Cytotoxic Cancer Chemotherapy Research Articles

A phase II study of maintenance rucaparib in patients with platinum sensitive, advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2: A four year survival update.

661 Background: We previously reported the results of a single arm, phase II study of maintenance rucaparib in patients with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2 or PALB2 variants (Reiss et al, JCO, 2021). We now report the five year follow-up of this trial. Methods: Patients with advanced PC and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 were enrolled in this single arm phase II study performed at the Abramson Cancer Center. Patients were required to have received ≥16 weeks of platinum-based treatment without evidence of platinum resistance, which was defined as growing lesions, new lesions or steadily rising tumor markers. Chemotherapy was discontinued and patients received rucaparib 600mg PO BID until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: Of 42 evaluable patients, seven (16.7%) remain progression-free for over four years (5 gBRCA2, 1 sBRCA2, 1 gPALB2) of whom four (9.5%) have been progression-free for five years. Two of these four patients discontinued rucaparib due to adverse events after three and four years of therapy, respectively, without signs or symptoms of progression to date. At the cutoff date, we observe an mPFS 12.9 months, mOS 24.3 months, ORR 41.6% (9 PRs, 6 CRs), noting that three patients converted from partial to complete response since our prior publication. Two patients with ongoing responses succumbed to treatment-related MDS/AML following 2.1 and 4.8 years on study, respectively. Prior to receiving rucaparib, these individuals had received 13 and 10 months of cytotoxic chemotherapy for pancreatic cancer, respectively. Conclusions: Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date. Given the cost and risk of treatment-related leukemia associated with PARP inhibition, this data highlights the need to better understand the highly variable biology of patients with PC and BRCA or PALB2 variants, and raises the possibility of whether a very small, select group may be cured by PARP inhibitors. Clinical trial information: NCT03140670 .

Dancing with the Surgeon: Neoadjuvant and Adjuvant Immunotherapies from the Medical Oncologist's Perspective.

Perioperative treatment with conventional cytotoxic chemotherapy for resectable non-small cell lung cancer (NSCLC) has proven clinical benefits in terms of achieving a higher overall survival (OS) rate. With its success in the palliative treatment of NSCLC, immune checkpoint blockade (ICB) has now become an essential component of treatment, even as neoadjuvant or adjuvant therapy in patients with operable NSCLC. Both pre- and post-surgery ICB applications have proven clinical efficacy in preventing disease recurrence. In addition, neoadjuvant ICB combined with cytotoxic chemotherapy has shown a significantly higher rate of pathologic regression of viable tumors compared with cytotoxic chemotherapy alone. To confirm this, an early signal of OS benefit has been shown in a selected population, with programmed death ligand 1 expression ≥50%. Furthermore, applying ICB both pre- and post-surgery enhances its clinical benefits, as is currently under evaluation in ongoing phase III trials. Simultaneously, as the number of available perioperative treatment options increases, the variables to be considered for making treatment decisions become more complex. Thus, the role of a multidisciplinary team-based treatment approach has not been fully emphasized. This review presents up-to-date pivotal data that lead to practical changes in managing resectable NSCLC. From the medical oncologist's perspective, it is time to dance with surgeons to decide on the sequence of systemic treatment, particularly the ICB-based approach, accompanying surgery for operable NSCLC.

Skin rash associated with combined cytotoxic chemotherapy and immunotherapy for cancer: A retrospective single-center case series.

In recent years, the development of combination therapies with immune checkpoint inhibitors (ICIs) and cytotoxic anticancer drugs has radically changed the management of diverse malignancies and significantly improved patient outcomes. Several clinical trials have shown that skin rash caused by combination therapy with ICIs and cytotoxic drugs may be more frequent and severe than that developing after administration of ICIs alone or cytotoxic drug monotherapy. However, most reports provide little information on severity, treatment, post-diagnosis course, and recurrence of rashes on drug rechallenges. We aimed to describe the experience of skin rashes developing within 2 weeks from the first administration of combination therapy with ICIs and cytotoxic drugs in 11 patients visiting our dermatology department. This study included seven men and four women, and the patients' median age was 52 years. The primary disease was non-small-cell lung cancer in eight patients, cervical cancer in two patients, and esophageal cancer in one patient. Nine patients had a maculopapular rash and two patients developed erythema multiforme-like eruptions. The skin rash was often accompanied by extracutaneous symptoms, such as fever (n=9), mucositis (n=4), and liver dysfunction (n=2). In all cases, the symptoms improved with topical steroid therapy alone, with no patients exhibiting severe symptoms requiring systemic steroids or immunosuppressive agents. In addition, when the causative drugs were re-administered after recovery from the rash, only two patients relapsed with accompanying systemic symptoms, and all patients except one were able to continue treatment using the same drug regimen. Although it was suggested that the rash caused by the combination therapy of ICIs and cytotoxic drugs may be more prominent than that caused by each agent alone, comprehensive judgment, including histopathological examination, may indicate the feasibility of continuing the treatment regimen for cancer.

Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy.

Simple SummaryAntiestrogen hormonal therapy is a relatively low side effect, orally administered cancer treatment option, yet response rates have been limited in epithelial ovarian cancer despite estrogen receptor expression in many tumors. This suggests that other pathways impact estrogen response. Cytokine signaling from the tumor microenvironment promotes ovarian cancer growth, and crosstalk between cytokine signaling and estrogen signaling has been reported in other tumor types. We therefore aimed to investigate whether cytokine signaling impacts estrogen signaling in high-grade serous ovarian cancer. We demonstrated crosstalk between these two pathways in patient-derived samples, in vitro and in animal studies. We found that inhibiting interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokine signaling activates estrogen signaling and blocking both pathways was synergistic in inhibiting tumor cell growth. These results suggest a potential role for combination therapy for epithelial ovarian cancer patients.Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer.

The Sleep, Cancer and Rest (SleepCaRe) Trial: Rationale and design of a randomized, controlled trial of cognitive behavioral and bright light therapy for insomnia and fatigue in women with breast cancer receiving chemotherapy

BackgroundInsomnia and fatigue symptoms are common in breast cancer. Active cancer treatment, such as chemotherapy, appears to be particularly disruptive to sleep. Yet, sleep complaints often go unrecognised and under treated within routine cancer care. The abbreviated delivery of cognitive behavioral therapy for Insomnia (CBTI) and bright light therapy (BLT) may offer accessible and cost-effective sleep treatments in women receiving chemotherapy for breast cancer. MethodsThe Sleep, Cancer and Rest (SleepCaRe) Trial is a 6-month multicentre, randomized, controlled, 2 × 2 factorial, superiority, parallel group trial. Women receiving cytotoxic chemotherapy for breast cancer at tertiary Australian hospitals will be randomly assigned 1:1:1:1 to one of four, non-pharmacological sleep interventions: (a) Sleep Hygiene and Education (SHE); (b) CBTI; (c) BLT; (d) CBT-I + BLT combined and simultaneously delivered. Each sleep intervention is delivered over 6 weeks, and will comprise an introductory session, a mid-point phone call, and regular emails. The primary (insomnia, fatigue) and secondary (health-related quality of life, rest activity rhythms, sleep-related impairment) outcomes will be assessed via online questionnaires at five time-points: baseline (t0, prior to intervention), mid-point intervention (t2, Week 4), post-intervention (t3, Week 7), 3-months (t4, Week 18), and 6-months follow-up (t5, Week 30). ConclusionsThis study will report novel data concerning the comparative and combined efficacy of CBT-I and BLT during chemotherapy. Findings will contribute to the development of evidence-based early sleep and fatigue intervention during chemotherapy for breast cancer.Clinical trial informationRegistered with the Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/), Registration Number: ACTRN12620001133921.

Abstract 1010: LIG1 deletion predicts chemotherapy resistance, chromosomal instability, and poor prognosis in triple negative breast cancer

