Darcy V. Spicer

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Preoperative Twice-Weekly Paclitaxel With Concurrent Radiation Therapy Followed by Surgery and Postoperative Doxorubicin-Based Chemotherapy in Locally Advanced Breast Cancer: A Phase I/II Trial

PURPOSE Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

Depot leuprolide acetate with estrogen and progestin add-back for long-term treatment of premenstrual syndrome * †

OBJECTIVE To test the effectiveness and safety of long-term depot leuprolide acetate (GnRH-a) plus estrogen and progestin add-back therapy in the treatment of moderate and severe premenstrual syndrome (PMS). DESIGN A prospective trial with each patient serving as her own control. SETTING University teaching hospital. PARTICIPANTS Ten women with regular menstrual cycles complaining of moderate to severe PMS. Premenstrual syndrome was diagnosed when symptoms increased > or = 25% during the luteal phase. TREATMENT Four-week cycles of IM injections of placebo or GnRH-a with all patients receiving saline (placebo), the first cycle followed by 12 cycles of GnRH-a, 7.5 mg. Conjugated equine estrogen (0.625 mg/d) was started Monday through Saturday within the first cycle and increased as needed. Medroxyprogesterone acetate (MPA), 10 mg/d, was taken orally for 10 days after 4, 8, and 12 cycles of GnRH-a therapy. MAIN OUTCOME MEASURES Changes in three symptom categories (water retention, pain, and psychological function), serum levels of total cholesterol and HDL, HDL-2, and LDL cholesterol, E2, and estrone. Endometrial biopsy was obtained 1 day after the end of the 12th GnRH-a cycle, and bone density was assessed using quantitative computer tomography at the end of the 12th GnRH-a cycle. RESULTS During treatment, there was a significant decrease compared with baseline and placebo in all three symptom categories. There were no significant changes in lipids. Endometrial biopsies revealed progestational changes with no evidence of hyperplasia. Quantitative computer tomography bone density dropped 3.7 on average compared with baseline after 12 months of treatment, but this was not statistically significant. CONCLUSION Gonadotropin-releasing hormone agonist therapy with hormonal add-back therapy is effective in treating PMS symptoms with progressive improvement over a 12-month period. This therapy prevents changes in lipids and adequately protects the endometrium with the addition of MPA every 4th cycle. Quantitative computer tomography bone density dropped at 12 months; further examination of bone changes is necessary.

Characteristics of Triple-Negative Breast Cancer in Patients With a BRCA1 Mutation: Results From a Population-Based Study of Young Women

PURPOSE Triple-negative breast cancers (TNBCs) are tumors with low or no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. These tumors have a poor prognosis, remain a clinical challenge, and are more common among women with BRCA1 mutations. We tested whether there are distinguishing features of TNBC after BRCA1 mutation status has been taken into account. PATIENTS AND METHODS We sequenced BRCA1 and BRCA2 genes in a population-based sample of 1,469 patients with incident breast cancer age 20 to 49 years from Los Angeles County (California). Information on tumor receptor status was available for 1,167 women. Clinical, pathologic, and hormone-related lifestyle characteristics were compared across patient subgroups defined by BRCA1 mutation status and triple-negative receptor status. RESULTS Forty-eight percent of BRCA1 mutation carriers had TNBC compared with only 12% of noncarriers. Within BRCA1 mutation carriers, as well as within noncarriers, triple-negative receptor status was associated with younger age at diagnosis and higher tumor grade. Among women without a BRCA1 mutation, we observed that women with TNBC had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age at menarche and other reproductive factors were not associated with triple-negative status regardless of BRCA1 mutation status. Within BRCA1 mutation carriers, Ashkenazi Jewish women were about five times more likely to have TNBC than non-Ashkenazi Jewish women. CONCLUSION Our results suggest that among BRCA1 mutation carriers, as among noncarriers, there are unique characteristics associated with the triple-negative subtype. The findings in Ashkenazi Jewish BRCA1 mutation carriers should be confirmed.

Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-Fluorouracil and radiation therapy

PURPOSE/OBJECTIVE 1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5-FU) and radiation (RT) in locally advanced breast cancer. 2) To study clinical and pathological response rates of 5-FU and radiation. 3) To attempt preliminary correlations between biological probes and pathological response. METHODS AND MATERIALS Previously untreated, locally advanced breast cancer patients were eligible: only patients who presented with T3/T4 tumors that could not be resected with primary wound closure were eligible, while inflammatory breast cancer patients were excluded. The protocol consisted of preoperative c.i. infusion 5-FU, 200 mg/m2/day with radiotherapy, 50 Gy at 2 Gy fractions to the breast and regional nodes. At mastectomy, pathological findings were classified based on persistence of invasive cancer: pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of microscopic foci of invasive cells in either the breast or nodal specimens; no pathological response (pNR) = pathological persistence of tumor. For each patient pretreatment breast cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR hormonal receptors, her2/neu and p53 overexpression. RESULTS Thirty-five women have completed the protocol and are available for analysis. 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1, and patient choice in another. Objective clinical response rate before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35 patients tumor response was sufficient to make them resectable with primary wound closure. Accordingly, all patients underwent modified radical mastectomy: primary wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%), 5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of cancer (pNR). Variables analyzed as potential predictors for pathological response (pPR and pCR) were: initial TNM clinical stage, clinical response, nuclear grade, hormonal receptor status, p53 overexpression, and Her2/neu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at immunohistochemistry) significantly correlated with achievement of a pathological response to this regimen (p = 0.010). CONCLUSION The combination of c.i. 5-FU and radiation was well tolerated and generated objective clinical responses in 71% of the patients. With the limitation of the small sample size, the complete pathological response achieved (20%) compares favorably with that reported in other series of neoadjuvant therapy for similar stage breast cancer. These preliminary data suggest that initial p53 status predicts for pathological response (pPR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer.

Effect of 2 month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women

There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a double-blind, randomized, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, polyphenon E (PPE). Postmenopausal women (n = 103) were randomized into three arms: placebo, 400-mg EGCG as PPE, or 800-mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. On the basis of urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low-density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P = 0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P = 0.008) and insulin (P = 0.01) were found. In summary, green tea (400- and 800-mg EGCG as PPE; ∼5–10 cups) supplementation for 2 months had suggestive beneficial effects on LDL-cholesterol concentrations and glucose-related markers. Cancer Prev Res; 5(3); 393–402. ©2012 AACR.

Phase II Studies of Gemcitabine and Cisplatin in Heavily and Minimally Pretreated Metastatic Breast Cancer

PURPOSE Cisplatin and gemcitabine have single-agent activity in metastatic breast cancer, and preclinical data support synergy of the combination. Two parallel, phase II trials were conducted to evaluate the response rate, response duration, and toxicities of the combination. Genetic polymorphisms were analyzed for correlation with outcomes. PATIENTS AND METHODS Eligible women had measurable disease and heavily or minimally pretreated metastatic breast cancer. The heavily pretreated protocol required prior anthracycline and taxane therapy; cisplatin as part of high-dose therapy was allowed. All patients received cisplatin 25 mg/m(2) on days 1 through 4 and gemcitabine 1,000 mg/m(2) on days 2 and 8 of a 21-day cycle with prophylactic granulocyte colony-stimulating factor in the heavily pretreated group. Sera from a subset of patients were evaluated by polymerase chain reaction restriction fragment length polymorphism for polymorphisms in 10 genes of interest. RESULTS Of 136 women enrolled, 74 were heavily pretreated. Both protocols accrued to their two-stage design. The response rate for both the heavily and minimally pretreated cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively. In a multivariate analysis, hormone receptor-negative disease was associated with a higher response rate. The most common grades 3 or 4 toxicities were thrombocytopenia (71%), neutropenia (66%), and anemia (38%). In a subset of 55 patients, the xeroderma pigmentosum group D (XPD)-751, x-ray cross-complementing group 3 (XRCC3) and cytidine deaminase polymorphisms were significantly associated with clinical outcomes. CONCLUSION Combination cisplatin and gemcitabine is active in metastatic breast cancer regardless of prior therapy. Genetic polymorphisms may tailor which patients benefit from this regimen.

