Harold A. Harvey

Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer.

PURPOSE Decisions concerning the use of hormone therapy to treat metastatic breast cancer are made on the basis of the presence of estrogen receptor (ER). Despite the presence of ER, half of patients will not respond to hormone treatment. The purpose of this study was to determine the effect of overexpression of HER-2/neu on the response to hormone therapy. PATIENTS AND METHODS Sera from 300 metastatic breast cancer patients with ER-positive (ER+), ER status unknown, or ER-/progesterone receptor-positive (PR+) randomized to receive second-line hormone therapy with either megestrol acetate or fadrozole were evaluated. An enzyme immunoassay (EIA) specific for the extracellular domain of the c-erbB-2 (HER-2/neu) oncogene product was used to detect serum levels. RESULTS Fifty-eight patients (19.3%) had elevated serum c-erbB-2 protein levels, using a selected cut-point of 30 U/mL. The response rate (complete responses [CRs] plus partial responses [PRs] plus stable disease [S]) to endocrine therapy was 40.9% in 242 patients with low serum c-erbB-2 levels and only 20.7% in 58 patients with elevated serum c-erbB-2 levels (P = .004). The median duration of treatment response was longer in the group with low serum c-erbB-2 levels (15.5 months) compared with the group with elevated serum c-erbB-2 levels (11.6 months). Survival was also significantly shorter in patients with elevated serum c-erbB-2 levels (P < .0001). CONCLUSION Patients with ER+/c-erbB-2+ metastatic breast cancer are less likely to respond to hormone treatment than ER+/c-erbB-2- patients. Their survival duration is also shorter.

Elevated Serum HER-2/neu Level Predicts Decreased Response to Hormone Therapy in Metastatic Breast Cancer

PURPOSE To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.

Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer.

PURPOSE We evaluated single-agent intravenous (IV) vinorelbine as first- and second-line treatment for advanced breast cancer (ABC) in patients who were not resistant to anthracyclines. Objective tumor response (TR) and toxicity were assessed. PATIENTS AND METHODS A total of 107 women were enrolled onto this multicenter, nonrandomized, open-label phase II study. Patients were stratified into first- and second-line treatment groups, based on prior treatment history. Vinorelbine was initially given at 30 mg/m2/wk, with dose modification for toxicity as indicated. Therapy was continued until disease progression or severe toxicity mandated withdrawal or until the patient asked to be removed from the study. RESULTS The objective response rate for all patients was 34% (95% confidence interval [CI], 25% to 44%): 35% (95% CI, 23% to 48%) for first-line patients and 32% (95% CI, 20% to 47%) for second-line patients. Nine first-line and three second-line patients obtained a complete response (CR). The median duration of objective response was 34 weeks in both groups. The overall survival durations of first- and second-line patients were 67 weeks and 62 weeks, respectively. Granulocytopenia was the predominant dose-limiting toxicity. Two patients died on study as a result of granulocytopenic sepsis. CONCLUSION Single-agent vinorelbine is an effective and well-tolerated agent for first- and second-line therapy of ABC. The results of this study confirm the findings of similar international trials and suggest vinorelbine should be considered a valid treatment option for patients with ABC and a potential component in future combination regimens for this disease.

Aminoglutethimide as Treatment of Postmenopausal Women with Advanced Breast Carcinoma

Hormone-dependent breast carcinomas respond to deprivation of biologically active estrogens with objectively quantifiable tumor regression. Aminoglutethimide, a known inhibitor of steroid synthesis, is also a potent blocker of the aromatase enzyme and, thus, of estrogen production. We developed an effective regimen to inhibit estrogen production in postmenopausal women using aminoglutethimide and replacement glucocorticoid. One hundred forty-seven women initially received aminoglutethimide and replacement glucocorticoid as treatment of metastatic breast carcinoma. One hundred twenty-nine women are currently evaluable for assessment of clinical and hormonal responses. Thirty-seven percent of unselected women and 49% of estrogen receptor-positive patients experienced objective tumor regression. Responses occurred predominantly in soft tissue (47%) and bone (35%) and lasted 30 +/- 9.1 months for complete and 14 +/- 1.5 months for partial regressions. Plasma and urinary estrogen levels fell equally in responder versus nonresponder groups whereas androgen levels declined less in patients with progressive disease.

Elevated soluble c-erbB-2 antigen levels in the serum and effusions of a proportion of breast cancer patients.