Abstract Introduction: Cytotoxic chemotherapy for sporadic Triple Negative Breast Cancer (TNBC) remains the standard of care and the recent approval for adjuvant PD1 therapy is not biomarker guided. Pathological complete response (pCR) is often not achieved and portends poor survival. Predictive markers for individual drugs have proven elusive. Approach: Microscaled proteogenomics (MPG) was applied to snap-frozen TNBC clinical trial core needle biopsies obtained before treatment with carboplatin and docetaxel (WashU: NCT201404107 and BCM: NCT02544987). Clinical endpoints for discovery analysis were pathological complete response (pCR) and residual cancer burden (RCB). Standard non-parametric statistical tests were employed to identify proteogenomic features associated with these endpoints. Results: Copy number aberrations (CNA) are a recurrent feature of TNBC and a potential driver of chemotherapy sensitivity. We therefore sought CNA with concordant changes at the mRNA and protein levels that also associate with pCR status. Genes located within a recurrent interstitial deletion at chromosomal location 19q13.3 were the most significantly down-regulated at mRNA and protein level in chemotherapy resistant cases. 19q13.3 encodes multiple DNA damage response (DDR) genes; however, only LIG1, a DNA ligase required for lagging strand synthesis and DNA repair, showed concordant changes at both the mRNA and protein level. In multiple independent TNBC data sets, LIG1 deletion was associated lack of pCR and poor metastasis-free survival. Additionally in the BrighTNess TNBC trial lower LIG1 mRNA levels were associated with increased chemotherapy resistance in the carboplatin containing arms (no pCR and residual cancer burden I-III; p=0.0008 and 0.003 respectively). In PDX-derived short-term cultures and PDXs treated with docetaxel or carboplatin, a specific association of carboplatin resistance with LIG1 deletion was observed. LIG1 depleted-tumors did not harbor elevated scores for homologous recombination defect signature, suggesting LIG1 loss is an orthogonal pathway for TNBC pathogenesis The high chromosomal instability index in LIG1 deletion tumors in our TNBC study was robustly reproduced in multiple datasets (including TCGA-BRCA ; Metastatic breast cancer project). LIG1 copy number deletion was also associated with poor progression free survival, and high chromosomal instability in multiple other cancers (including TCGA-​UCEC HR=2.23, TCGA-HNSC HR=1.46, TCGA-PRAD HR=2.07, TCGA- COAD HR=1.75 and TCGA-KIRP HR=4.00). Conclusion: Deletion of LIG1 is associated with chromosomal instability in TNBC and occurs in tumors without genomic evidence for defects in homologous recombination. Other clinical features of LIG1 deleted TNBC and how LIG1 loss may cause chromosomal instability and tumorigenesis will be discussed. Citation Format: Meenakshi Anurag, Eric Jaehnig, Jonathan Lei, Beom-Jun Kim, Anh Minh Tran Huynh, Yongchao Dou, Tanmayi Vashist, Erik Bergstrom, Xuxu Gou, Viktoriya Korchina, Donna Marie Muzny, Kristen Otte, Harshavardhan Doddapaneni, Lacey Dobrolecki, Gloria Vittone Echeverria, Bora Lim, Mothaffar Rimawi, Karsten Krug, Ian Hageman, Henry Rodriguez, Ana I. Robles, Tara Hiltke, Kent Osborne, Michael Gillette, George Miles, Steven Carr, Michael T Lewis, Bing Zhang, Foluso Ademuyiwa, Shankha Satpathy, Matthew J. Ellis. LIG1 deletion predicts chemotherapy resistance, chromosomal instability, and poor prognosis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1010.

Recent Advances in Medical Therapy for Urological Cancers.

The mainstay of medical treatment has been tyrosine kinase inhibitors (TKIs) for renal cell cancer (RCC), cytotoxic chemotherapy for urothelial cancer (UC), and androgen deprivation therapy for prostate cancer. These therapeutic modalities still play important roles in these malignancies. However, immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 or CTLA-4 are being rapidly introduced for the treatment of metastatic urological cancers, just as they have been for other malignancies. Currently, the paradigm of medical treatment for patients with metastatic urological cancer is dramatically changing. Accordingly, we need to organize and summarize the new therapeutic tools, which include immune checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs). This review provides an overview of agents and regimens that have just launched or will be launched in the near future in Japan. Based on the promising anti-tumor efficacy and manageable safety profiles being demonstrated in clinical trials, these new agents and therapies are expected to be rapidly introduced in Japanese clinical practice. Additionally, the newly designed ADC, enfortumab vedotin, which comprises a fully human monoclonal antibody conjugated to an anti-cancerous agent via a protease-cleavable linker, has just been launched in Japan. In order to provide the optimal treatment for our patients, we need to completely understand these new therapeutic tools.

Selective Inhibitors of Histone Deacetylase 10 (HDAC-10).

Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved "pan" HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2-6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 μM and 7.7 μM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.

Hymenialdisine is Cytotoxic Against Cisplatin-Sensitive but Not Against Cisplatin-Resistant Cell Lines.

