Citations

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m2 given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and ½ normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m2 IV for 1 hour in 500 mL of dextrose and ½ NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m2 IV for 2 to 3 hours in 750 to1,000 mL of dextrose and 5% water onday 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P = .429) and overall survival (P = .545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

LBA513 Background: Neoadjuvant aromatase inhibitor (AI) therapy is a rational and effective approach to improving the breast conservation surgery (BCS) rate for postmenopausal patients with large, estrogen receptor (ER) rich breast cancers. Barriers to adopting this strategy include lack of experience in this management approach in the US and uncertainty regarding the comparative effectiveness of the three approved aromatase inhibitors for this indication. Methods: ACOSOG Z1031 is a multicenter, open-label, neoadjuvant phase III screening study that randomized postmenopausal women with clinical stage II/III ER rich (Allred score 6-8) breast cancer to 16 weeks of either exemestane (EXE) 25 mg daily, letrozole (LET) 2.5 mg daily, or anastrozole (ANA) 1 mg daily. At baseline study participants were either marginal for BCS (MBCS), candidates for mastectomy only (MO), or inoperable (IO). Planned enrolment was 125 patients per arm in order that the likelihood of the treatment with the “best” 16-week clinical response rate (based on caliper measurements) by WHO criteria (cRR) was included among the subset of treatments with “similar” cRR (90% power). Secondary endpoints included: extent of surgery, radiologic and pathologic response rates. Results: From 4/1/2006 to 10/1/2009, 377 postmenopausal women with clinical stage II or III ER rich breast cancer were enrolled. 374 women began treatment and were included in an intent-to-treat analysis. Median age was 66 yrs (range: 43-90 yrs), Median tumor size was 4.0 cm (range: 2-13 cm). The 16-week cRR was 60.5% (95%CI: 51.3-69.1%) for EXE; 70.9% (95% CI: 62.2-78.6%) for LET, and 66.7% (95% CI: 57.6-74.9%) for ANA. Seventeen patients did not have surgery due to refusal (12 pts), progression (3 pts) or other medical conditions (2 pts). The BCS rate was 78% (163/207) in MBCS group; 42% (77/163) in MO group; and 75% in IO group (3/4). Surgeons made the decisions regarding procedure choice 75% of the time in both the MBCS and the MO categories. Conclusions: This large multicenter screening trial selected non-steroidal AIs for further development due to their higher observed cRR. The study demonstrates that high response and breast conservation rates and low rates of disease progression can be achieved through patient selection based on high ER expression. We are currently refining our approach for early detection of poor response to AIs through an assessment of the tumor Ki67 proliferation index at 2 to 4 weeks (Z1031 Cohort B). [Table: see text]

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).

Background In every field of medicine, comprehensive education should be delivered at the graduate level. Currently, no single specialty routinely provides a standardized comprehensive curriculum in venous and lymphatic disease. Method The American Board of Venous & Lymphatic Medicine formed a task force, made up of experts from the specialties of dermatology, family practice, interventional radiology, interventional cardiology, phlebology, vascular medicine, and vascular surgery, to develop a consensus document describing the program requirements for fellowship medical education in venous and lymphatic medicine. Result The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine identify the knowledge and skills that physicians must master through the course of fellowship training in venous and lymphatic medicine. They also specify the requirements for venous and lymphatic training programs. The document is based on the Core Content for Training in Venous and Lymphatic Medicine and follows the ACGME format that all subspecialties in the United States use to specify the requirements for training program accreditation. The American Board of Venous & Lymphatic Medicine Board of Directors approved this document in May 2016. Conclusion The pathway to a vein practice is diverse, and there is no standardized format available for physician education and training. The Program Requirements for Fellowship Education in Venous and Lymphatic Medicine establishes educational standards for teaching programs in venous and lymphatic medicine and will facilitate graduation of physicians who have had comprehensive training in the field.

Abstract Background: Intrinsic resistance has been linked to ER down-regulation and poor clinical outcome in breast tumors. Aurora-A kinase (AURKA) promotes distant metastases through activation of epithelial to mesenchymal transition (EMT) programming and expansion of breast tumor initiating cells (BTICs) harboring a CD44high/CD24low phenotype. Moreover, AURKA induces down-regulation of ERα expression and resistance to endocrine therapy that is mediated by SMAD5 transcription factor (D’Assoro et al., Oncogene 2014: 33:599-610). The aim of this study was to evaluate the role of AURKA in endocrine resistance induced by breast cancer stemness and ER down-regulation. Materials and Methods: We employed parental MCF-7 and variant MCF-7 cells ex-vivo (vMCF- 7/LCC9, vMCF-7/FR) that have high endogenous levels of AURKA, are ERlow, and exhibit in vivo resistance to fulvestrant. Real-Time Cell Proliferation and Apoptosis assays were performed to assess response to endocrine and/or AURKA-targeted therapy using the innovative IncuCyte ZOOM System. Stemness activity was assessed by culturing breast cancer cells under non-adherent conditions to generate mammospheres. Expression of ER, CD44 and CD24 markers was characterized by FACS analysis and immunofluorescence. Results: Pharmacologic inhibition of AURKA activity with the small molecule, alisertib, significantly restored sensitivity to fulvestrant in vMCF-7/LCC9 and vMCF-7/FR cells. To establish whether fulvestrant resistance was linked to enrichment of BTICs, breast cancer cells were cultured under non-adherent conditions to generate mammospheres. vMCF-7/FR cells generated mammospheres at higher efficiency compared to parental cells suggesting that vMCF-7/FR cells exhibited high self-renewal activity. vMCF-7/FR-derived mammospheres displayed a stem cell-like CD44high/CD24low phenotype that was further characterized by low levels of ER expression and resistance to fulvestrant. When vMCF-7 FR-derived mammospheres were treated with alisertib alone or combined with fulvestrant, the combination was more effective in mediating restoration of endocrine sensitivity. The phenotype of the alisertib-treated mammospheres was functionally linked to loss of CD44 expression, restoration of CD24 and ER expression, and sensitivity to fulvestrant. Conclusions: These findings provide further evidence that AURKA activity plays a central role in breast cancer progression through the genesis and clonal expansion of BTICs that are characterized by ER down-regulation and resistance to endocrine therapy. These results are important for the treatment of endocrine resistant breast tumors because they provide the rationale for the development of an innovative therapeutic approach to combine endocrine therapy with a targeted inhibitor of AURKA activity. Citation Format: Antonino B. D’Assoro, Tufia Haddad, Matthew Goetz, Mary Kuffel, John Hawse, Vera Suman, Jeffrey Salisbury, James Ingle, Evanthia Galanis. Pharmacologic targeting of Aurora-A kinase restores ERα expression and endocrine sensitivity through impairment of breast cancer stemness. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3313.

Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines.