John S. Link

Concurrent Trastuzumab and HER2/neu-Specific Vaccination in Patients With Metastatic Breast Cancer

PURPOSE The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected. RESULTS Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached. CONCLUSION Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.

Gemcitabine Plus Cisplatin Repeating Doublet Therapy in Previously Treated, Relapsed Breast Cancer Patients

PURPOSE To determine the safety and efficacy of gemcitabine plus cisplatin for patients with relapsed adenocarcinoma of the breast. PATIENTS AND METHODS Previously treated patients with adenocarcinoma of the breast received cisplatin (30 mg/m(2)) plus gemcitabine (1,000 mg/m(2)) on days 1, 8, and 15 of each 28-day cycle, which was changed after patient no. 12 to cisplatin (30 mg/m(2)) plus gemcitabine (750 mg/m(2)) days 1 and 8 of each 21-day cycle. RESULTS Of 30 patients, three (10%) had complete and 12 (40%) had partial responses, for an overall response rate of 50%. Two objective responses were observed among the four patients accrued after relapse that followed high-dose/stem-cell therapies. The median time to progression was 14 weeks. The median time to progression for objective responders was 23.5 weeks, with a range of 8 to 68 weeks. Toxicities included grades III and IV neutropenia in 13%, anemia in 6%, thrombocytopenia in 31%, grade III nausea in 4%, and grade II peripheral neuropathy in 2% of 151 treatment cycles. Moderate alopecia occurred in four patients. There were no treatment-related deaths. CONCLUSION Cisplatin plus gemcitabine is active and tolerable for patients with relapsed breast cancer. Responses observed in previously treated patients, including high-dose/stem-cell failures, indicate activity in otherwise drug-refractory patients.

Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity

We questioned whether the incidence or magnitude of the humoral or cellular immune response to the self-tumor antigen HER-2/neu is influenced by the level of HER-2/neu protein overexpression as defined by immunohistochemical staining of tumors in breast cancer patients. We obtained peripheral blood from 104 women with stage II, III, and IV pathologically confirmed HER-2/neu-overexpressing breast cancer. Patients were categorized with +1 (n = 14), +2 (n = 20), or +3 (n = 70) HER-2/neu overexpression by institutional pathologic report. Circulating antibodies to HER-2/neu were evaluated using ELISA. T-cell responses to HER-2/neu were measured using an antigen-specific tritiated thymidine incorporation assay. Eighty-two percent of subjects with HER-2/neu antibodies were +3 overexpressors compared with 18% +2 overexpressors and 0% +1 overexpressors, a highly significant difference (P < 0.001), and there were significant differences in the magnitude of the HER-2/neu-specific antibodies between groups with varying HER-2/neu protein expression (P = 0.022). In addition, 65% of subjects with HER-2/neu-specific T cells were +3 overexpressors compared with 16% +2 overexpressors and 19% +1 overexpressors (P = 0.001). Data presented here indicate that endogenous HER-2/neu-specific humoral and T-cell immunity is greater in patients with +3 protein overexpression in their tumors than in patients with lower levels of HER-2/neu expression. Overexpression of a self-tumor-associated protein is a potential mechanism by which immunogenicity is enhanced and may aid in the identification of biologically relevant proteins to target for immune-based molecular cancer therapies. [Mol Cancer Ther 2008;7(3):449–54]

Project connect online: randomized trial of an internet-based program to chronicle the cancer experience and facilitate communication.

PURPOSE Evidence suggests that expressing emotions related to cancer and receiving interpersonal support can promote psychological and physical health in women diagnosed with breast cancer. However, adaptive expression of feelings and communication with ones social network can pose challenges for patients with cancer. We report on a randomized controlled trial of an intervention, Project Connect Online, for patients with breast cancer to create personal Web sites to chronicle their experience and communicate with their social network. PATIENTS AND METHODS Women (N = 88) diagnosed with breast cancer (any stage, any interval since diagnosis) were randomly assigned to participate in a 3-hour workshop for hands-on creation of personal Web sites with a follow-up call to facilitate Web site use, or to a waiting-list control. Assessed before randomization and 6 months after the intervention, dependent variables included depressive symptoms, positive and negative mood, cancer-related intrusive thoughts, and perceived cancer-related benefits in life appreciation and strengthened relationships. RESULTS Relative to control participants, women randomly assigned to Project Connect Online evidenced significant benefit 6 months later on depressive symptoms, positive mood, and life appreciation, but not negative mood, perceived strengthened relationships, or intrusive thoughts. Treatment status moderated the intervention effects, such that women currently undergoing medical treatment for cancer benefitted significantly more from the intervention on depressive symptoms and positive mood than did women not receiving treatment. CONCLUSION Findings suggest the promise of an intervention to facilitate the ability of women diagnosed with breast cancer to chronicle their experience and communicate with their social network via the Internet.

