Publications

Searchable abstracts of presentations at key conferences in oncology ISSN 2631-4657 (online)

The treatment landscape for metastatic melanoma has increased dramatically in the past five years, with the pivotal discovery of activating BRAF mutations in half of all melanomas spurring the development for effective treatments that target mitogen-activated protein kinase (RAS/RAF/MEK/ERK) pathway. Vemurafenib, a selective mutant BRAF Val600 inhibitor, results in striking tumour responses and a survival advantage over conventional chemotherapy. We present here the case of a 38-year-old woman with metastatic BRAFV600E mutant melanoma and a severe tablet phobia, who was found to have been crushing and/or chewing her vemurafenib tablets. In this case, she attained a partial response and significant clinical benefit, albeit temporarily.

5511 Background: Germline BRCA1/2 (g BRCA1/2) mutations are associated with poor clinical outcomes in PC. Previous studies showed that g BRCA2 carriers present more CNV in several genes associated with more aggressive disease. These aberrations may explain the poor clinical outcomes of these patients, but larger studies are needed to confirm these findings. Methods: PROREPAIR-A is a multicenter case-control study in which g BRCA2 carriers with available diagnostic timor-tissue were matched 1:2 by Gleason and stage at diagnosis (M0 vs M1) with known non-carriers (NC). A minimum of 120 controls-60 cases were required to prove a 5yr Cause Specific Survival (CSS)-rate of 85% vs 60%. The primary endpoint was to confirm the independent prognostic value of g BRCA2 in PC CSS. In addition, we explored the prognostic role of g BRCA1 and somatic events in BRCA2, RB1, MYC, PTEN and TMPRSS2-ERG by FISH. Χ 2 , Kaplan-Meier, log-rank and cox-regression models were carried out to identify associations with baseline characteristics and outcomes: Metastases Free Survival (MFS), Time to Castration-Resistance (TTCR) and CSS. Results: A total of 80:160 matched cases-controls were initially included, but tumor tissue and clinical data were only available in 73 g BRCA2 and 127 NC. 14 g BRCA1 were also included. At diagnosis, g BRCA2 were younger (median 62.6 vs 64.5, p = 0.02) and had cT3-4 disease more often than NC (31.5% vs 9.4%, p < 0.01), but no other significant differences were found. Somatic BRCA2-RB1 codeletion (40.8% vs 11.8%, p < 0.01) and MYC amplification (51.4% vs 22.8%, p < 0.01) were more frequent in g BRCA2 compared to NC, but no significant differences in PTEN and TMPRSS2-ERG were observed. g BRCA2 mutations as well as somatic BRCA2-RB1 codel and MYC amplif were significantly associated with shorter CSS, MFS and TTCR (Table). MVA model confirmed the independent prognostic value of g BRCA2 (HR 1.94, p = 0.03), BRCA2-RB1 codel (HR 3.16, p < 0.01), MYC amplif (HR 2.36, p < 0.01), Gleason ≥8 (p < 0.01) and M1 at diagnosis (p < 0.01) for CSS. Conclusions: PROREPAIR-A confirmed the independent prognostic value of g BRCA2 for CSS. Somatic BRCA2, RB1 and MYC aberrations were more frequent in g BRCA2 carriers. Those alterations are associated with shorter CSS, MFS and TTCR, and may contribute to poor clinical outcomes in g BRCA2 and NC. [Table: see text]

<div>AbstractPurpose:<p>Brain involvement occurs in the majority of patients with metastatic melanoma. The potential of circulating tumor DNA (ctDNA) for surveillance and monitoring systemic therapy response in patients with melanoma brain metastases merits investigation.</p>Experimental Design:<p>This study examined circulating <i>BRAF, NRAS</i>, and <i>c-KIT</i> mutations in patients with melanoma with active brain metastases receiving PD-1 inhibitor–based therapy. Intracranial and extracranial disease volumes were measured using the sum of product of diameters, and response assessment performed using RECIST. Longitudinal plasma samples were analyzed for ctDNA over the first 12 weeks of treatment (threshold 2.5 copies/mL plasma).</p>Results:<p>Of a total of 72 patients, 13 patients had intracranial metastases only and 59 patients had concurrent intracranial and extracranial metastases. ctDNA detectability was 0% and 64%, respectively, and detectability was associated with extracranial disease volume (<i>P</i> < 0.01). Undetectable ctDNA on-therapy was associated with extracranial response (<i>P</i> < 0.01) but not intracranial response. The median overall survival in patients with undetectable (<i>n</i> = 34) versus detectable (<i>n</i> = 38) ctDNA at baseline was 39.2 versus 10.6 months [HR, 0.51; 95% confidence interval (CI), 0.28–0.94; <i>P</i> = 0.03] and on-therapy was 39.2 versus 9.2 months (HR, 0.32; 95% CI, 0.16–0.63; <i>P</i> < 0.01).</p>Conclusions:<p>ctDNA remains a strong prognostic biomarker in patients with melanoma with brain metastases, especially in patients with concurrent extracranial disease. However, ctDNA was not able to detect or monitor intracranial disease activity, and we recommend against using ctDNA as a sole test during surveillance and therapeutic monitoring in patients with melanoma.</p></div>

