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Last Updated: 11/01/19

2019 SPORE Advances

[+] Brain

Linda Liau, MD, PhD, MBA, FAANS — University of California, Los Angeles Brain Tumor SPORE

Randomized clinical study of neoadjuvant anti-PD-1 immunotherapy demonstrates a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

A randomized, multi-institution clinical trial evaluated immune responses and survival following neoadjuvant and/or adjuvant therapy with intravenous pembrolizumab (PD-1 blockade) in 35 patients with recurrent, surgically resectable glioblastoma (GBM). Patients who were randomized to receive neoadjuvant pembrolizumab had extended overall survival (median 13.7 months) compared to patients that were randomized to receive adjuvant, post-surgical pembrolizumab alone (median 7.5 months). Neoadjuvant pembrolizumab was also associated with upregulation of T cell- and interferon-γ-related gene expression. These findings suggest that the neoadjuvant PD-1 blockade enhances antitumor immune responses and may be a more efficacious approach to GBM treatment.

Citation:
Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, Kawaguchi ES, Du L, Li G, Yong WH, Gaffey SC, Cohen AL, Mellinghoff IK, Lee EQ, Reardon DA, O'Brien BJ, Butowski NA, Nghiemphu PL, Clarke JL, Arrillaga-Romany IC, Colman H, Kaley TJ, de Groot JF, Liau LM, Wen PY, Prins RM. Nat Med. 2019 Mar;25(3):477-486. doi: 10.1038/s41591-018-0337-7. Epub 2019 Feb 11. PMID: 30742122

[+] Breast

Jennifer Pietenpol, PhD and Ingrid Mayer, MD, MSCI — Vanderbilt University Breast SPORE

PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer.

Estrogen receptor-positive (ER+) breast cancer is the most common clinical subtype of breast cancer. Many patients demonstrate or develop therapeutic resistance to endocrine therapy (aromatase inhibition or selective estrogen receptor modulators/selective estrogen receptor down regulators; SERMs/SERDs). Mechanisms of resistance may include amplification of fibroblast growth factor receptor-1 (FGFR1), estrogen receptor-alpha (ESR1) mutations, and aberrant activation of cyclin-dependent-kinase 4/6 (CDK4/6) and PI3K/mTOR. Investigators performed analyses to determine possible biomarkers, aside from PIK3CA mutations status, that were associated with clinical benefit by examining samples from a cohort of patients from two phase Ib trials of buparlisib (a pan-PI3K inhibitor) and alpelisib (a PI3Kα inhibitor), each in combination with the aromatase inhibitor letrozole. Data indicates that mutations in MAP3K1 in ER+ breast cancer may be associated with clinical benefit from combined inhibition of PI3K and ER, and luminal A tumors may be a target population for this therapeutic combination.

Citation:
Nixon MJ, Formisano L, Mayer IA, Estrada MV, González-Ericsson PI, Isakoff SJ, Forero-Torres A, Won H, Sanders ME, Solit DB, Berger MF, Cantley LC, Winer EP, Arteaga CL, Balko JM. NPJ Breast Cancer. 2019 Sep 23;5:31. doi: 10.1038/s41523-019-0126-6. eCollection 2019. PMID: 31552290

[+] Endometrial

Karen Lu, MD and Russell Broaddus MD, PhD — UT/MD Anderson Cancer Center Endometrial Cancer SPORE

Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.

Women diagnosed with endometrial cancer have early-stage disease and a favorable prognosis than those with the involvement of pelvic lymph or paraaortic nodes, which have significantly higher rates of local recurrence, distant metastasis, and cancer-specific death. Investigators aimed to identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer. Results indicate that 1) the 5-year disease-specific survival (DSS) rate for all patients was 65%; 2) adjuvant CT (generally 4 to 6 cycles of carboplatin and paclitaxel) + RT (45 Gy most common dose) conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P=0.04 and 67% vs. 38%, P=0.02, respectively); 3) among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P=0.02); and 4) the 3-year pelvic recurrence rate was 5% with RT±CT and 35% with CT alone (P<0.001) for all patients. Thus, combined-modality therapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer.

Citation:
Chapman BV, Swanick CW, Ning MS, Allen PK, Soliman PT, Westin SN, Pardeshi V, Broaddus RR, Lu KH, Jhingran A, Eifel PJ, Klopp AH. Gynecol Oncol. 2019 Jul;154(1):22-28. doi: 10.1016/j.ygyno.2019.05.002. Epub 2019 May 17. PMID: 31109659

[+] Gastrointestinal

Sanford Markowitz, MD, PhD — Case Western Reserve University GI Cancers SPORE

Progress toward moving a device for early detection of esophageal carcinogenesis into clinical use.

The Case Western Gastrointestinal Cancer SPORE led by Dr. Sanford Markowitz has developed a balloon device that can be swallowed by patients in order to sample esophageal tissue. The tissue samples can then be checked for methylation-based biomarkers for early detection of Barrett’s esophagus. During FY19 the investigators were awarded 510(k) approval from the FDA to market this sampling balloon, commercially named “EsoCheck”. Together with their commercial partner, Lucid Diagnostics, the investigators are working to bring the companion methylated DNA diagnostic of Barrett’s esophagus forward for FDA review.

Citation:
Yu M, Maden SK, Stachler M, Kaz AM, Ayers J, Guo Y, Carter KT, Willbanks A, Heinzerling TJ, O'Leary RM, Xu X, Bass A, Chandar AK, Chak A, Elliott R, Willis JE, Markowitz SD, Grady WM. Gut. 2018 Jun 8. pii: gutjnl-2017-314544. doi: 10.1136/gutjnl-2017-314544. [Epub ahead of print] PMID: 29884612

[+] Lung

Roy Herbst, MD, PhD — Yale University Lung SPORE

SIGLEC 15 as a new immunotherapy target.

A genome-scale T cell activity array was used by Lieping Chen's group to identify SIGLEC 15 as a new, targetable immune suppressor. SIGLEC 15 is expressed on immune cells (M2 macrophages, myeloid-derived suppressor cells, dendritic cells and B cells), as well as on colon, endometrium, thyroid, bladder, lung, kidney, and liver cancer cells. In collaboration with NextCure, they have developed an antibody (NC318) that is currently used in a Phase 1/2 clinical trial in non-small cell lung cancer patients.

Citation:
Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, Zhang J, Song C, Zarr M, Zhou X, Han X, Archer KA, O'Neill T, Herbst RS, Boto AN, Sanmamed MF, Langermann S, Rimm DL, Chen L. Nat Med. 2019 Apr;25(4):656-666. doi: 10.1038/s41591-019-0374-x. Epub 2019 Mar 4. PMID: 30833750

[+] Neuroendocrine Tumors

Sue O’Dorisio, MD, PhD — University of Iowa SPORE in Neuroendocrine Tumors

90Y-DOTATOC dosimetry-based personalized peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy of neuroendocrine tumors uses radiolabeled octreotide analogs to deliver targeted radiation to somatostatin receptor-positive tumor tissue. 90Y-DOTATOC and 177Lu-DOTATATE are the most commonly used. The goal of this study was to develop a dosimetric method for 90Y-DOTATOC using 90Y-DOTATOC Positron-Emission Tomography/ Computed Tomography (PET/CT) and bremsstrahlung Single Photon Emission Computed Tomography/ Computed Tomography (SPECT/CT) and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. They found that renal dosimetry of 90Y-DOTATOC is feasible using 90Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles.

Citation:
Menda Y, Madsen MT, O'Dorisio TM, Sunderland JJ, Watkins GL, Dillon JS, Mott SL, Schultz MK, Zamba GKD, Bushnell DL, O'Dorisio MS. J Nucl Med. 2018 Nov;59(11):1692-1698. doi: 10.2967/jnumed.117.202903. Epub 2018 Mar 9. PMID: 29523629

[+] Prostate

Inter-SPORE Collaboration:
Massimo Loda, MD — Weill Cornell Medicine SPORE in Prostate Cancer
Himisha Beltran, MD and Steven Balk, MD, PhD — Dana Farber Cancer Institute Prostate SPORE
Howard Scher, MD — Memorial Sloan Kettering Cancer Center Prostate Cancer SPORE
Christopher Logothetis, MD and Timothy Thompson, PhD — UT/MD Anderson Cancer Center Prostate Cancer SPORE

PARP inhibition suppresses GR-MYCN-CDK5- RB1-E2F1 signaling and neuroendocrine differentiation in castration-resistant prostate cancer.

Preclinical investigations of PDX models, cell lines and organoids treated with enzalutamide (ENZ) and olaparib (OLA) uncovered mechanisms involved in neuroendocrine differentiation (NED) induced by ENZ, which may contribute to neuroendocrine prostate cancer (NEPC). The investigators identified and validated a GR-MYCN- CDK5-Rb1-E2F1-NED molecular pathway by which ENZ-treatment induces a transition from adenocarcinoma castrate-resistant prostate cancer (CRPC) to NEPC. They further found that PARP inhibition suppresses the development of enzalutamide-induced NED and NEPC in experimental models through repression of the same GR-MYCN- CDK5-Rb1-E2F1-NED signaling pathway. A clinical trial is planned to test if carboplatin and olaparib suppress the transcriptional activation of this signaling pathway.

Citation:
Liu B, Li L, Yang G, Geng C, Luo Y, Wu W, Manyam GC, Korentzelos D, Park S, Tang Z, Wu C, Dong Z, Sigouros M, Sboner A, Beltran H, Chen Y, Corn PG, Tetzlaff MT, Troncoso P, Broom B, Thompson TC. Clin Cancer Res. 2019 Aug 22. doi: 10.1158/1078-0432.CCR-19-0317. PMID: 31439587