Hideko Yamauchi

When Is a Tumor Marker Ready for Prime Time? A Case Study of c-erbB-2 as a Predictive Factor in Breast Cancer

PURPOSE c-erbB-2 (HER-2, c-neu) might play a role as a predictive factor in breast cancer. However, the clinical utility of the marker in this disease is still not established. We conducted a critical analysis of the literature, in which we reviewed the factors that contribute to the lack of acceptance of c-erbB-2 for clinical use and attempted to determine the predictive role of c-erbB-2 for response to specific therapies. METHODS We conducted a MEDLINE literature search using the keywords c-erbB-2, HER2, neu, and breast cancer, reviewed the references included in each publication, and reviewed abstracts that have been reported in the 1997-2000 proceedings to the American Association of Cancer Research and American Society for Clinical Oncology annual meetings. RESULTS The preclinical and clinical data reported to date suggest that amplification or overexpression of c-erbB-2 is a weak to moderate negative pure prognostic factor. c-erbB-2 seems to be a weak to moderate negative predictive factor for response to endocrine therapy. The marker is also a moderate negative predictive factor for response to alkylating agents and a moderate positive predictive factor for response to anthracyclines. The data regarding response to taxanes or radiotherapy are not sufficient to make recommendations regarding treatment decision making. Finally, c-erbB-2 is a strong predictive factor for response to trastuzumab. CONCLUSION We conclude that, in the adjuvant setting, c-erbB-2 status should not be used to determine whether a woman should receive adjuvant systemic therapy (weak prognostic factor). In addition, c-erbB-2 status should not be used to determine whether a patient should receive endocrine therapy. When adjuvant chemotherapy is recommended, anthracycline-based therapy should be the preferred regimen for c-erbB-2-positive patients. However, when anthracyclines are contraindicated, alkylating agent-based therapy should not be withheld. To determine the true predictive role and strength of the marker for response to each therapy, prospective randomized clinical trials or formal meta-analyses are required.

Inflammatory Breast Cancer: The Disease, the Biology, the Treatment

Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, local and distant metastases, younger age of onset, and lower overall survival compared with other breast cancers. Historically, IBC is a lethal disease with less than a 5% survival rate beyond 5 years when treated with surgery or radiation therapy. Because of its rarity, IBC is often misdiagnosed as mastitis or generalized dermatitis. This review examines IBCs unique clinical presentation, pathology, epidemiology, imaging, and biology and details current multidisciplinary management of the disease, which comprises systemic therapy, surgery, and radiation therapy. CA Cancer J Clin 2010.

Phase II Evaluation of Thalidomide in Patients With Metastatic Breast Cancer

PURPOSE To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

Circulating tumor markers in breast cancer: Accepted utilities and novel prospects

Detecting and/or monitoring changes in circulating tumor markers might assist in evaluating cancer risk, diagnosis, prognosis, or response to treatment. Several categories of circulating tumor markers have been investigated in breast cancer. These categories include classical tumor-associated antigens, such as CEA and CA 15-3, markers of tumor biology, including markers of angiogenesis, adhesion, and invasion, and antibody response to tumor-associated antigens such as HER2/neu and p53. We used a recently proposed Tumor Marker Utility Grading System to evaluate the use of several circulating tumor markers for different clinical utilities in breast cancer. While there are no tumor markers with established clinical utilities for most uses, tumor-associated antigens can be used for monitoring patients with metastatic disease. In addition, markers of tumor biology such as the circulating extracellular domain of HER2/neu might be useful in determining not only prognosis, but also response to specific treatments. However, further investigations are required to further assess the utility of individual tumor markers for specific clinical uses.

Inflammatory breast cancer: what we know and what we need to learn.

