after treatment with neoadjuvant chemotherapy (NAC) is poor. We aimed to assess the impact of the type of surgery in the PORT plan and the role of the PORT fields in clinical outcomes in breast cancer patients who had undergone NAC followed by surgery.Materials and methodsWe performed a retrospective analysis of all non-metastatic breast cancer patients treated between 2008 and 2014 at our institution who had received NAC and PORT.ResultsA total of 528 women were included of whom 396 were submitted to mastectomy or nipple-sparing/skin-sparing mastectomy. Most (92.8%) of the patients had locally advanced disease (clinical stage IIB to IIIC). All patients underwent irradiation for breast or chest wall. Most patients received PORT to the supraclavicular and axillary (levels II and III) nodes (87.1% and 86.4% for breast-conserving surgery and 95.1% and 93.8% for mastectomy and nipple-sparing/skin-sparing mastectomy, respectively). Irradiation of level I axillary and internal mammary nodes was uncommon. The disease-free survival and overall survival rates at 3 years were 72% and 85%, respectively. There were no statistically significant differences in clinical outcomes according to the use of nodal irradiation.ConclusionsAfter NAC, most patients received irradiation of the breast/chest wall and axillary and supraclavicular nodes. In this setting, PORT to breast/chest wall with or without regional nodal irradiation was safe and effective, with acceptable disease-free and overall survival rates reported in this high-risk population.     

Locally advanced breast cancer in Saudi Arabia: high frequency of stage III in a young population

In the Kingdom of Saudi Arabia (KSA), breast cancer constitutes 18% of all cancers in Saudi women. Whilst locally advanced breast cancer disease is unusual in Western countries, it constitutes more than 40% of all non-metastatic breast cancer in KSA. The relative frequency of locally advanced disease among our breast cancer population and the lack of a uniform consensus in the literature about its optimal management have prompted this retrospective analysis of the medical records of patients with Stage III breast cancer patients seen at King Faisal Specialist Hospital and Research Center between 1981 and 1991. In all, 315 patients were identified. Their median age ±SD was 46±11.6 years which is distinctly different from the 60–65 years median age in industrial Western nations. Most patients were younger than 50 years (64%) and premenopausal (62%). Patients were approximately equally divided between Stage III A and Stage III B Patients received multimodality treatment, including surgery., adjuvant chemotherapy, tamoxifen, and adjuvant radiotherapy. Sixty-one patients were excluded from survival analysis as they were considered lost to follow-up. Of the remaining 254 patients, 73 (29%) were alive and disease free, and 18 patients (7%) were alive but, with evidence of the disease. The remaining 163 (64%) had died from breast cancer or its related complications. Their median overall survival (OS) was 54 months, (95%, Cl, 27 to 121 months) and the median progression-free survival (PFS) was 28.8 months (95% Cl, 14.2 to 113 months). Cox proportional hazard, model identified Stage III B and the number of positive axillary lymph nodes as poor predictors of OS and PFS. Radiotherapy was the only adjuvant modality that affected survival favourably. The prognosis of patients with Stage III disease remains poor despite the use of a multimodality approach. The overall young age of our patients may have contributed to the poor outcome. Moreover, the adverse effect of Stage III B disease (as compared with Stage III A) and axillary nodal status was evident. Whilst the favourable effect of radiotherapy on survival was demonstrated, the lack of independent efficacy of other modalities (adjuvant chemotherapy and tamoxifen) or the apparent deleterious effect of neoadjuvant chemotherapy should be addressed with discretion in such retrospective analysis. Optimal management of patients with locally advanced breast cancer disease should be appraised in well designed, prospective, randomised studies.     

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

BackgroundAn essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.ResultsHere, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.ConclusionsConsidering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0599-z) contains supplementary material, which is available to authorized users.     

Preclinical and clinical aspects of TNF-α and its receptors TNFR1 and TNFR2 in breast cancer

Breast cancer is the most common malignancy in women and a public health problem worldwide. Breast cancer is often accompanied by an inflammatory process characterized by the presence of proinflammatory cytokines such as tumor necrosis factor (TNF-α), which has important implications in the course of the disease. Inflammation has been described primarily as a favorable environment for tumor development. However, under certain conditions TNF-α can promote signals for activation, differentiation, survival or cell death, so the study of the variants of this cytokine, its receptors, the presence of polymorphisms and its implication in different phenotypes of breast cancer is necessary. Although the clinical application of TNF-α has been limited by its toxicity and side effects, preclinical and clinical studies have shown that these effects may partially be avoided via tumor-targeted delivery strategies. In this manner, TNF-α alone or combined with chemotherapy and radiotherapy can function as an adjuvant in the treatment of breast cancer.     

The thyroid gland function assessment in women after mastectomy and chemotherapy during breast cancer therapy

INTRODUCTION: For many years much attention has been focused on an interaction between the breast disease and the thyroid gland function in the literature. In those studies the question whether disease changes in the thyroid gland can induces the breast disease was addressed. On the other hand there are a few works concerning the inverted question whether the breast cancer therapy, in particular after mastectomy and chemotherapy, can disturb the thyroid gland function. The aim of the study is to investigate the influence of the mastectomy and chemotherapy on the thyroid gland function in women after breast cancer therapy. MATERIAL AND METHODS: 173 patients aged 30-80 (average 56) were included in this study. The studied group comprised 97 women after breast cancer therapy (average age 60). The control group consisted of 76 patients (average age 55). 75 patients after mastectomy of the studied group were additionally treated with chemotherapy, but in 22 women chemotherapy was not applied. The following methods were used to carry out the research: the USG method was applied to evaluate thyroid morphological condition in women after mastectomy and chemotherapy; the color Doppler technique was used for dynamic presentation and fine- needle aspiration biopsy: examination of the thyroid functional state by measuring the TSH, fT(3), fT(4) hormone concentration and the level of antithyroid antibodies. RESULTS: An average concentration of antithyroid antibodies: anti-TPO and anti-Tg was found significantly higher in the studied group of women after chemotherapy, comparing with the control group. The level of fT(3) hormone concentration was comparable in all investigated groups. Nevertheless, the average concentration of TSH was found higher in women after mastectomy and chemotherapy and as a consequence leading to hypothyroidism. CONCLUSION: Taking into consideration the high level of the concentration of antithyroid antibodies: (anti-TPO and anti- Tg), which lead to destruction of the thyroid gland tissue, the thyroid gland function of the women after mastectomy and chemotherapy should be monitored morphologically as well as functionally.     

CEA determination in the follow-up of extracolorectal neoplasms.

CEA was initially described as a tumor and organ specific colorectal antigen, but later found by more sensitive methods in other tumors (stomach, pancreas, lung, breast) and in minor amounts in inflammatory, normal adult and fetal organs of the gastrointestinal tract. The main clinical application of CEA concerns its pretherapeutic and serial determination as circulating antigen in serum and other body fluids by means of CEA-specific, commercially available test kits. By clinical studies a significant correlation has been proven between the pretherapeutic serum CEA level and tumor stages and prognosis. Moreover, serial CEA level changes have been shown a valuable monitor following operation or during radio/chemotherapy anticipating and reflecting the clinical course of disease. In combination with newly established tumor markers, the main clinical indication for CEA determination in addition to colorectal cancer concerns monitoring of patients with stomach (+CA 72-4), lung (+NSE/SCC) and breast cancer (+CA 15-3/MCA).     

Metabolic syndrome and breast cancer: an overview

Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the most important cause of cancer-related deaths among women. This disease is on the rise in Turkey. Metabolic syndrome is a cluster of metabolic disturbances including insulin resistance, dyslipidemia, hypertension, abdominal obesity and high blood sugar. Several studies have examined the association of the individual components of the metabolic syndrome with breast cancer. More recent studies have shown it to be an independent risk factor for breast cancer. It has also been associated with poorer prognosis, increased incidence, a more aggressive tumor phenotype. Basic research studies are now in progress to illuminate the molecular pathways and mechanisms that are behind this correlation. Given the fact that all of the components of metabolic syndrome are modifiable risk factors, preventive measures must be established to improve the outcome of breast cancer patients. In this review we set the background by taking into account previous studies which have identified the components of metabolic syndrome individually as breast cancer risk factors. Then we present the latest findings which elaborate possible explanations regarding how metabolic syndrome as a single entity may affect breast cancer risk.     

Self examination of the breast: is it beneficial? Meta-analysis of studies investigating breast self examination and extent of disease in patients with breast cancer.

The question whether the aggregated published research suggests that breast self examination is beneficial was explored in a meta-analysis of 12 studies including a total of 8118 patients with breast cancer that related the practice of breast self examination to regional lymph node state or tumour diameter. Based on the six studies for which data were available, 39% of patients (1115/2852) who reported having done breast self examination at least once before their illness had evidence of cancer in the lymph nodes compared with 50% of women (1348/2713) who had not done the examination. Logistic regression analysis showed this difference to be significant (odds ratio 0.66, confidence interval 0.59 to 0.74). Combining six studies which reported the circumstances of detection disclosed that 42% of women (272/652) who found their tumour while doing breast self examination had evidence of cancer in the nodes compared with 46% of women (871/1901) who found the tumour accidentally; this difference was not significant. Analysis of eight studies which used the diameter of the tumour to indicate the extent of disease tended to confirm the findings on lymph node state, in particular the benefit of premorbid breast self examination. Significantly fewer women who had practised the examination before the illness (56%; 1205/2137) had tumours of 2 cm or more diameter compared with women who had not practised the examination (66%; 1500/2260). The combined odds ratio for that analysis was 0.56, confidence interval 0.38 to 0.81. These findings appear to be good evidence of the benefit of encouraging women to practise self examination of the breasts regularly.     

