Chemotherapy for breast cancer (Review)

The use of cytotoxic chemotherapy in both advanced and early stage breast cancer has made significant progress in the last 10 years with several landmark studies identifying clear survival benefits for newer therapies. In spite of these developments the optimal approach for any specific patient can not be determined from a literature review or decision-making algorithm alone. Treatment choices are predominantly based on practice determined by individual or collective experience and the historical development of treatment within a locality. The improvement in the understanding of the molecular biological basis of breast cancer provides possible targets for novel therapies. Personalised therapies for breast cancer based on the molecular characteristics of the tumour could improve the risk: benefit ratio of current therapies. Increased improvements in the use of a panel of biomarkers will thus not only move us towards tailored therapies but will also spare a group of patients that do not benefit from adjuvant chemotherapy. At the same time a better understanding of tumour biology will also streamline the development of new regimens for those who are unlikely to benefit from existing drugs. This review will focus on the evidence for the use of chemotherapy and highlight advances in chemotherapy treatments with the addition of new and novel drugs marching into our clinics as standard treatments based on evidence from clinical trials and from a better understanding of tumour biology that has transformed the outlook in breast cancer in both the adjuvant and metastatic setting.     

Factors that influence surgical choices in women with breast carcinoma

BACKGROUND: In the absence of medical contraindications, survival after undergoing breast-conserving therapy (BCT), mastectomy (M), and mastectomy with immediate reconstruction (MIR) is equal. The authors studied demographic factors to identify the variables that differed significantly among women making different surgical choices. METHODS: Women with ductal carcinoma in situ or clinical Stage I or II breast carcinoma with no contraindications for BCT or MIR who were treated between 1995 and 1998 were identified from a prospectively collected data base. Demographic and tumor factors were compared using the Fisher exact test. RESULTS: There were 578 women with 586 tumors who did not have contraindications for BCT or MIR. Among this group, 85.2% of women chose BCT, 9.2% of women chose M, and 5.6% of women chose MIR. Women undergoing M alone were older and were more likely to have Stage II carcinoma compared with women undergoing BCT. Patients undergoing M or MIR were more likely to have had a prior breast biopsy compared with patients who chose BCT. Marital status and employment approached significance (P = 0.06); however, a family history of breast carcinoma was not a predictor of treatment choice. CONCLUSIONS: The current findings suggest a need for patient education strategies that emphasize the lack of influence of age and prior breast biopsy on the use of BCT. Differences in demographic variables may reflect true variations in patient preference among groups, emphasizing the need to address the spectrum of treatment options with patients.     

Factors that influence mammography use and breast cancer detection among Mexican-American and African-American women

Objective

This study examined factors that influence mammography use and breast cancer detection, including education, health insurance, and acculturation, among Mexican-American (MA) and African-American (AA) women.

Methods

The study included 670 breast cancer cases (388 MAs and 282 AAs), aged 40?C86?years at diagnosis. Data on mammography use, detection, and delay in seeking care were collected via questionnaires and medical records. Using a language-based bidimensional acculturation measure, MAs were classified as English-dominant (n?=?67), bilingual (n?=?173), and Spanish-dominant (n?=?148). Mammography prior to diagnosis was assessed by racial/ethnic acculturation subgroup using logistic regression.

Results

In age-adjusted models, mammography use was non-significantly lower among English-dominant (OR?=?0.84; 95% CI: 0.45?C1.59) and bilingual (OR?=?0.86; 95% CI: 0.55?C1.35) MAs and significantly lower among Spanish-dominant MAs (OR?=?0.53; 95% CI: 0.34?C0.83) than among AA women. After adjustment for education or insurance, there was no difference in mammography use by race/ethnicity and acculturation subgroup. Despite high self-reported mammography use (75%), a large proportion of cases reported self-detection (59%) and delay in seeking care >90?days (17%).

Conclusions

These findings favor promoting culturally appropriate messaging about the benefits and limitations of mammography, education about breast awareness, and prompt reporting of findings to a health professional.     

Factors that influence the incidence of microscopic carcinoma in frozen and preserved specimens from patients with breast carcinoma after breast-conserving surgery