PURPOSE An enzyme-linked immunosorbent assay (ELISA) for the extracellular domain of the c-erbB-2 oncogene product was developed and evaluated to determine if soluble c-erbB-2 could be detected in the serum and effusions of cancer patients. PATIENTS AND METHODS Sera from 208 previously untreated or progressing cancer patients and 69 healthy controls were assayed in a double-antibody sandwich ELISA that used two monoclonal antibodies to the native extracellular domain of the c-erbB-2 receptor. Fishers exact test was used to analyze the statistical significance of the frequency of elevated serum c-erbB-2 levels. Immunoprecipitation and Western blotting were used to characterize further the c-erbB-2 immunoreactivity in the serum of four breast cancer patients. RESULTS Sera from 12 of 53 patients (23%) with metastatic or locally advanced breast cancer, zero of 69 controls, one of 31 patients with ovarian cancer (3%), and two of 124 other cancer patients (2%) had soluble c-erbB-2 values greater than or equal to 5 U/mL. The number of breast cancer patients with elevated serum c-erbB-2 levels was significantly greater than that of the control group (P less than .0001), the ovarian cancer group (P less than .03), and the other cancers group (P less than .0001). Also, two of five effusions (40%) from breast cancer patients had an elevated soluble c-erbB-2 antigen level, compared with zero of 17 effusions from patients with benign diseases. Western blotting of four sera from breast cancer patients with elevated serum c-erbB-2 antigen levels produced bands of approximately 105 kD that seemed to correlate in intensity with increasing ELISA serum levels. CONCLUSION Serum c-erbB-2 levels are elevated in approximately one fourth of patients with locally advanced or metastatic breast cancer.

Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen

PURPOSE To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.

Aromatase activity in primary and metastatic human breast cancer

Aromatase activity was measured in 104 primary and 24 metastatic breast cancer patients. The assay employed quantitates the production of 3H water release from 1β‐[3H] androstenedione after aromatization. Of 104 human primary breast tumors studied, 64 contained measurable aromatase activity, ranging from 5–70.5 pmol estrone formed/g protein/hour. In primary breast cancers there was no difference in levels of aromatase activity when analyzed by menstrual status or age by decade. Aromatase activity was similar in small and large primary tumors. The median aromatase activity of primary breast tumors (8.6 pmol/g/h) was similar to that found in metastatic breast cancer deposits (12.0 pmol/g/h). Aromatase activity did not correlate with either estrogen (ER) or progesterone (PR) receptor concentration in the tissues assayed. In this regard there were 33 ER− PR− tumor biopsies. Twelve of these 33 tumors contained aromatase activity greater than 10 pmol/g/hour. Cancer 59:779‐782, 1987.

Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome.

We conducted a randomized clinical trial in men with stage D2 prostate cancer to test whether androgen priming potentiates the efficacy of cytotoxic chemotherapy. Eighty-five men with progressive prostate cancer refractory to orchiectomy were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal androgen secretion and were administered cyclic intravenous (IV) chemotherapy. The patients were randomized to receive either androgen priming or no additional treatment for three days before and on the day of chemotherapy. Median duration of follow-up was 43 months. Response rate (remission plus disease stabilization) was not significantly different between the stimulation and control arm when the analysis was restricted to evaluable patients (79% v 73%, respectively) or when it was extended to all patients (46% v 61%). Median duration of response was similar for the stimulation and control arm (9 and 10 months, respectively). Median survival was 10 months in the stimulation and 15 months in the control group (P = .0047). The androgen sensitivity of the tumors was supported by the greater toxicity in the stimulation arm associated with androgen administration. Factors found to be independently associated with improved clinical outcome included a high Karnofsky score and hematocrit, long duration of response to the initial castration, and normalization of an elevated serum acid phosphatase on treatment. We conclude that in this group of patients with advanced disease, androgen priming does not potentiate the efficacy of chemotherapy and is actually associated with a worse outcome. Furthermore, our data emphasize the heterogeneity of biologic behavior of prostate cancer.

Unmet needs of persons with cancer in pennsylvania during the period of terminal care

A stratified random sample of recent cancer deaths was drawn from the Pennsylvania death registry, and 433 family members or close friends were interviewed concerning unmet needs during the last month of life. It was estimated that 72% of persons who died of cancer in Pennsylvania experienced at least one unmet service need during this period. The most frequently reported was help with activities of daily living, estimated at 42% of cancer deaths, involving over 11,000 persons each year in the state. There were significantly more unmet needs during the terminal period, compared with just after diagnosis, in activities of daily living, obtaining health care, transportation, and problems with medical staff. Our findings indicate a need to increase a broad range of support programs during the terminal period, especially of home‐care services.

Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer

Background. Letrozole (CGS 20267), a triazole derivative, is a new, once‐daily, oral nonsteroidal inhibitor of aromatase activity.