Faculty Bibliography

Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34-years-old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline-containing neo-adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo-adjuvant chemotherapy, the patient underwent breast-conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo-adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options.

Targeting the human epidermal growth factor receptor 2 (HER2) has yielded major advances in breast cancer treatment. Accordingly, it has generated interest in targeting HER2 to treat gynecologic malignancies. Multiple studies have evaluated the rates of HER2 overexpression and/or amplification in ovarian and uterine cancers. HER2 has also been studied as a prognostic factor but resulting data has been contradictory. Moreover, clinical trials of HER2-directed therapies, including trastuzumab, pertuzumab, and lapatinib in ovarian and uterine cancers have been largely disappointing. Current research on HER2 in gynecologic malignancies has focused on identifying mechanisms of resistance and looking further into how HER2 signaling in gynecologic cancers differs from breast cancer. In this review, we highlight the existing data of targeting HER2 in ovarian and uterine carcinomas, many dating back more than a decade, and discuss future directions in pursuing HER2 as a potential target in these diseases.

Targeted therapies are increasingly being explored in the treatment of ovarian cancer. The epidermal growth factor receptor (EGFR) has received much attention as this pathway is overexpressed and/or amplified in ovarian cancer. Anti-EGFR tyrosine kinase inhibitors (TKIs) and monoclonal antibodies have been studied in combination with chemotherapy and as single agents in both the first-line and relapsed settings but unfortunately, the results have been disappointing. In this editorial, we review a recently published large randomized phase III trial conducted by Vergote et al. evaluating maintenance erlotinib in patients with ovarian, peritoneal, or fallopian tube cancer who experienced a response or stable disease (SD) after primary therapy. This study did not show a benefit to maintenance erlotinib and moreover, was not able to identify any subgroups that benefited from erlotinib. Testing for EGFR overexpression and/or amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively, and mutation testing were performed on archival tumor tissue. Patients who were EGFR positive did have a worse progression-free survival (PFS) and overall survival (OS) but EGFR positivity or the presence of a mutation was not predictive of erlotinib efficacy. At this time, EGFR inhibition in ovarian cancer has not been successful and further targeting of this pathway requires an understanding of resistance mechanisms and the role of other pathways that interplay with EGFR.

Objective: Treatment of recurrent epithelial ovarian cancer (REOC) remains a major challenge because of development of platinum resistance. Recent evidence has suggested that BRCA mutation carriers may have improved outcome to treatment compared to patients with non-hereditary (NH) disease. We summarized the experience following chemotherapy treatment of REOC in one institution and compared the outcome in BRCA mutation carriers versus NH subsets. Methods: We retrospectively analyzed 256 patient records with REOC who were treated with second-, third-, and fourth-line treatment with the usual sequential regimens consisting of either pegylated liposomal doxorubicin (PLD), taxanes, gemcitabine, or topotecan (alone or in combination with platinum) between 2002 and 2012 at our institution and compared the outcome in BRCA mutation carriers with that of patients with NH disease. Results: BRCA mutation carriers treated with PLD (with or without platinum), gemcitabine plus platinum, or platinum alone had improved progressionfree survival (PFS) and a lower risk for disease progression (adjusted for age, line of treatment and platinum sensitivity) compared with patients with NH disease. By contrast, treatment with taxanes (with or without platinum) or topotecan led to similar PFS in BRCA mutation carriers and in patients with NH disease. Under all treatment regimens, BRCA mutation carriers showed improved overall survival after adjusting for age, line of treatment, and platinum sensitivity. Conclusions: This single-institution experience provides indications of an enhanced benefit in PFS for BRCA mutation carriers compared to patients with NH disease across a number of drug regimens (PLD, platinum, or gemcitabine plus platinum) regardless of platinum sensitivity and line of therapy

BACKGROUND: Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. METHODS: Topotecan 0.4 mg/m(2) per day was administered by continuous infusion for 9-10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1-10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. RESULTS: Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. FIGURE 1: Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A):: Topotecan and erlotinib. (B):: CA-125 in units/mL. CONCLUSION: Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

Author Summary BACKGROUND: Transcatheter arterial chemoembolization (TACE) has been used to curtail tumor vasculature and delay tumor progression in hepatocellular carcinoma (HCC). We conducted a phase I trial to evaluate the efficacy and toxicity of thalidomide when combined with TACE in patients with advanced HCC. METHODS: Between June 2000 and November 2003, 56 patients with unresectable HCC and amenable to TACE were enrolled. The starting dose of thalidomide was 200 mg/day and was escalated every 2 weeks as tolerated to a maximum dose of 1,000 mg/day. Dose reductions and discontinuation were determined by toxicity. TACE was performed 4 weeks after initiation of thalidomide therapy and repeated as necessary. RESULTS: Overall, 47 and 55 patients were evaluable for response and toxicity, respectively; the median dose of thalidomide given was 200 mg/day. Three patients (6.38%) patients achieved complete responses, whereas 10 (21.3%) had partial responses, for an overall response rate of 27.7%, and 27 (57.5%) had stable disease. Median progression-free survival was 7 months (95% confidence interval [CI]: 5-10 months), and median OS was 21 months (95% CI: 16-28 months) (Fig. 1). Fatigue and lethargy (49.1%), constipation (47.3%), and nausea (43.6%) were common. Grade 3-4 toxicities consisted mostly of increased aspartate aminotransferase (43.6%) and elevated alanine aminotransferase (38.2%) (Table 1). CONCLUSION: Thalidomide and TACE were commonly associated with nonhematologic side effects, with fatigue and constipation being prominent. With a lack of clear therapeutic benefit, this combination is unlikely to be pursued for HCC.

Abstract Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 degrees C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m(2); in the second trial, 11 subjects received LTLD at 40 or 50 mg/m(2). RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m(2) of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m(2), with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m(2) and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.