Eleonora Teplinsky

Targeting HER2 in ovarian and uterine cancers: challenges and future directions.

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.

Fatal hepatitis B reactivation due to everolimus in metastatic breast cancer: case report and review of literature

Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.

EGFR and HER2: is there a role in ovarian cancer?

Advanced ovarian cancer carries a grim prognosis and development of targeted therapies to improve outcomes has become an active area of research in this disease. The epidermal growth factor receptor (EGFR) and HER2/neu have shown to be overexpressed in ovarian cancer and there have been several clinical trials evaluating anti-EGFR and HER2 therapies in ovarian cancer. Unfortunately, the drugs have shown minimal efficacy and more recent work has now focused on identifying mechanisms of resistance and alternative ways of targeting these pathways. This review will discuss the currently published trials with anti-EGFR and HER2 agents in ovarian cancer and the further directions of study with these pathways.

Integrating targeted drugs with taxanes and platinums: opportunities and challenges

The field of surgery is a complex environment of constant innovation. With persistent advancement in technique and tools, there also comes the need for proper surgical education in order to maximize technical proficiency in a short period of time. In recent times, the concept of a learning curve has been the focus of surgical education. A learning curve is essentially a positive curvilinear relation of performance and experience; this curve is par-ticularly steep in antireflux laparoscopic surgery. There are, however, certain fundamental secrets that allow any individual to efficiently and successfully adapt to such an arduous learning curve. In order to identify these secrets, we conducted a thorough search on PubMed and systematically reviewed relevant literature on the learning curve of laparoscopic surgery, with a focus on antireflux surgery, from 1995 to 2016. The following key words were used in our search: “Learning Curve”, “Anti-Reflux Surgery” and “Surgery Education”. Based on our review of literature, the authors of this perspective manuscript propose three key fundamental secrets to successful adaption of the steep learning curve of laparoscopic surgery.In ovarian cancer, multiple attempts to adjust the standard taxane/platinum doublet by adding cytotoxic therapy or varying scheduling, dosage, and delivery have been met with limited success. Alternative methods to improve the grim prognosis of ovarian cancer, including molecular therapies, are currently under investigation. Efforts have been made to study tyrosine kinase inhibitors (including imatinib and pazopanib), Src kinase inhibitors and histone deacetylase inhibitors (HDACi) in combination with taxanes/platinums in order to improve efficacy. Unfortunately, while many pre-clinical and early phase clinical trials argue that the utilization of these molecular targets may enhance survival, only modest benefit has been seen in larger clinical trials. Other agents that have been evaluated include proteasome inhibitors, folate receptor antagonists, MEK inhibitors and opiate antagonists. In this review, we discuss the mechanisms of these targeted therapies and highlight the current and ongoing clinical trials that utilize these targeted agents in combination with taxanes and platinums in advanced ovarian cancer.The field of surgery is a complex environment of constant innovation. With persistent advancement in technique and tools, there also comes the need for proper surgical education in order to maximize technical proficiency in a short period of time. In recent times, the concept of a learning curve has been the focus of surgical education. A learning curve is essentially a positive curvilinear relation of performance and experience; this curve is par-ticularly steep in antireflux laparoscopic surgery. There are, however, certain fundamental secrets that allow any individual to efficiently and successfully adapt to such an arduous learning curve. In order to identify these secrets, we conducted a thorough search on PubMed and systematically reviewed relevant literature on the learning curve of laparoscopic surgery, with a focus on antireflux surgery, from 1995 to 2016. The following key words were used in our search: “Learning Curve”, “Anti-Reflux Surgery” and “Surgery Education”. Based on our review of literature, the authors of this perspective manuscript propose three key fundamental secrets to successful adaption of the steep learning curve of laparoscopic surgery.

Abstract P4-14-21: A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC)

Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m 2 ) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m 2 , 150mg/m 2 and a 3 rd cohort of 125mg/m 2 , if needed . Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m 2 (n=3) and 150 mg/m 2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m 2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of ganetespib is 150mg/m 2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D9Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.

