An alternative approach for treatment of breast cancer

Summary Since adjuvant chemotherapy and hormonal therapy generally extend disease free survival in breast cancer rather than provide a cure, we have examined the current breast cancer paradigm. Heterogeneity is a fundamental characteristic of breast cancer tissue and a well recognized aspect of the disease. There are variations in natural history, histopathology, biochemistry and endocrinology, and molecular biology of cancer tissues and cells within the tissues. A variety of data indicate that growth kinetics are also variable, not only from tumor to tumor, but also during the natural history of an individual's tumor. To better understand kinetic heterogeneity, a stochastic numeric computer model of the natural history of breast cancer has been developed. To be consistent with inter- and intratumor kinetic heterogeneity and with late relapse, the model predicts that tumors grow in an irregular fashion with alternating periods of growth and periods of dormancy rather than the generally accepted modified exponential, or Gompertzian fashion. The prediction of irregular growth has been compared to data relevant to growth characteristics of human breast cancer. Much data support the concept of irregular kinetics and temporary dormancy rather than steady, Gompertzian growth of human breast cancer. Thus, in addition to drug resistance, kinetic heterogeneity may help explain the limited impact that traditional chemotherapeutic treatment has had on mortality from breast cancer. Although the mechanisms underlying irregular growth need to be better understood, non-Gompertzian growth kinetics indicates that there may be alternative approaches for breast cancer treatment.     

Dissemination of adjuvant multiagent chemotherapy and tamoxifen for breast cancer in the United States using estrogen receptor information: 1975-1999

BACKGROUND: Clinical trials have shown tamoxifen to be effective only in women with estrogen receptor (ER)-positive tumors. In a previous model, trends in the utilization of adjuvant therapy were modeled only as a function of age and stage of the disease and not ER status. In this paper, we integrate this previous estimate on the use of adjuvant systemic therapy for breast cancer in the United States with information on ER status from the Patterns of Care (POC) data to estimate the dissemination of adjuvant therapy for women with different ER-status tumors. We also summarize efficacy of adjuvant systemic therapy reported in the overviews of early breast cancer clinical trials. These two inputs, dissemination and efficacy, are key pieces for models that investigate the effect of breast cancer adjuvant therapy on the decline of U.S. breast cancer mortality. METHODS: The adjustments to the previous models are calculated using the POC data on 7116 women with breast cancer diagnosed from 1987 to 1991 and in 1995 who were randomly selected from the Surveillance, and Epidemiology, and End Results (SEER) program registries. The POC data provide more accurate information on treatment and clinical variables (e.g., ER status) than the SEER data because medical records are reabstracted and further verified with treating physicians. RESULTS: Use of multiagent chemotherapy is higher for younger women (<50 years) and for women whose tumors were shown to be ER negative or borderline. The use of tamoxifen is higher among older women and women with ER-positive tumors. After 1980 the combined use of multiagent chemotherapy and tamoxifen for women diagnosed with breast cancer at ages 69 or younger increased more for women whose tumors were ER status positive or unknown than ER status negative. Older women (>69 years) seem to receive almost exclusively tamoxifen irrespective of ER status, except for a small percentage of those with more advanced stages (II- and II+/IIIA) who also receive multiagent chemotherapy. DISCUSSION: The estimated dissemination trends by ER status, based on modeling the POC data, reveal that treatment strategies with demonstrated efficacy in clinical trials have been adopted into practice. The dissemination and efficacy are the two factors necessary to input into models to determine the population impact of these therapies on U.S. breast cancer mortality. The largest decline in mortality would be expected for younger women (<60 years) with ER-positive tumors or whose tumors are of unknown status because of the largest efficacy and dissemination of adjuvant therapy in this group.     