Because a positive margin is an important risk factor for decreased survival of patients with breast cancer after breast-conserving surgery (BCS), we examined the rate of positive surgical margins after BCS, determined from intraoperative frozen and preserved sections, and we assessed factors that influence the incidence of positive margins in surgical specimens. The cases of 172 patients who underwent BCS between June 1989 and March 2001 were studied. The pathologic features and positive margins were evaluated by microscopic examination of frozen and preserved sections. The grade of each positive margin was arbitrarily classified into one of four groups: i) cancer involved; ii) closed margin (<2 mm); iii) partially closed margin (>3 mm and <5 mm) and iv) free margin (>5 mm). Biomarkers were estimated by immunohistochemistry and DNA ploidy, and the relationship of clinical parameters was statistically analyzed using the chi(2) test. In 59 of 172 cases (34.3%), the surgical margin was positive: horizontal in 47 cases (27.3%) and vertical in 12 cases (6.9%). The free margin was significantly correlated with positive status of estrogen and progesterone receptors and middle age (35-50 years) in the patients, while clinicopathologic factors were not correlated with positive margins in surgical specimens. Although 17 cases of cancer were found in 9 frozen specimens and 8 preserved sections, the mammographic findings showed spiculated masses in 7 of the 9 frozen specimens (77.7%) and 4 of the 8 preserved sections (50%), and microcalcification in 2 frozen specimens (22.2%) and 4 preserved sections (50%). The overexpression (2+ or 3+) of the HER-2 protein was found in 8 of the 9 frozen specimens (87.5%) and in 7 of the 8 preserved sections (88.8%). In the 11 cases with spiculated masses, extensive intraductal components (EICs) of various grades were found; the presence of EICs in a spiculated lesion was observed in 5 of the 7 frozen specimens and in all 4 of the preserved sections. The local extension of breast carcinoma cells in BCS is associated in part with the findings of spiculation and microcalcification, which are associated with EICs. The overexpression of HER-2 protein appears to play a role in EICs in positive margins, and needs to be considered for avoiding positive margins in BCS on patients with breast carcinoma.     

Rationale for the use of gemcitabine in breast cancer (Review)

Many active cytotoxic drugs and several regimens exist for breast cancer therapy. However, these conventional treatments have not changed the outcome of patients with locally advanced and metastatic disease. As a consequence, the dynamic balance between chemotherapy-induced side effects and benefits attributable to relief of cancer-related symptoms must be carefully considered in this setting. Gemcitabine is a pyrimidine nucleoside antimetabolite that has shown activity in a variety of solid tumors, a good toxicity profile, and non-overlapping toxicity with other chemotherapeutic drugs. As a single agent, gemcitabine yields response rates ranging from 14 to 37% as first-line treatment for advanced breast cancer and 12-30% as salvage therapy for patients previously treated with anthracycline and/or taxane treatment. Combined with vinorelbine, platinum, anthracyclines, and taxanes as doublets or triplets, response rates of 50 to 80% have been reported in phase II clinical studies. Gemcitabine in combination with anthracyclines and taxanes has been evaluated in the neoadjuvant setting in patients with early-stage breast cancer with interesting clinical and pathological response rates. Preliminary results of gemcitabine in combination with the biologic agent, trastuzumab, are encouraging. Phase III trials of gemcitabine combinations compared to standard regimens are ongoing with the aim to assess the independent contribution of gemcitabine.     

No evidence that social stress is associated with breast cancer incidence

Women commonly attribute the experience of stress as a contributory cause of breast cancer. The purpose of this study is to investigate the associations between a history of social stress and breast cancer risk. A total of 11,467 women with no prior history of breast cancer, participants in the European Prospective Investigation into Cancer (EPIC)-Norfolk population-based prospective cohort study, completed a comprehensive assessment of lifetime social adversity exposure. Summary measures of social adversity were defined according to difficult circumstances in childhood, stressful life events and longer-term difficulties in adulthood, derived measures representing the subjective ‘impact’ of life events and associated ‘stress adaptive capacity’, and perceived stress over a 10-year period. Incident breast cancers were identified through linkage with cancer registry data. During 102,514 (median 9) person-years of follow-up, 313 incident breast cancers were identified. No associations were observed between any of the summary social adversity measures and subsequent breast cancer risk, with or without adjustment for age, menopausal status, parity, use of menopausal hormones, age at menarche, age at first birth, family history of breast cancer, physical activity, social class, body mass index, height, and alcohol intake. This study found no evidence that social stress exposure or individual differences in its experience are associated with the development of breast cancer. These findings may aid strategies designed to meet the psychosocial and emotional needs of breast cancer survivors and may be interpreted in a positive way in the context of commonly voiced beliefs that the experience of stress is a contributory cause of their disease.     

Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6-87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33-4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61-4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42-3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC.     

The influence of mammographic screening on national trends in breast cancer incidence.

