Paula Silverman

Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer: A Phase 2 Randomized Study

CONTEXT Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. DESIGN, SETTING, AND PATIENTS A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. INTERVENTION Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. MAIN OUTCOME MEASURES Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). SECONDARY OUTCOMES toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. RESULTS The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. CONCLUSIONS In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00324259.

Phase I Dose Escalation and Pharmacokinetic Study of Lapatinib in Combination With Trastuzumab in Patients With Advanced ErbB2-Positive Breast Cancer

PURPOSE The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer. PATIENTS AND METHODS Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination. RESULTS A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone. CONCLUSION The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: Impact on angiogenic biomarkers

Purpose: Taxanes have effects on angiogenesis causing difficulties in separating biological effects of chemotherapy from those due to angiogenesis inhibitors. This randomized phase II trial was designed to evaluate the additional biomarker effect on angiogenesis when bevacizumab is added to docetaxel. Experimental Design: Patients with inoperable breast cancer were randomized to either 2 cycles of preoperative docetaxel (D) 35 mg/m2 i.v. weekly for 6 weeks, followed by a 2-week break; or docetaxel with bevacizumab 10 mg/kg i.v. every other week for a total of 16 weeks (DB). Plasma and serum markers of endothelial damage, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and tumor microvessel density were assessed before treatment and at the end of each preoperative cycle. Results: Forty-nine patients were randomized (DB, 24; D, 25). There was no difference in overall clinical response, progression-free survival, or overall survival. Vascular endothelial growth factor increased during treatment; more so with DB (P < 0.0001). Vascular cell adhesion molecule-1 (VCAM-1) also increased (P < 0.0001); more so with DB (P = 0.069). Intercellular adhesion molecule increased (P = 0.018) and E-selectin decreased (P = 0.006) overall. Baseline levels of VCAM-1 and E-selectin correlated with clinical response by univariate analysis. DCE-MRI showed a greater decrease in tumor perfusion calculated by initial area under the curve for the first 90 seconds in DB (P = 0.024). DCE-MRI also showed an overall decrease in tumor volume (P = 0.012). Conclusion: Bevacizumab plus docetaxel caused a greater increase in vascular endothelial growth factor and VCAM-1, and a greater reduction in tumor perfusion by DCE-MRI compared with docetaxel. Clinical outcomes of inoperable breast cancer were predicted by changes in VCAM-1 and E-selectin.

Phase II trial of taxol in salivary gland malignancies (E1394): a trial of the Eastern Cooperative Oncology Group.

Malignant tumors of the salivary glands make up approximately 5% of head and neck cancers. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II evaluation of paclitaxel in patients with locally recurrent or metastatic salivary gland malignancies.

Breast Conservation Surgery Achieving ≥ 2 mm Tumor-Free Margins Results in Decreased Local-Regional Recurrence Rates

Abstract:  Whether cosmetically acceptable tumor‐free (≥2 mm) surgical margins reduce the local‐regional recurrence risk for patients treated with fractionated radiation therapy, chemotherapy, and hormonal therapy is unknown. The benefit of a minimum cosmetically acceptable tumor‐free margin remains speculative because no contemporary studies have investigated the extent of invasive disease infiltration within the breast beyond the primary tumor. To address these clinical issues, we conducted a retrospective study of 341 women diagnosed with stage I or II invasive breast cancer to determine the rate of local in‐breast, elsewhere in‐breast, and ipsilateral regional lymph node recurrences of breast cancer after conservation surgery achieving either tumor‐free (≥2 mm) or close (>0 mm to <2 mm) surgical margins followed by whole breast radiation therapy over a 6‐year period from January 1996 to December 2002. Women may have received adjuvant chemotherapy or hormonal therapy as clinically indicated. After a median follow‐up of 56 months from the completion of breast conservation surgery, 14 of the 341 women (4.1%) developed breast cancer recurrences. Crude ipsilateral recurrence rates were 1.8% (4 of 222) for tumor‐free (≥2 mm) versus 8.4% (10 of 119) for close (>0 mm to <2 mm) surgical margins (p = 0.007). The estimated 5‐year cumulative local recurrence rate was significantly less for women with tumor‐free margins (2.1%) as compared to close surgical margins (8.9%) (p = 0.004). Multivariate analyses identified negative estrogen receptor expression (p = 0.004), close surgical margins (p = 0.012), and the presence of angiolymphatic invasion (p = 0.040) as prognostic factors for local‐regional recurrences. Microscopically the extent of invasive disease infiltration beyond the primary tumor was on average 1 mm, with all measured invasive disease less than 1 cm. Based on our findings, cosmetically acceptable tumor‐free (≥2 mm) surgical margins significantly reduce local in‐breast and regional lymph node recurrences with fractionated radiation therapy, chemotherapy, and hormonal therapy.