Feasibility of a cell kinetic-based adjuvant chemotherapy trial in axillary node-negative breast cancer

AIMS AND BACKGROUND: Accumulated information on biologic prognostic indicators and predictors of response to different types of treatment in patients with different tumor characteristics has made it possible to design clinical protocols on biologic bases. Among cell proliferation indices, the thymidine labelling index (TLI) has proved to be an independent and consistent prognostic indicator over time. Moreover, experimental and retrospective analyses of clinical studies have revealed a direct relation between TLI and response to chemotherapy. On the basis of the results, a prospective clinical protocol on axillary node-negative breast cancer was activated in Italy in 1989. METHODS: Patients with low TLI tumors were treated with local-regional therapy alone, whereas patients with high TLI tumors were randomized to receive local-regional therapy followed or not by adjuvant chemotherapy consisting of 6 cycles of CMF. RESULTS AND CONCLUSIONS: The present paper reports on the feasibility of a prospective clinical protocol based on a subgroup of patients with specific pathologic (node negative) and biologic (rapidly proliferating) breast cancers. However, patient eligibility was only 11%.     

Monoclonal antibodies as effective therapeutic agents for solid tumors

Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti-HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large-scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti-HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2-overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti-EGFR mAb) and bevacizumab (humanized anti-VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti-idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.     

Management of cancer in the elderly

With the aging of the Western population, cancer in the older person is becoming increasingly common. After considering the relatively brief history of geriatric oncology, this article explores the causes and clinical implications of the association between cancer and aging. Age is a risk factor for cancer due to the duration of carcinogenesis, the vulnerability of aging tissues to environmental carcinogens, and other bodily changes that favor the development and the growth of cancer. Age may also influence cancer biology: Some tumors become more aggressive (ovarian cancer) and others, more indolent (breast cancer) with aging. Aging implies a reduced life expectancy and limited tolerance to stress. A comprehensive geriatric assessment (CGA) indicates which patients are more likely to benefit from cytotoxic treatment. Some physiologic changes (including reduced glomerular filtration rate, increased susceptibility to myelotoxicity, mucositis, and cardiac and neurotoxicity) are common in persons aged 65 years and older. The administration of chemotherapy to older cancer patients involves adjustment of the dose to renal function, prophylactic use of myelopoietic growth factors, maintenance of hemoglobin levels around 12 g/dL, and proper drug selection. Age is not a contraindication to cancer treatment: With appropriate caution, older individuals may benefit from cytotoxic chemotherapy to the same extent as the youngest patients.     

Neoadjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive early breast cancer: a new concept

Patients with resectable, nonmetastatic (stage I–IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer.     

CDK12基因在恶性肿瘤中的研究进展

CDK12属于转录相关的细胞周期蛋白依赖性激酶（cyclin-dependent kinases,CDKs）,在转录调控、mRNA剪接、DNA损伤修复、细胞生长和分化、调控表观遗传修饰、维持基因组稳定等多种细胞进程中发挥重要作用。目前已在多种实体瘤中检测到CDK12基因的体细胞变异,如前列腺癌、卵巢癌、乳腺癌、黑色素瘤、食管癌、子宫内膜癌、膀胱癌、结直肠癌和头颈鳞状细胞癌等。近期研究表明CDK12发生突变或缺失会引起恶性肿瘤患者对PARP抑制剂、铂类化疗药物以及免疫治疗敏感,因此有望成为肿瘤治疗的新靶点。     

Systemic therapy for older women with breast cancer

Breast cancer is a common problem in older women. As the number of medical illnesses increases with age and the life expectancy decreases, the benefits of systemic therapy for women with breast cancer become questionable. All women over age 65 years are at high enough risk of breast cancer to consider the risk/benefit ratio of preventive therapy with tamoxifen (Nolvadex) or participation in the Study of Tamoxifen and Raloxifene (STAR) trial. Adjuvant chemotherapy and hormonal therapies for early breast cancer significantly improve disease-free and overall survival; recommendations for their use are based on risk of tumor recurrence. Use of tamoxifen in the adjuvant setting in women with receptor-positive tumors is a relatively simple decision in light of its favorable toxicity profile. The delivery of adjuvant chemotherapy is a more complicated decision, and the patient's wishes, estimated life expectancy, presence of comorbid conditions, and estimated benefit from treatment should be considered. The primary goal of the treatment of metastatic breast cancer is palliation. We discuss trials specific to older women and make appropriate treatment recommendations. Unfortunately, there is a paucity of data from clinical trials in women over age 70 years. However, because the clinical trial is the primary scientific mechanism for testing the efficacy of a treatment, every effort should be made to enter older women into treatment protocols.     

Evaluation of CEA and GCDFP-15 plasma level during hormonally induced cancer stimulation

Preliminary clinical trials indicate that transient stimulation of breast and prostate cancer growth by hormonal means may enhance tumor sensitivity to chemotherapy. In none of these studies, however, has an attempt been made to measure parameters that might reflect perturbations in cell kinetics induced by the treatment schedules. While conducting two, controlled, randomized clinical trials in advanced breast cancer and prostate cancer using a similar approach, we have measured plasma levels of two tumor markers, carcinoembryonic antigen (CEA) and breast gross cystic disease fluid protein (GCDFP-15). These served as a possible means of monitoring hormonal stimulation of tumor growth. Both markers failed to increase following administration of estrogens to patients with breast cancer and of androgens to men with prostatic carcinoma. In contrast, transient stimulation of tumor growth probably occurred as shown by exacerbation of symptoms and, in patients with prostate cancer, rise in acid phosphatase. We conclude that CEA and GCDFP-15 are not useful for monitoring pertubations in tumor cell kinetics induced by hormone stimulative protocols.     

Thalidomide and chemotherapy combination

Angiogenesis has been shown to be important in tumor growth and metastasis. Thalidomide, an oral sedative, has recently been found to inhibit angiogenesis. We therefore set out to ask whether thalidomide can be used as therapy for breast cancer. In a mouse model of breast cancer, we found that thalidomide alone did not suppress tumor growth. However, mice treated with thalidomide in combination with cytoxan and adriamycin had significantly smaller tumors than those given the two chemotherapeutic agents alone (3,432 +/- 303 mm(3) versus 4,643 +/- 203 mm(3), p = 0.0005). We proceeded to administer thalidomide together with chemotherapy to seven breast cancer patients in the context of a Phase I trial. Side effects attributed to thalidomide were minimal, and included constipation and a rash. We concluded that an approach at cancer therapeutics combining an antiangiogenic agent such as thalidomide with conventional chemotherapy may be feasible and deserves further studies.     

Computer Model Challenges Breast Cancer Treatment Strategy

The breast cancer treatment failure rate remains unacceptably high. The current breast cancer treatment paradigm, based primarily on Gompertzian kinetics and animal models, advocates short-course, intensive chemotherapy subsequent to tumor debulking, citing drug resistance and host toxicity as the primary reasons for treatment failure. To better understand treatment failure, we have studied breast cancer from the perspective of computer modeling. Our results demonstrate breast cancers grow in an irregular fashion; this differs from the Gompertzian mode of animal models and thus challenges the validity of the current paradigm. Clinical and laboratory data support the concept of irregular growth rather than the common claim that human tumors grow in a Gompertzian fashion. Treatment failure mechanisms for breast cancer appear to differ from those for animal models, and thus treatments optimize on animal models may not be optimal for breast cancer. A failure mechanism consistent with our results involves temporarily dormant tumor cells in anatomical or pharmacological sanctuary, which eventually result in aggressive metastatic disease.     