ObjectivesNew compounds are needed to overcome the resistance to commonly used cytotoxic chemotherapy for epithelial ovarian cancer. Marine sponges are a rich source of diverse chemical compounds and hymenialdisine has been found to have antiproliferative effects. This study aimed to investigate the cytotoxic effect of hymenialdisine in cisplatin-sensitive and cisplatin resistant ovarian cancer cell lines.MethodsThis study took place at Sultan Qaboos University, Muscat, Oman between August and November, 2019. The anti-cancer effects of hymenialdisine or cisplatin were assessed using treating cells with different concentrations of hymenialdisine and cisplatin. Cell viability was determined using the AlamarBlue® Assay.ResultsThe half-maximal inhibitory concentration (IC50) of cisplatin was estimated at 31.4 μM for A2780S and 76.9 μM for A2780CP, whereas the IC50 of hymenialdisine was evaluated at 146.8 μM for A2780S cells. Despite the higher concentrations of hymenialdisine (up to 300 μM), IC50 could not be determined for the A2780CP cell line.ConclusionWhen compared to cisplatin, hymenialdisine was less toxic against both A2780S and A2780CP ovarian cancer cell lines.

Viral and immunological markers of HIV-associated Kaposi sarcoma recurrence.

Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy highly prevalent in Sub-Saharan Africa. The main objective of this study was to determine the factors associated with recurrence of HIV-associated KS. We recruited a cohort of individuals on antiretroviral therapy who were in remission for HIV-associated KS after undergoing cytotoxic cancer chemotherapy. Collected variables included sociodemographic and clinical parameters, cytokines and chemokines, HIV viral loads, and CD4 counts. Compared to individuals who had KS recurrence, IL-5 was significantly higher at time of follow-up in individuals who had sustained remission (22.7pg/ml vs. 2.4pg/ml; p = 0.02); IL-6 was significantly higher at baseline and time of follow-up in individuals who had sustained remission, (18.4pg/ml vs. 0pg/ml; p = 0.01) and (18.0pg/ml vs. 0.18pg/ml; p = 0.03) respectively; IP-10 was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (534pg/ml vs. 920pg/ml; p = 0.04) and (446pg/ml vs.1098pg/ml; p = 0.01) respectively; while HIV viral load was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (0copies/ml vs. 113copies/ml; p = 0.004) and (0copies/ml vs. 152copies/ml; p = 0.025) respectively. Plasma levels of IL-5, IL-6, and IP-10 are associated with recurrence of HIV-associated KS, while persistently detectable HIV viral loads increase the risk of KS recurrence.

Outcomes of COVID-19 Patients under Cytotoxic Cancer Chemotherapy in Brazil.

Simple SummaryCancer patients present a distinct vulnerability to COVID-19. It is unclear if chemotherapy per se increases the overall risk in this population. In our study, we analyzed retrospective COVID-19 data linked to oncological information systems to evaluate outcomes in COVID-19 cancer patients under chemotherapy. We identified 681 patients with a past history of chemotherapy. Patients in active chemotherapy did not have an increased mortality compared to non-active chemotherapy COVID-19 cases. We identified the use of topoisomerase II inhibitors and alkylating agents as protective factors, while palliative intent of treatment and hematological neoplasms were risk factors.Background: Cancer patients present a distinct vulnerability to COVID-19. It is unclear if chemotherapy could accentuate the overall risk in these patients. Methods: We performed a retrospective analysis linking COVID-19 data and oncological information systems to compare lethality in patients undergoing cytotoxic chemotherapy before COVID-19. We considered patients who received chemotherapy in the last 30 days as in “active treatment”, and patients who did not receive drugs in this period as “non-active treatment” for propensity-score pair matching. We also tested the influence of baseline variables in our results in a multivariate model. Results: 66.1% (162/246) of patients in matched active chemotherapy died vs. 70.2% (172/246) in the matched non-active chemotherapy group. The risk of death was positively associated with palliative intent of treatment and hematologic neoplasms. Being in active chemotherapy was not associated with increased mortality compared to non-active treatment. We also noted in exploratory propensity-score matchings that the use of alkylating agents (odds ratio [OR] 0.38, 95% confidence interval [CI], 0.21–0.70) and topoisomerase II inhibitors (OR 0.28, 95% CI 0.14–0.56) were protective factors. Conclusions: This study does not demonstrate an increase in mortality for cancer patients under active cytotoxic chemotherapy with COVID-19.

Phase I trial of nedaplatin and S-1 in patients with advanced squamous cell lung cancer.

