Faculty Bibliography

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A-500 mg intramuscular (i.m.) day -14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B-1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (alpha=0.10, beta=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 alpha level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided chi2-test; 95% CI for difference (14.5%)=-0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.

Breast cancer prognosis and breast cancer molecular subtype vary by race/ethnicity. We determined whether the distribution of breast cancer subtypes varies among different Asian ethnic groups. Using immunohistochemical surrogates for the four molecularly defined breast cancer subtypes, we characterized breast cancer subtype for 346 Asian subjects treated at two New York City institutions. We found that Chinese and Japanese had a higher proportion of good-prognosis luminal A cancers (66.7 and 80.0%, respectively) compared to Filipinos and Koreans (48.5 and 47.1%) (P = 0.001). Filipinos had a higher proportion of HER-2/neu positive cancers (45.6%) compared to other ethnic groups (23.6%) (P = 0.002). Koreans had a higher proportion of triple negative cancers (23.5%) compared to other ethnic groups (7.5%) (P = 0.06). The results suggest that differences exist in breast cancer tumor biology among distinct Asian ethnic groups and have implications for cancer care and research. Future studies of breast cancer in Asian-Americans should distinguish among the different ethnic groups.

In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.

BACKGROUND:Hypercalcemia has been reported in association with a number of malignancies, but it is an unusual manifestation of ovarian cancer. This finding at presentation (possibly aggravated by oral calcium intake) led to discovery of a clear cell carcinoma of the ovary. The implications and pathophysiology of this association are reviewed. CASE REPORT/METHODS:Following presentation with abdominal symptoms, this premenopausal woman was found to have bilateral adnexal masses and hypercalcemia. Her parathormone-related polypeptide was found to be elevated. After surgery and staging, she received adjuvant carboplatin and paclitaxel (later substituted by docetaxel). She has done well on her long-term follow-up. CONCLUSIONS:This rare paraneoplastic manifestation of ovarian cancer may be associated with long-term survival if discovered at an early stage. In this instance, further benefit may have been obtained from adjuvant platinum-based chemotherapy.

Testosterone is important for the development of secondary sexual characteristics in female-to-male (FtM) transsexuals, but it may increase breast cancer risk. To date, only one breast cancer case has been reported in the literature in a FtM transsexual after 10 years of testosterone therapy. We describe 2 cases of breast cancers diagnosed in FtM transsexuals who have been treated with supraphysiological doses of testosterone. Our 2 cases demonstrate the unique issues that concern the management of FtM transsexuals with breast cancer and examine possible roles of testosterone in the development of breast cancer.

PURPOSE: There is no consensus regarding treatment for patients with breast cancer and isolated sternal involvement. Though classified as AJCC stage IV, this group of patients may have prolonged distant disease free survival. PATIENTS AND METHODS: Retrospective case series of 8 patients with isolated sternal recurrence. Information regarding age, menopausal status, hormonal receptor status, HER2 status, initial treatment, time to sternal recurrence, treatment of sternal involvement, and outcome was obtained. RESULTS: Median follow-up, 6 years. Seven of 8 diagnosed with metachronous sternal recurrence at a median of 3 years from initial breast cancer diagnosis, 1 with sternal involvement at initial diagnosis. Seven of 8 are alive, with one death from metastatic breast cancer 10 years after sternal recurrence. Six of 8 are without evidence of distant spread, 2 in continuous complete remission (CR) at 7 and 14 years from sternal recurrence. CONCLUSION: While a small cohort, the excellent survival of the group identifies this as a distinct subset of metastatic disease, requiring special treatment considerations. Isolated sternal involvement could represent direct local-regional extension rather than systemic spread.

The diagnostic power of an integrated positron emission tomography/computed tomography (PET/CT) system for whole-body 2-fluoro-2-deoxy-d-glucose (FDG) imaging is clearly demonstrated in this case report. The precise anatomic localization of FDG uptake with CT in a PET/CT scan of a patient with known breast carcinoma helped identify a contralateral breast tumor with axillary lymph node metastasis despite the presence of extensive physiologic brown fat FDG uptake. Accordingly, the patient received appropriate surgical management and pathologic confirmation of the disease.

BACKGROUND: The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS: BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS: Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS: This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positron emission tomography scanning in the work-up of an unknown primary.