Introduction: moving beyond chemotherapy

Epithelial ovarian cancer and related cancers arising in extrauterine Mullerian epithelium are generally chemosensitive—particularly to the platinum drugs, cisplatin and carboplatin, that form the backbone of first-line treatments upon diagnosis even at early stages. Doublets of platinums with paclitaxel have represented the standard-of-care since the late 1990s, with further notable advances taking place by intraperitoneal administration (in Gynecologic Oncology Group studies) after optimal surgical cytoreduction is achieved, and by divided doses of paclitaxel (in a Japanese GOG study). Adding another agent to improve on these results has otherwise proven to be quite challenging. Nevertheless, continued forays into introducing ‘targeted therapies’ are beginning to bear fruit, and form part of this Translational Cancer Research ( TCR ) supplement. The purpose of this supplement is to provide a summary of the advances in tumor biology and a glimpse into where targeted therapeutics are moving, and their successes to date.

Abstract P5-19-23: A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer

Introduction: Targeted therapies in HER2+ metastatic breast cancer (MBC) have significantly improved survival, however efficacy is limited by development of therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Ganetespib is a novel, synthetic HSP90 inhibitor with increased potency and tolerability compared with earlier agents. Our group has conducted a single agent ganetespib trial in unselected patients which showed anti-tumor activity in HER2+ and triple negative breast cancer. In addition, preclinical data suggests HSP90 inhibition is synergistic with taxanes with potential for significant clinical activity. Ganetespib has been combined with docetaxel in non-small cell lung cancer, it has not previously been combined with paclitaxel and trastuzumab. This study will define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ganetespib when given with paclitaxel and trastuzumab for patients with HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab resistant HER2+ MBC receive trastuzumab (4mg/kg loading dose, then 2mg/kg) and paclitaxel weekly (80mg/m2) with ganetespib day 1, 8 ,15 of 28 day cycle. Patients are required to have prior pertuzumab and T-DM1 (prior pertuzumab and T-DM1 are not mandated if heavily pretreated prior to their respective FDA approvals). Hormone receptor positive patients are required to have at least one prior line of endocrine therapy. The single agent dose limiting toxicity (DLT) of ganetespib is diarrhea and therefore patients receive prophylactic anti-motility agents. The anticipated MTD of ganetespib in this combination has been informed by experience with docetaxel and based on this only three dose levels of ganetespib are being explored 100mg/m2, 150mg/m2 and a third intermediate cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics of paclitaxel and preliminary assessment of efficacy of the combination (scans at 8 weeks and every 12 weeks thereafter, RECIST 1.1). Results: The first dosing cohort has fully enrolled and there were no significant toxicities or DLTs reported. Median age was 48 years (range 39-49), median prior lines of chemotherapy were 4 (range 3-7) and included prior pertuzumab and T-DM1 in all 3 patients. 5 adverse events have been defined as possibly/probably related to ganetespib – grade 2 anemia and leukopenia, grade 1 diarrhea (2 patients), fatigue, and rash. Enrollment to the second and potentially final cohort is underway. Conclusion: This study will define the RP2D of ganetespib in combination with paclitaxel and trastuzumab. Final safety, pharmacokinetic and preliminary response data for all patients will be presented. This combination, with a novel anti-HER2 agent, has encouraging potential for activity in HER2+ breast cancer which is refractory to other HER2 targeting agents. Citation Format: Komal Jhaveri, Karen Cadoo, Sarat Chandarlapaty, Eleonora Teplinsky, James Speyer, Gabriella D9 Andrea, Sujata Patil, Sofia Haque, Kent Friedman, Scott Heese, Deirdre Neville, Francisco Esteva, Clifford Hudis, Shanu Modi. A phase I clinical trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-23.

Epidermal growth factor receptor: will it ever become a therapeutic target in ovarian cancer?

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.

Hyperactivated mTOR and JAK2/STAT3 pathways: Crucial molecular drivers and potential therapeutic targets of inflammatory breast cancer (IBC).