The platinum doublet is considered to be the standard cytotoxic chemotherapy for advanced lung cancer. It has been previously reported that nedaplatin and S-1 have clinical efficacy against squamous cell lung cancer. As the combination of nedaplatin and S-1 has never been studied for advanced squamous cell lung cancer, a phase I trial of this combination in the first-line setting was conducted. Patients who had not received chemotherapy previously, aged ≤75 years and with advanced squamous cell lung cancer were recruited. Nedaplatin was administered intravenously (day 1), and S-1 was orally administered (days 1-14) at a fixed dose based on the body surface area (BSA) <1.25 m2, 80 mg/day; BSA=1.25-1.5 m2, 100 mg/day; and BSA ≥1.5 m2, 120 mg/day. A total of 9 patients were enrolled. The maximum tolerated dose was 80 mg/m2 for nedaplatin. At this dosage, dose-limiting toxicity was observed in 2 of the 6 patients. A total of one patient experienced grade 3 thrombocytopenia, and the other patient experienced grade 3 anorexia and grade 3 nausea. The recommended dose for phase II studies was determined as being 70 mg/m2 for nedaplatin (clinical trial registration no. UMIN-CTR UMIN000036387).

Structural Basis for the Selective Inhibition of HDAC10, the Cytosolic Polyamine Deacetylase.

The cytosolic class IIb histone deacetylase HDAC10 is an emerging target for drug design. As an inducer of autophagy, its selective inhibition suppresses the autophagic response that otherwise attenuates the efficacy of cytotoxic cancer chemotherapy drugs. HDAC10 is a zinc-dependent polyamine deacetylase exhibiting maximal catalytic activity against N8-acetylspermidine. As revealed in the structure of Danio rerio (zebrafish) HDAC10, two conserved structural motifs direct this narrow substrate specificity: a 310 helix containing the P(E,A)CE motif that sterically constricts the active site and an electrostatic "gatekeeper," E274, that confers selectivity for cationic polyamine substrates. To accelerate drug design efforts targeting human HDAC10, we now report the preparation of "humanized" zebrafish HDAC10 in which two amino acid substitutions, A24E and D94A, yield an active site contour more similar to that of human HDAC10. X-ray crystal structures of this HDAC10 variant complexed with Tubastatin A and indole analogues bearing pendant tertiary amines reveal that inhibitors capable of hydrogen bonding with gatekeeper E274 exhibit high affinity and selectivity for HDAC10 over HDAC6 (the other class IIb isozyme). Moreover, these structures reveal that the P(E,A)CE motif helix can shift by up to 2 Å to accommodate the binding of bulky inhibitors. Thus, slender polyamine-like inhibitor structures are not exclusively required for selective, high affinity binding to HDAC10. Indeed, the flexibility of the P(E,A)CE motif helix could conceivably enable the binding of certain protein substrates.