PURPOSE We review the current status of multidisciplinary care for patients with inflammatory breast cancer (IBC) and discuss what further research is needed to advance the care of patients with this disease. DESIGN We performed a comprehensive review of the English-language literature on IBC through computerized literature searches. RESULTS Significant advances in imaging, including digital mammography, high-resolution ultrasonography with Doppler capabilities, magnetic resonance imaging, and positron emission tomography-computed tomography, have improved the diagnosis and staging of IBC. There are currently no established molecular criteria for distinguishing IBC from noninflammatory breast cancer. Such criteria would be helpful for the diagnosis and development of novel targeted therapies. Combinations of neoadjuvant systemic chemotherapy, surgery, and radiation therapy have led to an improved prognosis; however, the overall 5-year survival rate for patients with IBC remains very low (∼30%). Sentinel lymph node biopsy and skin-sparing mastectomy are not recommended for patients with IBC. CONCLUSION Optimal management of IBC requires close coordination among medical, surgical, and radiation oncologists, as well as radiologists and pathologists. There is a need to identify molecular changes that define the pathogenesis of IBC to enable eradication of IBC with the use of IBC-specific targeted therapies.

Molecular targets for treatment of inflammatory breast cancer

Despite progress in combined-modality treatment with chemotherapy, surgery, and radiation therapy, the long-term outcome for patients with inflammatory breast cancer (IBC) remains poor. Therapies that target vasculolymphatic processes—angiogenesis, lymphangiogenesis, and vasculogenesis—have shown potential in the treatment for IBC, as represented by bevacizumab. Although the therapeutic effect of targeting lymphangiogenesis and vasculogenesis requires further investigation, targeting of angiogenesis has potential, not only through true antiangiogenic effects, but also through antitumor effects in concert with other pathways. Therapies that target cell proliferation pathways are the most promising targeted therapies for IBC. In particular, therapies that target human epidermal growth factor receptor 2 (for example, trastuzumab and lapatinib) have performed well in the clinical setting, leading to improved outcomes for patients with IBC. Metastatic pathways could have a unique, key role in the aggressiveness of the IBC phenotype. Further extensive work on the unique molecular characteristics of IBC is essential to ensure improved outcomes for patients with this disease. In this Review we discuss three pathways—vasculolymphatic, cell proliferation and metastatic—that could represent important targets in the treatment of IBC.

The role of c-erbB-2 as a predictive factor in breast cancer

Most women diagnosed with primary invasive breast cancer are potential candidates to receive adjuvant systemic treatment. Tumor markers that predict the likelihood of response to therapy might help select optimal treatment for individual patients. Of these, c-erbB-2 is the most promising marker. In the past 15 years, over 200 reports related to c-erbB-2 and breast cancer have been published. However, its clinical role remains unclear.c-erbB-2 might serve as either a pure prognostic factor, with no association with therapy, or as a predictive factor of benefit from specific types of systemic treatments. A recent overview suggested that c-erbB-2 is only a weak prognostic factor. A review of the literature suggests that c-erbB-2 overexpression might predict for relative, but not absolute, resistance to endocrine therapy in estrogen receptor-positive women. When adjuvant chemotherapy is indicated, c-erbB-2 positive patients may receive more benefit from anthracycline-containing regimens than alkylating agents. However, if anthracyclines are contraindicated, women with c-erbB-2 positive tumor do derive benefit from alkylating agents. Importantly, c-erbB-2 status appears critical for selecting patients who should receive trastuzumab. Well-designed prospective randomized clinical trials or formal meta-analysis will help to establish the predictive role of c-erbB-2.