Occult Breast Tumor Reservoir: Biological Properties and Clinical Significance

Small, occult, undiagnosed breast cancers are found at autopsy in up to 15.6 % of women dying from unrelated causes with an average of 7 % from eight separate studies. The mammographic detection threshold of breast tumors ranges from 0.88 to 1.66 cm in diameter based on the patient’s age. Tumor growth rates, expressed as “effective doubling times,” vary from 10 to >700 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. Our models facilitate interpretation of the Women’s Health Initiative (WHI) and antiestrogen breast cancer prevention studies. A nude mouse xenograft model was used to validate our assumption that breast tumors grow in a log-linear fashion. We then used our previously reported occult tumor growth (OTG) and computer-simulated tumor growth models to analyze various clinical trial data. Parameters used in the OTG model included a 200-day effective doubling time, 7 % prevalence of occult tumors, and 1.16 cm detection threshold. These models had been validated by comparing predicted with observed incidence of breast cancer in eight different populations of women. Our model suggests that menopausal hormone therapy with estrogens plus a progestogen (E?+?P) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. We provide a potential explanation for the lack of an increase in breast cancer incidence in the subgroup of women in the WHI who had not received E?+?P prior to randomization. This result may have reflected a leftward skew in the distribution of occult tumor doublings and insufficient time for stimulated tumors to reach the detection threshold. Our model predicted that estrogen alone reduced the incidence of breast cancer as a result of apoptosis. Understanding of the biology of occult tumors suggests that breast cancer “prevention” with antiestrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our models suggest that occult, undiagnosed tumors are prevalent, grow slowly, and are the biologic targets of a hormone therapy in menopausal women and of antiestrogen therapy for prevention.     

The Role of Cancer Stem Cells in Breast Cancer Initiation and Progression: Potential Cancer Stem Cell‐Directed Therapies

Recent studies have identified a small population of highly tumorigenic cells with stem cell properties in human breast and other solid tumors that are considered to be the source of tumor initiation and maintenance; these cells are referred to as cancer stem cells (CSCs). Preclinical data suggest that current breast cancer treatment strategies lead to CSC enrichment, contributing to chemotherapy and radiotherapy resistance, although a strong correlation with clinical parameters and prognosis is yet to be established. Importantly, overcoming treatment failure by effective targeting of CSCs may be an appealing approach, potentially leading to improved clinical outcomes for patients with breast cancer. Several preclinical studies provide promising results that support this hypothesis. The purpose of this review is to summarize the role of CSCs in breast cancer recurrence and resistance and to discuss current attempts of CSC targeting.     

Preoperative (neoadjuvant) chemotherapy in patients with breast cancer

The concept of using preoperative chemotherapy in patients with operable breast cancer originated from experimental and clinical observations, as well as from theoretical hypotheses on tumor cell growth and dissemination. Results from nonrandomized studies with different chemotherapeutic agents or combination regimens given preoperatively demonstrated substantial clinical response rates but low pathologic tumor response rates. In addition, several such studies were able to show that-by reducing primary breast tumor size-preoperative chemotherapy can lead to an increase in the rate of breast-preserving procedures. Although nonrandomized studies provided useful clinical information about the effect of preoperative chemotherapy on primary breast tumors and on axillary nodes involved with tumor, they could not address the relative efficacy of preoperative versus postoperative (adjuvant) chemotherapy on disease-free survival (DFS) and overall survival (OS). As a result, several randomized trials were implemented to address the above questions. Some of the earlier trials, however, were not designed as straightforward comparisons of preoperative versus postoperative chemotherapy and, thus, did not provide meaningful answers to the fundamental question of whether DFS and OS can be prolonged by the administration of chemotherapy before surgery rather than after. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial was the largest randomized trial that aimed to compare preoperative to postoperative chemotherapy in operable breast cancer. Results from this trial on the effect of preoperative chemotherapy on local-regional disease and outcome are presented. The potential advantages and disadvantages of each approach, as well as surgical considerations and current and future directions in the use of preoperative chemotherapy, are also discussed.     