Outpatient screening and its place in better detection of breast tumors

The authors state their opinion on this problem by analyzing their 5-year use of their programme specially developed for detection of breast disease, mainly cancer, among females visiting specialized rooms of non-mammological profiles (gastroenterology, endocrinology, rheumatology, pulmonology, neurology, cardiology, hematology, nephrology, etc.) in the consulting polyclinics of regional (territorial) hospitals and large city hospital-polyclinic complexes. In this period, mammographic studies were made in 9169 women included into a breast cancer-risk group. Of them 1370 young female patients with well-developed glandular tissue that makes mammographic diagnosis of presumed masses difficult underwent breast ultrasonography. Abnormalities were found in 6092 (66.44%) patients. Breast cancer and nodal benign masses (including cysts and fibroadenomas) were detected in 278 (3.03%) and 669 (7.30%) women, respectively. The detection rates of unpalpable breast malignant and benign masses carcinomas were 0.4 and 3.03%, respectively. The findings allow the authors to recommend their proposed screening programme for wide use in large regional (territoreal), city, and town polyclinic complexes.     

Crossover Effects of Estrogen Receptor Status on Breast Cancer-Specific Hazard Rates by Age and Race

Background

Previous studies found that the risk of breast cancer–related death is greater in estrogen receptor (ER)-negative disease than in ER-positive disease within 5 years of diagnosis, but greater for ER-positive disease than for ER-negative disease more than 5 years after diagnosis. This phenomenon is referred to as ER-positive and -negative crossover. Our aim was to evaluate this crossover by determining the timing of the hazard of breast cancer death by patient, clinical, and tumor factors.

Methods

Patients with breast cancer diagnosed between 1990 and 2005 were identified from the Surveillance, Epidemiology, and End Results database. The cohort was evaluated by age at diagnosis, race, tumor ER status, tumor and nodal stage, and tumor grade. Disease-specific (DS) hazard rates were calculated.

Results

Of the 439,444 patients identified, 77.5% had ER-positive disease. Overall, ER-negative to ER-positive DS hazard rates crossed between the years 7 and 8 after diagnosis. Earlier crossover was linked to black or Hispanic race, young age (<40 years), or tumors that were larger, higher grade, or affected the nodes. Young black (<40 years) patients who had a T3/T4 tumor with positive nodes, grade III or undifferentiated, had the earliest crossover, in year 4.

Conclusions

The timing of crossover of death hazard for ER-positive and ER-negative disease varies by clinical and tumor factors. These findings may help guide recommendations regarding the duration of endocrine therapy for patients with ER-positive cancer.     

Clinical evaluation of CA 15.3 in the post-operative follow-up of breast cancer patients

In 265 patients operated for breast carcinoma the monoclonal antibody serum test CA 15.3 was predictive of metastatic diffusion of the disease. Its level increased in cases of distant metastasis with no significant difference between multiple and single sites (p = 0.014). The concentration of the marker was higher in 21 (23.8%) patients without nodal involvement and in 19 (27.5%) with nodal involvement (p = 0.193). Our study suggests that CA 15.3 may be an aid in the follow-up of patients with metastatic diffusion of breast cancer.     

Characteristics of a population of women with breast implants compared with women seeking other types of plastic surgery

Several previous studies have shown that breast implant patients demonstrate a number of differences compared with the general population. However, studies have not compared patients with breast implants with women receiving other types of plastic surgery, of interest because this latter group has been proposed as a comparison group for assessing the long-term health effects experienced by breast implant patients. Questionnaire data obtained from 7447 breast implant patients and 2203 patients with other types plastic surgery were collected during the course of a retrospective cohort study, to determine whether implant patients demonstrate different characteristics compared with a more restricted group of patients. In contrast to previous investigations that compared implant patients with the general population, distinctive differences with respect to family income, number of pregnancies, alcohol consumption, cigarette smoking, or histories of previous gynecologic operations or operations for benign breast disease were not found. However, implant patients were significantly more likely than other plastic surgery patients to be white, have low levels of education, have early ages at first birth, be thin, and be screened frequently for breast disease. Furthermore, implant patients reported somewhat greater use of exogenous hormones and familial histories of rheumatoid arthritis. These results support the notion that other plastic surgery patients are a more appropriate comparison group than women in the general population for studies of the health effects of breast implants; however, there continue to be distinctive characteristics possessed by breast implant patients, which need to be taken into account in an assessment of what disease effects can be uniquely attributed to silicone breast implants.     