Elastographic evaluation of mucinous carcinoma of the breast

BackgroundElastography is widely used as a diagnostic tool for the diagnosis of invasive breast cancer. However, no study has yet shown if elastography for diagnosing mucinous carcinoma is as useful as that for diagnosing the usual invasive carcinoma. Mucinous carcinoma is considered as a soft tumor. In this study, we used elastography to evaluate the elasticity of mucinous carcinoma.MethodsAmong 1,015 patients who underwent surgery for primary breast cancer between February 2007 and August 2008 in our facility, the final pathological diagnosis showed only 32 mucinous carcinomas. We evaluated 16 of the 32 mucinous carcinoma patients who underwent preoperative elastography.ResultsThere were 13 cases of the pure-type and 3 cases of the mixed-type mucinous carcinoma. B-mode ultrasound (US) imaging showed mass formation in 16 patients. The elasticity score was 2 in 1 case (8%), 3 in 3 cases (23%), 4 in 7 cases (54%), and 5 in 2 cases (15%). The fat-to-lesion ratio (FLR) was evaluated in 7 cases. The mean value of the FLR was 12 (range 3–30).ConclusionTwelve of the 16 (75%) cases had an elastography score of 4 or 5. Although mucinous carcinoma had an elastography score similar to that of usual invasive carcinoma, elastography may be useful for distinguishing mucinous carcinoma from benign fibroadenoma.

Role of circulating tumor cells and disseminated tumor cells in primary breast cancer

Metastasis remains a main cause of death in patients with breast cancer regardless of improvements in treatment. Prospective clinical studies of this minimal residual disease have shown disseminated tumor cells (DTCs) in bone marrow and circulating tumor cells (CTCs) in peripheral blood, neither of which can be detected by conventional imaging, to be prognostic and predictive markers for responsive treatment in patients with metastatic breast cancer. However, the guideline from the American Society of Clinical Oncology does not recommend measuring CTCs for clinical decisions because of a lack of evidence for an established, sound methodology and with proven clinical relevance. The Southwest Oncology Group trial S0500 to validate the clinical relevance of CTCs for treatment decisions in patients with metastatic breast cancer is ongoing. In patients with primary breast cancer, the low detection rate of CTCs has been overcome by recent advances in technology. Although generally DTCs were more detectable than CTCs and the association between presence of DTCs and poor prognosis has been shown, the invasiveness of sample collection of DTCs from bone marrow is generally hard for patients to accept. In this review, we concentrate on the question of whether we need to consider CTCs and DTCs in the management of primary breast cancer on the basis of the evidence of the clinical relevance of CTCs and DTCs. The promising role of the molecular characterization of CTCs, which does have the potential for being a predictor for tumor behavior and development, is suggested as a new targeting strategy.

A Pilot Surrogate End Point Biomarker Trial of Perillyl Alcohol in Breast Neoplasia

Purpose: Efficient strategies to screen promising agents in early phase development are essential for rapid progress in breast cancer chemoprevention. We report our experience with the natural compound perillyl alcohol (POH) administered in a short-term surrogate end point biomarker (SEB) protocol, using the “window” between diagnostic and definitive surgery. Experimental Design: Eligible patients included those with a diagnosis of atypical ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, or invasive carcinoma (<3 cm in size) that required further surgery. Thirty-seven of 267 women screened were enrolled in the study (14%). Five women received single-dose POH (1.5 g/m2) 2 days before surgery, 16 received escalating doses of POH (1.2 g/m2 to 4.8 g/m2/day) for 2 days before surgery, and 16 served as untreated controls. Exploratory SEB analysis [estrogen receptor, progesterone receptor, proliferation, apoptosis, M6P/insulin-like growth factor (IGF)-2R, IGF1, IGF2 and transforming growth factor β] was conducted before and after POH. Results: Only a small portion of the population screened entered the study. Reasons for nonparticipation included protocol ineligibility, conflict of timing of surgery, miscellaneous logistical reasons, or patient’s choice. POH administration was well tolerated and did not interfere with surgical management. The power to observe changes in candidate SEB was diminished by a 44% incidence of cases in which the index lesion was not present in the definitive surgical specimen. Conclusions: Preoperative POH exposure was safe and suitable for a more definitive phase II SEB study. Further investigations must overcome logistical obstacles to accrual, and they must focus on approaches to maximize tissue collection and to incorporate genomic analysis of target lesions.