Cancer chemotherapy based on evidence--metastatic breast cancer

Breast cancer is relatively sensitive to chemotherapy. However, although response rate to chemotherapy is reported to be from 50 to 70% in metastatic breast cancer, it is incurable. Current standard chemotherapeutic regimens do not provide a large survival benefit according to the evidence obtained from clinical studies. Before developing a treatment program, we should therefore realize that the aims of chemotherapy for metastatic breast cancer are improvement of quality of life through relief of symptoms, and prolonging survival.     

Estimation of tamoxifen's efficacy for preventing the formation and growth of breast tumors

BACKGROUND: Several randomized clinical trials have tested the hypothesis that tamoxifen is effective in preventing breast cancer. The largest such trial, the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (BCPT), reported a 49% reduction in risk of invasive breast cancer for the tamoxifen group. However, it is unclear whether the effect of tamoxifen in this trial was mainly due to prevention of newly forming tumors or to treatment of occult disease. METHODS: We used various tumor growth models (i.e., exponential and Gompertzian [growth limited by tumor size]) and a computer simulation to approximate the percentage of detected tumors that were initiated after study entry. Maximum likelihood techniques were then used to estimate separately the efficacy of tamoxifen in treating occult disease and in preventing the formation and growth of new tumors. RESULTS: Under the assumptions of most of the growth models, the trial was sufficiently long for substantial numbers of new tumors to form, grow, and be detected during the trial. With the Gompertzian model and all available incidence data from the BCPT, it was estimated that 60% (95% confidence interval [CI] = 40%-80%) fewer new tumors were detected in the tamoxifen group than in the placebo group. Likewise, 35% (95% CI = 6%-63%) fewer occult tumors were detected in the tamoxifen group. With this model, the estimated incidence rate of invasive breast cancer among women in the placebo group of the BCPT was 7.7 (95% CI = 6.6-8.9) per 1000 women per year. Similar results were obtained with three exponential tumor growth models. CONCLUSIONS: These results support the concept that tamoxifen reduced cancer incidence in the BCPT through both treatment of occult disease and prevention of new tumor formation and growth. However, data from prevention trials may never be sufficient to completely distinguish prevention of new tumor formation from treatment of occult disease.     

Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin-based neoadjuvant chemotherapy

BACKGROUND: To the authors' knowledge there are few data that correlate the expression of the epidermal growth factor receptor (EGFR) with the outcome of patients who have breast carcinoma and are treated with anthracycline chemotherapy. METHODS: Pretreatment tumor tissue samples were available from 82 patients who had locally advanced breast carcinoma and were treated on 2 protocols investigating neoadjuvant 5-fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Immunohistochemical staining for EGFR (diluted 1:50) was performed, and the staining results were interpreted without knowledge of outcome. RESULTS: Fourteen tumors (17%) were EGFR-positive, and 68 tumors (83%) were EGFR-negative. EGFR expression did not correlate with clinical stage (P = 0.361), HER-2/neu overexpression (P = 0.503), estrogen or progesterone receptor status (P = 0.631 and P = 0.838, respectively), nuclear grade (P = 0.448), or proliferative index (P = 0.769). Patients who had EGFR-positive tumors had a worse 5-year disease-free survival (DFS) rate (46% vs. 76%; P = 0.026) and overall survival (OS) rate (46% vs. 76%; P = 0.037) compared with patients who had EGFR-negative tumors. The pathologic complete response rate did not differ between the 2 groups (P = 0.389), although patients with EGFR-positive disease more commonly had > or = 4 positive lymph nodes after chemotherapy (64% vs. 29%; P = 0.028). EGFR expression continued to show a significant correlation with poorer DFS and OS in a Cox regression analysis model that included the presence or absence of four or more lymph nodes and EGFR status. CONCLUSIONS: EGFR expression may have prognostic significance in patients with locally advanced breast carcinoma who are treated with anthracycline chemotherapy. These data warrant further studies aimed at correlating EGFR expression and outcome in patients who have breast carcinoma treated with doxorubicin-based chemotherapy.     