Recent advances in X-ray imaging of breast tissue: From two- to three-dimensional imaging

Breast cancer is a globally widespread disease whose detection has already been significantly improved by the introduction of screening programs. Nevertheless, mammography suffers from low soft tissue contrast and the superposition of diagnostically relevant anatomical structures as well as from low values for sensitivity and specificity especially for dense breast tissue. In recent years, two techniques for X-ray breast imaging have been developed that bring advances for the early detection of breast cancer. Grating-based phase-contrast mammography is a new imaging technique that is able to provide three image modalities simultaneously (absorption-contrast, phase-contrast and dark-field signal). Thus, an enhanced detection and delineation of cancerous structures in the phase-contrast image and an improved visualization and characterization of microcalcifications in the dark-field image is possible. Furthermore, latest studies about this approach show that dose-compatible imaging with polychromatic X-ray sources is feasible. In order to additionally overcome the limitations of projection-based imaging, efforts were also made towards the development of breast computed tomography (BCT), which recently led to the first clinical installation of an absorption-based BCT system. Further research combining the benefits of both imaging technologies is currently in progress. This review article summarizes the latest advances in phase-contrast imaging for the female breast (projection-based and three-dimensional view) with special focus on possible clinical implementations in the future.     

Understanding the dual nature of CD44 in breast cancer progression

CD44 has been the subject of extensive research for more than 3 decades because of its role in breast cancer, in addition to many physiological processes, but interestingly, conflicting data implicate CD44 in both tumor suppression and tumor promotion. CD44 has been shown to promote protumorigenic signaling and advance the metastatic cascade. On the other hand, CD44 has been shown to suppress growth and metastasis. Histopathological studies of human breast cancer have correlated CD44 expression with both favorable and unfavorable clinical outcomes. In recent years, CD44 has garnered significant attention because of its utility as a stem cell marker and has surfaced as a potential therapeutic target, necessitating a greater understanding of CD44 in breast cancer. In this review, we attempt to unify the literature implicating CD44 in both tumor promotion and suppression, and explain its dualistic nature.     

Mixture modeling of progression pathways of heterogeneous breast tumors

Uncovering pathways of tumor progression is an important topic in cancer research that has led to numerous studies, including several pathway models proposed and investigated by Sontag and Axelrod [Progression of heterogeneous breast tumors. J. Theoret. Biol. 210, 107-119, 2005]. In their comparative studies, the authors focused on relative goodness of fits of the various pathways, but a simple test revealed that even the "best" model did not provide an adequate explanation for the observed breast tumor data. The heterogeneous nature of breast tumors leads to the question of whether more than one (i.e., a combination of) pathway models are needed in order to explain the observed data. In the current paper, we address this question based on the finite mixture modeling framework and utilizing the four pathways proposed in Sontag and Axelrod as our individual pathway models. The expectation-maximization algorithm was used to derive estimates for the mixing proportions of the mixture models. Indeed, a two-pathway mixture provides a dramatic improvement over any of the single pathway models for explaining the data derived under either the Van Nuys or the Holland system. In particular, for data graded under the Van Nuys system, the mixture model was shown to be consistent with the observed data at the 1% significant level.     

Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer

Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines.     

Angiogenesis and Antiangiogenesis in Triple-Negative Breast cancer

Several data support a central role for angiogenesis in breast cancer growth and metastasis. Observational studies have demonstrated that microvascular density (MVD) is a prognostic factor in invasive breast cancer, whereas others reached the opposite conclusion. Vascular endothelial growth factor is the most important angiogenic factor with proven significance in breast cancer, as it has been assessed in both experimental and clinical studies. Triple-negative breast cancer (TNBC) is a type of breast cancer which lacks estrogen, progesterone, and HER-2/neu receptors. MVD in both basal-like and TNBC is significantly higher than in non–basal-like and non-TNBC. In breast cancer and other malignancies, the development of agents that inhibit tumor angiogenesis has been an active area of investigation. In TNBC, clinical trials combining targeted agents and chemotherapy have failed to show substantial survival improvement. There is evidence that patients with TNBC may have a greater probability of obtaining some kind of clinical efficacy benefit from bevacizumab-based therapy.