<div>Abstract<p><b>Background:</b> High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.</p><p><b>Methods:</b> This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.</p><p><b>Results:</b> Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (<i>P</i> = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (<i>P</i> < 0.0001): good prognosis [score 0–1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2–3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).</p><p><b>Conclusion:</b> CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. <i>Clin Cancer Res; 17(15); 5188–96. ©2011 AACR</i>.</p></div>

Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population). PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice.

Abstract Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genomewide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance ( p -values 0.03, 3.07×10 -8 ). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories. Statement of significance Lethal prostate cancer evolves from a single clone of origin and upon a treatment-mediated selection, progresses to lethal disease via a limited number of related clones harboring patient-unique androgen receptor gene architectures.

5079 Background: ENZAMET (NCT02446405) showed that enzalutamide added to testosterone suppression (TS) with or without docetaxel improves overall survival (OS) compared with TS plus standard non-steroidal anti-androgen (NSAA) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed PSA levels in ENZAMET participants at 7 months after randomization to determine correlations with OS. In CHAARTED, participants with mHSPC high volume disease (HV), 20% achieved PSA ≤ 0.2 with ADT (androgen deprivation therapy) alone versus 44% with low volume disease (LV) and for HV with ADT + Docetaxel, 36% achieved PSA ≤ 0.2 vs 64% with LV. Methods: Participants were included if they were followed for at least 7 months after randomization, and had availability of PSA and outcome data. Landmark analysis at 7 months used prognostic classifiers as previously identified in SWOG 9346 and CHAARTED of PSA ≤ 0.2 and &gt; 0.2 at 7 months after initiation of therapy. Results: The total number of ENZAMET participants (pts) with PSA at 7 months of ≤0.2ng/mL was 646 of 1125 (57%): 271/562 (48%) in the NSAA arm versus 375/563 (67%) in the ENZA arm. Five-year OS for TS + NSAA (±Doc) arm PSA ≤ 0.2 = 71% vs PSA &gt; 0.2 = 36% and for TS + ENZA (±Doc) arm PSA ≤ 0.2 = 74% vs PSA &gt; 0.2 = 43%. The % of pts with PSA levels at 7 months ≤0.2ng/mL and corresponding 5-year OS outcomes by key prognostic groups (HV vs LV) ± docetaxel is shown (Table). In comparison with CHAARTED in those with HV, 37% achieved PSA ≤ 0.2 with ADT alone versus 61% with LV which increased to 55% for HV and 79% for LV respectively with addition of enzalutamide. In those with HV treated with ADT + D 39% achieved PSA ≤ 0.2 vs 58% with LV increasing to 60% for HV and 74% for LV respectively with addition of enzalutamide. Conclusions: A PSA nadir of ≤0.2 at 7 months is associated with a longer OS regardless of treatment and prognostic group (HV vs LV). Enzalutamide increased the rate of achievement of PSA &lt;0.2 for all groups. Clinical trial information: NCT02446405 . [Table: see text]

At present, the emerging drug-resistance of Mycobacterium tuberculosis (M. tb) against existing frontline drugs has prompted the development of novel anti-tuberculosis agents based on new targets. Activity of the bifunctional enzyme, glucosamine-1-phosphate acetyltransferase activity and N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) is essential for biosynthesis of the mycobacterium cell wall components and has been proposed as a potential drug target for therapeutic interventions. On the basis of the high-throughput screening of the GlmU AT inhibitor, an extract of Euphorbia ehracteolata displayed a significant inhibitory effect among 49 tested herbal medicines. Using the bioassay-guided separation, an aromatic diterpenoid ebractenoid F was identified as a GlmU AT inhibitor (IC50: 4.608 μg mL-1). Inhibition kinetics showed that ebractenoid F acted as a competitive inhibitor for substrate acetyl-CoA and an uncompetitive inhibitor for substrate GlcN-1-P. Ala434 was deduced to be the key active residue for the interaction between ebractenoid F and GlmU. Furthermore, ebractenoid F displayed an anti-mycobacterial effect against M. tb H37Ra with a minimal inhibitory concentration (MIC) of 12.5 μg mL-1 along with an inhibitory effect on the formation of biofilm and a synergistic effect with isoniazid against M. tb H37Ra. Above all, a GlmU inhibitor was identified from E. ehracteolata and is proposed to be a potential therapeutic anti-tumberculosis agent.