The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2

Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR+/HER2+ breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR+/HER2+ breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-HER2 therapy in postmenopausal women with HR+/HER2+ advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR+/HER2+ breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR+/HER2+ advanced breast cancer.     

Genetic counseling program in familial breast cancer: analysis of its effectiveness, cost and cost-effectiveness ratio

Women with a family history of breast cancer are at increased risk for developing this neoplasm. Starting surveillance more frequently at a younger age than the general population and the possibility of undergoing genetic testing are options for their medical management. We analyzed the benefits and costs of our clinical program in familial breast cancer (FBC) and carried out a cost-effectiveness analysis of such procedure. The benefits and costs of performing genetic counseling and a screening program in FBC based on 143 high-risk families registered in our database between June 1995 and December 2001 were analyzed. A decision tree was constructed to estimate the survival benefit and cost-effectiveness of the clinical genetic counseling program compared with the strategy of not performing any screening protocol. We estimated that the prevalence of a BRCA mutation in an unaffected relative of our high-risk cohort was 10% and that 53% of the mutations are found in the BRCA1 gene. We assigned a 58.5% lifetime risk of breast cancer for a 30-year-old mutation carrier according to the SEER data. The effectiveness of the screening was obtained from our experience and data for estimating survival were derived from other studies with longer follow-up. We used our local payment data to calculate the costs of the program. A mutation in the BRCA1 or BRCA2 genes was identified in 20% of the probands. Seventy primary breast cancer cases were recorded since the onset of the program. Thirty percent of the tumors were diagnosed through the screening program and 71% of them were lymph node-negative compared to 49% of the tumors diagnosed outside the program (p=0.1). The cost-effectiveness ratio of our FBC genetic counseling and screening program was 4,294 euros per life-year gained. The model was sensitive to the prevalence of mutation carriers, the lifetime risk of breast cancer and the effectiveness of the screening. In our setting and according to our model, this analysis suggests that a program of genetic testing and screening for breast cancer in a high-risk population may be cost-effective. These results need to be confirmed as more effective interventions for cancer prevention and screening are being implemented.     

Targeting the HER/EGFR/ErbB family to prevent breast cancer

Preventing breast cancer is possible with selective estrogen receptor (ER) modulators and aromatase inhibitors, which reduce the risk of invasive disease by up to 65% (up to 73% for ER-positive and no effect for ER-negative cancer) and the risk of preinvasive disease [ductal carcinoma in situ (DCIS)] by up to 50%. Clearly, approaches for preventing ER-negative, and increased prevention of ER-positive breast cancers would benefit public health. A growing body of work (including recent preclinical and clinical data) support targeting the HER family [epidermal growth factor receptor (EGFR), or human epidermal growth factor receptor (HER) 1 or ErbB1) and HER2, HER3, and HER4] for preventing ER-negative and possibly ER-positive breast cancer. Preclinical studies of HER family-targeting drugs in mammary neoplasia show suppression of (i) ER-negative tumors in HER2-overexpressing mouse strains, (ii) ER-negative tumors in mutant Brca1/p53(+/-) mice, and (iii) ER-positive tumors in the methylnitrosourea (MNU) rat model; tumors arising in both the MNU and mutant Brca1/p53(+/-) models lack HER2 overexpression. Clinical trials include a recent placebo-controlled phase IIb presurgical trial of the dual EGFR HER2 inhibitor lapatinib that suppressed growth of breast premalignancy [including atypical ductal hyperplasia (ADH) and DCIS] and invasive cancer in patients with early-stage, HER2-overexpressing or -amplified breast cancer. These results suggest that lapatinib can clinically suppress the progression of ADH and DCIS to invasive breast cancer, an effect previously observed in a mouse model of HER2-overexpressing, ER-negative mammary cancer. The preclinical and clinical signals provide a compelling rationale for testing HER-targeting drugs for breast cancer prevention in women at moderate-to-high risk, leading perhaps to combinations that prevent ER-negative and ER-positive breast cancer.