Inflammatory breast cancer as a model disease to study tumor angiogenesis : Results of a phase IB trial of combination SU5416 and doxorubicin

Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.

Breast cancer: overview & updates.

AbstractBreast cancer is a complex disease and treatment recommendations are continually changing. It is the leading cancer in women and the second leading cause of cancer mortality. This overview of breast cancer will discuss pathologic features, local and systemic treatment considerations, endocrine therapy, metastatic treatment regimens, and follow-up for optimal breast health. Recent approvals that advance the treatment of metastatic breast cancer are also addressed.

Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: Results from the American college of surgeons oncology group Z1031 trial (alliance)

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Phase II trial of neoadjuvant docetaxel with or without bevacizumab in patients with locally advanced breast cance.

727 Background: The anti-angiogenic agent, bevacizumab (rhuMAbVEGF) is a humanized monoclonal antibody against VEGF which, when combined with docetaxel in preclinical models, results in synergistic suppression of capillary vessel formation. Based on these data, a randomized phase II trial was developed to evaluate the vascular effects on tumor regression with combination bevacizumab/docetaxel vs. docetaxel in the treatment of locally advanced breast cancer. METHODS 33 patients (pts) were randomized to receive neoadjuvant therapy with bevacizumab (10 mg/kg qowk) and docetaxel (two 8-week cycles of 35 mg/m2 weekly x 6 with a 2 wk break) or docetaxel alone. Eligible pts had locally unresectable breast cancer with or without metastasis. Pts who responded underwent definitive surgery, radiation, 4 cycles of adjuvant conventional Adriamycin/cyclophosphamide, followed by tamoxifen (if ER/PR+). RESULTS 26 pts completed pre-operative treatment. 3 pts with inflammatory breast cancer were not operable at the conclusion of therapy because of residual disease. The median number of pathologically + lymph nodes (ln) was 1 (range 0-16); 40% were ln negative. The median size of residual tumor was 3.2cm (range 0-14cm). Toxicity included: grade 4 neutropenia-4; grade 3: anorexia-3; GI bleed-1; stomatitis-3; neuropathy-1; wound healing-1. There was no change in LVEF, no hypertension, protienuria, or thrombosis. Preliminary analysis of correlative studies suggests a reduction in tumor Kep by DCE-MRI and a reduction of tumor microvessel density. CONCLUSIONS Neoadjuvant therapy for locally advanced breast cancer using docetaxel with or without bevacizumab is well tolerated and effective. This study requires a total of 60 pts before an analysis can be made of a treatment difference in vascular and disease response. Laboratory correlatives evaluating effects on tumor vasculature are ongoing. (Sponsored by grants: K23CA 87725-01, M01 RR 00080, UO1 CA 62502, P30 CA43703S NCI/Avon) No significant financial relationships to disclose.

Neglecting to Screen Women Between the Ages of 40 and 49 Years With Mammography: What Is the Impact on Breast Cancer Diagnosis?

OBJECTIVE The purpose of this study was to compare breast cancer stage at diagnosis in two groups of women between 40 and 49 years old: women undergoing screening mammography and women with a symptom needing diagnostic workup. This comparison is indicative of the impact of forgoing screening in this age group, as recommended by the United States Preventive Services Task Force. MATERIALS AND METHODS A retrospective chart review was used to collect the results of imaging-guided core needle biopsies performed in women between the ages of 40 and 49 years from January 1, 2008, to December 31, 2009. In patients diagnosed with breast cancer or a high-risk lesion, the reason for presentation, pathology, tumor size, stage, and receptor characteristics were recorded. The chi-square test was used for statistical analysis. RESULTS Of 108 primary breast cancers, 71 were detected in the screened group and 37 in the unscreened group. The screened group was significantly more likely to be diagnosed with ductal carcinoma in situ than the unscreened group (22 vs 1, chi-square = 11.6, p = 0.001). Furthermore, screened patients with invasive carcinoma were significantly more likely to be diagnosed at earlier stages (chi-square = 5.02, p = 0.025). The size of invasive breast cancer in the screened group was significantly smaller as well (chi-square = 9.3, p = 0.002). Of the high-risk lesions, atypical ductal hyperplasia (n = 29) and lobular carcinoma in situ (n = 8) were most frequently seen. CONCLUSION Breast cancer patients undergoing screening mammography were diagnosed at earlier stages with smaller tumors. Screening also allows detection of high-risk lesions, which may prompt chemoprevention and lower subsequent breast cancer risk. We continue to support screening mammography in women between the ages of 40 and 49 years.