Introducing an organized mammographic screening programme affects the breast cancer incidence rate in a population. The diagnosis is advanced in time, and initially, an increase will occur in the number of cases, followed by a drop in the rate when women leave the programme. The aim of this study was to quantify the potential effects that mammographic screening programmes have on breast cancer incidence. In addition, we wanted to investigate how the incidence of breast cancer varies between different birth cohorts, age groups and time periods in the five Nordic countries Finland, Denmark, Iceland, Norway and Sweden, adjusting for the effects of the screening programmes. Time trends were analysed over the period 1978-1997, using age-period-cohort models. In Sweden, the rates more than doubled (relative risk (RR)=2.20, 95% confidence interval (CI) 1.8-2.6) in women offered screening for the first time compared with women not offered screening. The risk remained elevated (RR=1.34, 95% CI 1.2-1.6) for women who were continued to be offered screening, compared with women who were not offered screening. Finally, the rates dropped (RR=0.68, 95% CI 0.6-0.8) when the women left the programme. This indicates that screening advances the time of diagnosis, which is a prerequisite to subsequent reduction in mortality. Analysis of secular trends, corrected for the influence of screening, showed that the rates in Finland increased by 13% per 5-year period, with a more modest increase in the other countries. There were strong cohort effects in all Nordic countries, and the risk seemed to be flattening for the youngest cohorts in most of the countries.     

Male breast cancer: risk factors, diagnosis, and management (Review)

Male breast cancer (MBC) is extremely rare, with an incidence in the general US population of <1%. It tends to be diagnosed at later stages than breast cancer in females, likely because of low awareness on the part of the patient and low suspicion by the physician. Risk factors include genetic predisposition, alterations to the estrogen-testosterone ratio, radiation exposure, and occupational hazards. Because of the rarity of MBC, mammography in men is more often utilized as a diagnostic tool to evaluate breast symptoms rather than as a tool for widespread screening. While clinical breast examinations are effective at evaluating breast symptoms, mammography also may be beneficial in separating malignant from benign breast disease. This study reviews MBC and its risk factors, recommendations for screening and diagnosis, the roles of mammography and genetic testing in surveillance, and management of patients with MBC. Heightened awareness of the increased risk in certain men by both physicians and patients, and adherence to guidelines recommended for the surveillance of men at increased risk, may result in earlier detection.     

Effect of twinship on incidence of cancer of the testis,breast, and other sites (Sweden)

It has been suggested that cancers of the testis and breast are associated with exposure to estrogens and other hormones in utero. Twin pregnancies have higher levels of pregnancy-associated hormones than singleton pregnancies, and these levels may be higher in dizygotic than in monozygotic twin pregnancies. Through a large population-based study of twins, we assessed the hypothesis that levels of pregnancy-associated hormones have etiologic importance for cancers of the testis, breast, and other sites. The incidence of all cancers among 46,767 members of the Swedish Twin Registry was compared with the incidence among the Swedish general population. We found testicular cancer excess among dizygotic twins (observed/expected [O/E] ratio=1.6, 95 percent confidence interval [CI]=1.0–2.6) that was greater for men younger than 35 years (O/E ratio=2.3, CI=1.1–4.2) compared with older men (O/E ratio = 1.2, CI=0.5–2.4). In addition, a substantially elevated incidence of breast cancer was observed in dizygotic twin women aged 20 to 29 years (O/E=6.7, CI=2.9–13.1). None of the other age or zygosity groups showed notable elevations in incidence of testicular, breast, or other cancers. We conclude that dizygotic twinship may be associated with cancer of the breast and testis among young adults. These findings support the concept that pregnancy hormones are associated with risk of testicular and breast cancer, although non-hormonal aspects of twin pregnancy that vary with respect to zygosity cannot be excluded as explanatory factors.The Swedish Twin Registry is supported by funds from the John D. and Catherine T. MacArthur Foundation.     

Astrocyte elevated gene-1 and breast cancer (Review)

Astrocyte elevated gene-1 (AEG-1), also known as MTDH and Lyric, is a novel gene that was first cloned by subtraction hybridization in 2002 and has recently been shown to play a role as a crucial oncogene that acts as a promoter of tumor malignancy. Overexpression and inhibition studies both in in vitro and in vivo models have partly shown the oncogenic roles of AEG-1 in a number of crucial aspects of tumor development and progression, including transformation, evasion of apoptosis, proliferation, cell survival, migration, invasion, metastasis, angiogenesis and chemoresistance through the activation of numerous signaling pathways, such as the nuclear factor κB, PI3K/AKT, Wnt/β-catenin and mitogen-activated protein kinase signaling pathways. However the potential roles of AEG-1, particularly in specific organs or tissues, such as breast tissue, require further clarification. Studies have found that in normal human breast tissue, AEG-1 is always expressed at low levels or is absent, while it is widely overexpressed in many breast cancer cell lines and breast tumors. The present review evaluates the current literature with regards to AEG-1 relative to breast cancer development and progression and highlights new perspectives relative to this molecule, indicating its potential to become a new target for the clinical treatment of breast cancer.     