Carboplatin plus Gemcitabine Repeating Doublet Therapy in Recurrent Breast Cancer

PURPOSE The combination of cisplatin plus gemcitabine is active in metastatic breast cancer. Carboplatin plus gemcitabine, widely used in ovarian and non-small-cell lung cancers, has also been used in breast cancer. This trial examined the efficacy and toxicity of split-dose carboplatin plus gemcitabine in advanced breast cancer. PATIENTS AND METHODS Patients with measurable disease, recurrent after adjuvant and < or = 1 previous treatment for systemic disease, received carboplatin area under the curve = 2.0 (Calvert) plus gemcitabine 800 mg/m2, both drugs administered days 1 and 8 every 21 days. Of 15 patients accrued, 13 are fully evaluable. RESULTS There were 2 complete (13.3%) and 6 partial (40%) responses, for an overall response rate by intention to treat of 53.3% (95% CI, 28%-82%). The median time to progression was 4.5 months (95% CI, 2.03-6.97 months), and median overall survival was 28.8 months (95% CI, 9.4-48.2 months). There were 2 patients with grade 3 (13.3%) anemia, 7 patients with grade 3 (46.6%) and 4 patients (26.6%) with grade 4 neutropenia, 4 patients with grade 3 (26.6%) and 3 patients (20%) with grade 4 thrombocytopenia. CONCLUSION The repeating doublet of split-dose carboplatin plus gemcitabine reveals activity comparable to that of cisplatin plus gemcitabine, is well tolerated, and warrants evaluation in patients with recurrent breast cancer.

Breast cancer patients unknowingly dosing themselves with estrogen by using topical moisturizers.

TO THE EDITOR: A 46-year-old woman with estrogen receptor– positive breast cancer presented to us with impressive “youth enhancing results” after 4 weeks of daily application of a commercially available skin moisturizer after bathing. We were concerned about the possible presence of estrogenically active substances in the cream, despite the absence of any mention in the ingredient list. A sample similar to the patient’s cream along with samples of other commercially available moisturizers that were obtained from department stores and pharmacies were sent for measurement of estradiol, estrone, and estriol. Products were selected based on their claims of “rejuvenating” or “youth enchancing” capabilities. The price for the moisturizers ranged from a high of several hundred dollars to a low of 10 dollars per unit. None of the ingredient lists contained any mention of an estrogen or estrogenic molecules. Unopened samples were mailed to Analytic Research Laboratories (Oklahoma City, OK). Each of the 16 products was tested for estradiol, estriol, and estrone. High performance liquid chromatography analysis equipped with ultraviolet detection was used to provide component analysis. Four samples contained more than 0.40% estriol, one contained 0.17% estriol, and one contained 0.05% estrone. A summary of the results are presented in Table 1. This testing was only a screening process. Levels of estadiol, estrone, and estriol were documented only above 0.05%. For reference, Estrace vaginal cream produced by Warner Chilcott is 0.01% estradiol. Testing was done only for the three estrogens noted. No designer estrogens, estrogen-like molecules, or progesterones were evaluated. These samples were obtained in April 2007, and since cosmetic companies frequently change their formulations, contents of each product may not currently be similar to those obtained at that time. It is our belief that the release of the brand names may be misleading. Cosmetic laws are based on an outdated concept that an intact skin is a barrier to topically applied substances. Manufacturers of cosmetics (including moisturizers) are relied on to ensure the safety of their products and to provide accurate ingredient labels. No government agency (ie, the US Food and Drug Administration) tests these products unless a problem is reported. Daily application of topical “youth enhancing” moisturizers containing estrogen or estrognically active compounds could theoretically be a risk to women with breast cancer, particularly those with estrogen receptor–positive breast cancers who take aromatase inhibitors. Komori et al described a 93-year-old patient with a history of extensive topical use of an estradiol-containing cream. She presented with a hyperplastic uterus as large as an adult menstruating female, and also with invasive breast cancer. Kendall et al documented short-term elevation of systemic estradiol levels in patients using estradiol vaginal tablets while on aromatase inhibitors. They advised caution when using these products concurrently. The extent to which chemicals applied to the skin are absorbed is unknown. Darbre notes personal care products are left on the skin, allowing for absorption through the dermis, with the net result of a chemical deposition in underlying local tissues. Donovan et al documented multiple cases of clinical effects from topically absorbed hormone products. Harvey and Everett emphasized that human exposure to increasingly sophisticated cosmetic formulations is largely regulated by the manufacturers. Reviewing Chadwick et al, Cheibowski et al, Harvey et al, and Mai et al may provide helpful background information, raise related questions, and suggest additional complementary avenues of research. We believe that women, especially patients with a history of breast cancer, should be able to understand the potential risks when exposed to estrogenically active molecules in commercially available topical moisturizers. Because our testing methodology was only intended as a screening process, we strongly encourage the scientific community and the US Food and Drug Administration to repeat and expand on the results of these screening tests.