Abstract Background: Prostate epithelium is exquisitely sensitive to the overexpression of the proto-oncogene MYC which causes neoplastic transformation. Indeed, MYC protein is almost universally overexpressed in metastatic castration-resistant prostate cancer (CRPC) making targeting MYC an attractive option for treating advanced stage disease. Unfortunately, the development of therapeutic agents directly targeting MYC has been largely unsuccessful, thus emphasizing the need to indirectly target MYC activity through inhibition of downstream cellular processes it regulates. One of the main effects of MYC in cancer cells is to accelerate proliferative growth via stimulation of high levels of ribosome biogenesis. Accordingly, the control of protein synthesis rate has emerged as the “Achilles' heel” of a wide array of tumors. MYC also regulates and cooperates with PIM kinases to increase the activity of the eIF4F translation initiation complex and MYC-driven tumors are addicted to eIF4E. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer (PC). Experimental design: We employed numerous models of PC, including a novel CRPC patient derived xenograft system, which showed the pre-clinical efficacy of therapies that combine to target MYC directed signaling to the ribosome. The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription has been successfully exploited therapeutically, but only in models of hematological malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in PC cell lines, in Hi-MYC and PTEN-deficient mouse models and in patient derived xenografts (PDX) of metastatic tissue obtained from a castration-resistant PC patient. Results: CX-5461 inhibited anchorage-independent growth and induced cell cycle arrest in PC cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced p53 expression and activity and reduced proliferation (Ki-67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of PC. Conclusion: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of PC. In addition, a key conclusion of our study is that the androgen receptor (AR) presence or activity has no significant impact on the therapeutic activity of our novel combination therapy. Therefore, we believe our new exciting combination therapy could be used in the clinic in combination with current anti-androgens or as salvage therapy in multi-drug resistant CRPC. Citation Format: Richard J. Rebello, Eric Kusnadi, Don P. Cameron, Helen B. Pearson, Analia Lesmana, Jennifer R. Devlin, Denis Drygin, Ashlee K. Clark, Laura Porter, John Pedersen, Shahneen Sandhu, Gail P. Risbridger, Richard B. Pearson, Ross D. Hannan, Luc Furic. Inhibition of ribosomal RNA synthesis as a new therapeutic approach to treat advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B23.

&lt;p&gt;All Supplementary Methods and associated references&lt;/p&gt;

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer with poor prognosis and limited treatment options. As NEPC aberrantly expresses delta-like ligand 3 (DLL3), the activity of tarlatamab, a bispecific T-cell engager (BiTE®) that directs cytotoxic T cells to DLL3‑positive (DLL3+) cells, was evaluated in the DeLLpro-300 study (NCT04702737). This was a phase 1b, open-label study evaluating tarlatamab monotherapy in patients with metastatic de novo or treatment-emergent NEPC defined by histologic, genomic, or immunohistochemistry (IHC) criteria. Tarlatamab was administered intravenously every 2 weeks at a dose of 100 mg with a 1-mg step dose. The primary objective was safety, and a secondary objective was objective response rate (ORR) per RECIST v.1.1; DLL3 expression was retrospectively assessed by IHC. Forty patients were enrolled (DLL3+ tumors, n=18; DLL3- tumors, n=14; DLL3 unknown tumors, n=8). The most common treatment-related adverse events were cytokine release syndrome (CRS; 82.5%), dysgeusia (42.5%), and decreased appetite (40.0%). CRS was predominantly low grade (grade 1/2/3/4+, 62.5%/15%/5%/0%), occurred exclusively in cycle 1, and was transient in duration (median duration, 3 days). ORR was 10.5% (95% CI, 2.9-24.8); the median duration of response was 7.3 months in the overall cohort. Patients with DLL3+ tumors (vs patients with DLL3-/DLL3 unknown tumors) acheived a higher ORR (22.2% [95% CI, 6.4-47.6] vs 0% [95% CI, 0-15.4]) and radiographic progression-free survival rate at 6 months (27.7% [95% CI, 8.7-50.9] vs 0%). The DeLLpro-300 study provides preliminary evidence for the safety and antitumor activity of tarlatamab in DLL3+ NEPC.