GRP78 as potential predictor for breast cancer response to adjuvant taxane therapy

Few predictive markers exist for response to adjuvant chemotherapy in breast cancer. The 78‐kDa glucose‐regulated protein (GRP78) is a potent antiapoptotic factor, conferring drug resistance. Recently, we reported that high GRP78 expression in breast cancer specimens predicts a shorter recurrence‐free survival in patients who received doxorubicin‐based adjuvant chemotherapy. Interestingly, the opposite effect was observed in 25 patients who additionally received a taxane. To confirm this potentially paradigm shifting finding, we investigated whether GRP78 is associated with recurrence‐free survival in an independent cohort of taxane‐treated breast cancer patients. Immunohistochemical staining of GRP78 was performed on archival paraffin‐embedded formalin‐fixed tumor specimens obtained from 48 female breast cancer patients before chemotherapy treatment. These patients received doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel on a clinical trial. GRP78 expression level was evaluated by a pathologist, masked to all clinical and outcome data. Association between GRP78 expression and recurrence‐free survival was evaluated. GRP78 positivity predicts a better recurrence‐free survival, independent of other prognostic factors [hazard ratio (HR) for moderate positivity: 0.40 (95% confidence interval (CI): 0.087–1.83); HR for strong positivity: 0.16 (95% CI: 0.018–1.50); ptrend = 0.053]. In a pooled analysis with the previous 25 patients, almost identical HRs were obtained with ptrend = 0.024. This provides further evidence that GRP78 is a potential independent predictor for response to taxane‐based adjuvant chemotherapy in breast cancer.

Low HER2/neu gene expression is associated with pathological response to concurrent paclitaxel and radiation therapy in locally advanced breast cancer

PURPOSE The objective of this study was twofold: first, to identify patients with locally advanced breast cancer (LABC) who will achieve a pathological response to a preoperative regimen of concurrent paclitaxel and radiation; and second, to explore associations between molecular markers from the original tumors and pathological response. METHODS AND MATERIALS Patients with previously untreated LABC were eligible to receive a regimen of preoperative concurrent paclitaxel, 30 mg/m(2) twice a week for a total of 8 weeks, and radiation delivered Weeks 2--6, 45 Gy at 1.8 Gy per fraction to the breast, ipsilateral axilla, and supraclavicular nodes. At mastectomy, pathologic findings were classified as pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of < or = 10 microscopic foci of invasive cells; no pathological response (pNR) = pathological persistence of tumor. For each patient, pretreatment breast cancer biopsies were prospectively analyzed by immunohistochemistry (IHC) for estrogen and progesterone (ER/PR) hormonal receptors, HER2/neu and p53 overexpression. Estrogen receptor (ER), HER2/neu, metablastin, beta-tubulin III and IV, microtubule-associated protein-4 (MAP-4), bcl-2, bax, and cyclooxygenase-2 (COX-2) gene expression were measured using real-time quantitative polymerase chain reaction (PCR). RESULTS A total of 36 patients had pretreatment biopsies and were evaluable for the analysis of the association of molecular markers with pathological response. Pathological response in the mastectomy specimen was achieved in 12 of these 36 patients (33%). Only HER2/neu and ER gene expression were found to be significantly associated with the extent of pathological response to the regimen, i.e., tumors with low HER2/neu gene expression and negative estrogen receptors were more likely to respond to the tested regimen (p = 0.009 and p = 0.006, respectively). Conversely, p53 protein expression measured by IHC did not appear to be associated with pathological response (p = 0.67). CONCLUSION Further studies in LABC should assess whether patient selection for treatment based on the original tumor molecular characteristics could affect their chance to achieve a pathological response.

Reduced mammographic density with use of a gonadotropin-releasing hormone agonist - Based chemoprevention regimen in BRCA1 carriers

Purpose: Women with a BRCA1 mutation (BRCA1mut) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1mut carriers. Experimental Design: The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E2), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1mut, and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey). Results: Six of eight BRCA1mut women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life. Conclusions: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1mut carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1mut carriers.