60 Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality Rx results in a 5 year OS of 30-50%, underscoring the unmet need for targeted Rx. Our preclinical research in cell lines and xenografts identifies a role for activated PI3K/mTOR pathway in IBC. IBC cells express IL-6 and IL-8 and recruit tumor activated macrophages (TAMs) that further induce IL-6, IL-8 and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC tissues. METHODS Archived tissues of 42 IBC pts and 13 controls (nl breast) were analyzed using IHC and scored by 3 independent pathologists. Results defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (P-S6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (P-JAK2; P-STAT3), cytokine (IL-6), macrophage (mØ) infiltration (CD68) and TAM (CD163). Proportions of IBC cases with pos expression were compared with controls (Fishers exact tests). Clinical and survival data were obtained. RESULTS Median age at diagnosis: 46 yrs (31-62) in early-stage IBC [EIBC] (n=37) and 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n=5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) and 3/4 were HER2+ (1 unk). 88% Rx with neoadjuvant and/or adjuvant anthracycline and taxane w/o adjuvant trastuzumab. 24 pts died (5/5 MIBC). Median OS: 86 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). All controls: neg for P-S6, JAK2, STAT3 and TAMs and 92% neg for mØ and IL-6. Proportion of IBC with pos expression when compared to controls listed in table (p <0.0001). Of 31 pts with complete biomarker data who were PS6+, 97% had activated JAK2, 58% had activated STAT3, 80% had strong mØ and TAM infiltration and 97% were IL6+. CONCLUSIONS This is the first study that validates preclinical findings and shows a strong association between mTOR, cytokines, TAMs and JAK/STAT pathways in most IBC pt tissues. Findings suggest a key role for dual blockade of mTOR and JAK/STAT pathways in phase I trials. [Table: see text].

Abstract PD5-6: Sustained hyperactivated mTOR & JAK2/STAT3 pathways in inflammatory breast cancer (IBC): Evidence for mTOR plus JAK2 therapeutic targeting

Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality therapy results in a 5 year OS of 30%, underscoring the unmet need for targeted therapy. Our preclinical research in cell lines & xenograft tumor models has identified a role for hyper-activated PI3K/mTOR signaling in IBC. IBC cells express IL-6 and IL-8, which recruit tumor activated macrophages (TAMs) that further induce inflammatory cytokines and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC patient tissues. Methods: Archived tissue specimens of 42 IBC patients (dx 1999-2009) and 27 non-IBC patients (dx 2001-2005) with invasive ductal carcinoma (IDC) were obtained. Surrounding non-tumor normal tissue from IBC (companion controls) was also utilized. All specimens were analyzed using immunohistochemistry (IHC) and scored by 3 independent pathologists. Results were defined as 0 = negative; 1+,2+ = positive for activated mTOR (P-S6); activated JAK2/STAT3 (P-JAK2; P-STAT3); cytokine (IL-6); macrophage infiltration (CD68) and TAM (CD163). Proportions of IBC cases with positive expression were compared with non-IBC cases (Fisher9s exact test) & companion controls (McNemar9s test). Clinical & survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early stage IBC [EIBC] (n = 37) & 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n = 5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) & 3/4 were HER2+ (1 unk). 88% were rx with neoadjuvant &/or adjuvant anthracycline & taxane w/o adjuvant trastuzumab. There were 24 pt deaths (5/5 MIBC). Median f/u for EIBC: 6.3 yrs and for MIBC: 3.4 yrs. Median OS: 81.4 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). The non-IBC patients were all stage 2-3 with median age at diagnosis: 58 yrs (39-94). 19/27: ER+; 7/25 HER2+ (2 unk); 15/25 ER+/HER2-; 3/25 ER-/HER2-. 78% were rx with adjuvant anthracycline & taxane, 4% were rx with FEC and 18% did not receive adjuvant chemotherapy. 18% received adjuvant trastuzumab. Median f/u: 8.0 yrs. Median OS: not yet reached and median RFS: 111.3 mo (95% CI lower 34.5 mo). EIBC cases were compared with non-IBC cases & companion controls (Table 1). PS6, pJAK2 and pSTAT3 expression was significantly increased in IBC compared to non-IBC. Of the 29 EIBC patients with complete biomarker data who were PS6+, 28/29 (97%) were JAK2+, 15/29 (52%) were STAT3+, 26/29 (90%) were CD68+, 20/29 (69%) were CD163+ and 28/29 (97%) were IL6+. Conclusion: This is the first study to validate preclinical findings & show a strong co-association between hyper-activation of mTOR & JAK/STAT pathways in most IBC patient tumors when compared to surrounding non-tumor tissue and non-IBC (IDC) tumors and tissues. These findings suggest a key role for dual blockade of mTOR & JAK/STAT pathways for IBC in phase I trials. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-6.