Urokinase-type plasminogen activator system and breast cancer (Review)

Malignant tumors have a capacity to degrade the extracellular matrix (ECM) by controlled proteolysis. One proteolytic system involved in these processes is the urokinase-type plasminogen activator (uPA) system, which consists of uPA, uPA receptor (uPAR) and uPA inhibitors 1 and 2 (PAI-1 and PAI-2). In the past two decades, study of the uPA system in human breast cancer has yielded valuable insights. Increased levels of uPA, PAI-1 and uPAR have been reported to be associated with poor prognosis in patients with breast cancer. Furthermore, uPA and PAI-1 may be new prognostic markers for axillary node-negative patients. To date, a growing body of evidence has suggested that uPA system promotes tumor metastasis by several different mechanisms, not just by breaking down the ECM. This article is focused on reviewing the current understanding of uPA system members as prognostic markers in breast cancer, and their cellular localization and tissue distribution. Correlations of the uPA system with other informative markers of breast cancer are also discussed.     

Strategies of medical treatment for metastatic breast cancer (Review)

Presently, metastatic breast cancer cannot be cured and therefore good palliation of symptoms and longer overall survival make the most important targets, always considering quality of life. In addition to the established hormonal therapies or chemotherapy regimens, several recent advances have accelerated progress in metastatic breast cancer treatment. As demonstrated in recent studies, the third-generation aromatase inhibitors are playing a significant role in the improvement of the therapeutic approach. The development of new drugs with novel mechanisms of action, such as taxanes, used alone in innovative schedules or in association with other drugs (mainly the anthracyclines), vinorelbine and gemcitabine, or capecitabine, which is administered orally, has broadened the scope of metastatic breast cancer chemotherapy. A new investigation field is represented by high-dose chemotherapy with stem cell support, which has provided controversial preliminary results but is also acknowledged to deserve larger and randomized trials. Finally, the emergence of biological therapies such as the anti-HER2 monoclonal antibody Trastuzumab opens new and exciting prospects for the treatment of this disease. Moreover, the present trend is to try to rationalize the therapeutic approach on the basis of biological parameters which are prognostic and predictive of treatment response.     

Impressive time-related influence of the Dutch screening programme on breast cancer incidence and mortality, 1975-2006

The aim of this study was to assess changes in the trends in breast cancer mortality and incidence from 1975 to 2006 among Dutch women, in relation to the implementation of the national breast cancer screening programme. Screening started in 1989 for women aged 50-69 and was extended to women aged 70-75 years in 1998 (attendance rate approximately >80%). A joinpoint Poisson regression analysis was used to identify significant changes in rates over time. Breast cancer mortality rates increased until 1994 (age group 35-84), but thereafter showed a marked decline of 2.3-2.8% per annum for the age groups 55-64 and 65-74 years, respectively. For the age group of 75-84 years, a decrease started in the year 2001. In women aged 45-54, an early decline in breast cancer mortality rates was noted (1971-1980), which is ongoing from 1992. For all ages, breast cancer incidence rates showed an increase between 1989 and 1993, mainly caused by the age group 50-69, and thereafter, a moderate increase caused by age group 70-74 years. This increase can partly be explained by the introduction of screening. The results indicate an impressive decrease in breast cancer mortality in the age group invited for breast cancer screening, starting to show quite soon after implementation.     

Trends in late-stage breast and cervical cancer incidence rates in Connecticut (United States)

Objective: This study examined the temporal trend in late-stage incidence rates for breast and cervical cancer in Connecticut, where a statewide screening program (targeted to poor or uninsured women) began in late 1995. Methods: Age-standardized incidence rates (ASIRs) for late-stage breast and cervical cancer in Connecticut were analyzed prior to (1988–1991 and 1992–1995) and during (1996–1999) operation of a statewide screening program for lower-income or uninsured women. Results: ASIRs for late-stage cancer declined from the 1988–1991 to 1992–1995, including a reversal in the black–white difference in late-stage breast cancer, while declines from 1992–1995 to 1996–1999 were largely limited to cervical cancer among African American (black) women. Conclusions: Little progress was evident toward reducing late-stage ASIRs in the 1990s, but continued surveillance is needed to determine if declines in black–white disparities in late-stage cervical cancer ASIRs continue, and to further assess the impact of a statewide screening program.     

Recent trends in breast cancer incidence,mortality, and mammography

Summary The recent trends in mammography, and in breast cancer incidence and mortality, demonstrate the impact of an effective cancer control effort. The number of women over age 40 years who have ever had mammography has increased over 200% since 1980. Concomitantly, breast cancer incidence has increased about 32%, with nearly all of the increase in early stage disease. Analytic studies of these changes have demonstrated persuasively that the vast majority of this increase is temporary and is attributable to the lead-time afforded by mammography. As a result of this early detection and treatment of breast cancer, mortality has begun to decline in 1991–92. Although the search for practical preventive measures should continue, the benefits of early detection can be realized now. Further research is needed to define age groups most appropriately screened and the optimum intervals for screening.