Abstract PD4-01: First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial

Abstract Background: BROCADE3 (NCT02163694) evaluated the PARP inhibitor veliparib in combination with carboplatin/paclitaxel (C/P) vs placebo + C/P in patients with HER2-negative locally advanced/metastatic breast cancer and a germline BRCA1/2 mutation. In the intent-to-treat (ITT) population, investigator-assessed median progression-free survival (PFS) was 14.5 months for veliparib vs 12.6 months for placebo (hazard ratio=0.71 [95% CI 0.57-0.88], p=0.002); 75th percentile PFS was 39.9 months for veliparib vs 20.7 months for placebo. In this preplanned analysis, we evaluated efficacy and safety of veliparib plus C/P in patients with no previous cytotoxic chemotherapy for metastatic disease. Methods: Patients with ≤2 prior lines of cytotoxic chemotherapy for metastatic breast cancer were randomized 2:1 to C/P with veliparib or C/P with placebo. Veliparib (120 mg p.o. BID) or placebo was given on Days −2 to 5, C (AUC 6 mg/mL/min IV) on Day 1, and P (80 mg/m2 IV) on Days 1, 8, and 15 (21-day cycles). Patients who discontinued both C and P for toxicity or reasons other than disease progression could continue veliparib/placebo monotherapy until progression. Monotherapy dose was 300 mg BID, increasing to 400 mg BID if tolerated. Although randomization was not stratified by lines of prior cytotoxic chemotherapy, the treatment arms were well-balanced with respect to this baseline characteristic. The primary endpoint was PFS as assessed by investigator. Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), and objective response rate (ORR). Adverse events were monitored throughout the study. Analysis of PFS in patients with no prior cytotoxic therapy for metastatic disease was pre-planned. Results: In the ITT population, 337 patients (81% of the entire cohort) received treatment as first line and were randomized to veliparib plus C/P and 172 patients to placebo plus C/P. Most patients received prior cytotoxic chemotherapy in the neo-adjuvant/adjuvant setting (66%, placebo plus C/P; 70%, veliparib plus C/P). Among the 81% of patients in each arm who had no prior cytotoxic chemotherapy in the metastatic setting, median PFS was longer in patients receiving veliparib plus C/P compared to placebo plus C/P (16.6 mo vs 13.1 mo), and median PFS for both arms was over 1 year (Table). Proportion of patients with a serious AE was 30.9% for placebo plus C/P and 33.1% for veliparib plus C/P; proportion with an AE leading to study drug discontinuation was 10.8% for placebo plus C/P and 15.6% for veliparib plus C/P. Additional safety data will be presented. Conclusions: In patients with HER2-negative advanced/metastatic breast cancer and a germline BRCA1/2 mutation who had no prior cytotoxic chemotherapy for metastatic disease, veliparib with C/P demonstrated an improvement in median PFS over C/P alone. This benefit was durable with 25% of patients alive and progression free at nearly 4 years. Table. Efficacy in patients with no prior cytotoxic chemotherapy for metastatic disease.Veliparib + C/P, n=274Placebo + C/P, n=139mPFS per INV (mo, 95% CI)16.6 (13.4, 18.7)13.1 (11.4, 14.5)PFS HR (95% CI)0.69 (0.54, 0.88)PFS 75th percentile (mo, 95% CI)46.3 (29.3, NR)22.6 (16.5, 27.2)mPFS per ICR (mo, 95% CI)21.5 (18.7, 29.2)14.0 (12.5, 16.5)PFS HR (95% CI)0.63 (0.47, 0.84)PFS 75th percentile (mo, 95% CI)NR33.3 (19.7, NR)mOS (mo, 95% CI) [interim]36.0 (32.0, 43.1)29.9 (26.0, 39.3)OS HR (95% CI)0.92 (0.68, 1.2)CBR at 24 weeks (% [95% CI])92.8 (90.0, 94.9)93.4 (89.1, 96.0)ORR (% [95% CI])79.7 (74.0, 84.7)76.3 (67.4, 83.8) C/P, carboplatin and paclitaxel; CBR, clinical benefit rate; HR, hazard ratio; m, median; mo, months; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; INV, investigator; ICR, independent central review. Citation Format: Banu K. Arun, Hyo S. Han, Bella Kaufman, Hans Wildiers, Michael Friedlander, Jean-Pierre Ayoub, Shannon L. Puhalla, Bruce A. Bach, Matthew Dudley, Christine K. Ratajczak, David Maag, Véronique Diéras. First-line veliparib plus carboplatin/paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: Planned subgroup analysis from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-01.

Ambulatory management in low risk neutropenic sepsis – A plea for integrated acute cancer care

Neutropenic Sepsis (NS) is a well recognised treatment complication, typically occurring 7-10 days following cancer cytotoxic chemotherapy. Colleagues in acute medicine will be only too familiar with the scenario of cancer patients that present with fever in the absence of localising signs and symptoms and with a very low yield from microbiological cultures. The incidence and mortality of NS are poorly defined and historically, management guidelines have often been developed in relative isolation from the broader subject of infection and sepsis care. Despite the lack of a clear and pragmatic definition, NICE guidance CG151 (2012) identified suspected NS as a medical emergency requiring prompt empirical broad spectrum antibiotics.

Recent advances in medical therapy for metastatic urothelial cancer

Cytotoxic chemotherapy has been the mainstay of medical therapy for metastatic urothelial cancer. Currently, the gemcitabine/cisplatin regimen is widely used worldwide as the standard first-line medical treatment. Very recently, in 2017, pembrolizumab, a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1, was approved as a second-line treatment to be used after platina-based chemotherapy for metastatic urothelial cancer in Japan. Based on its promising anti-tumor efficacy and manageable safety profile as demonstrated in the phase III KEYNOTE-045 trial, pembrolizumab therapy is expected to be rapidly introduced for treating metastatic urothelial cancer in clinical practice. The paradigm of medical treatment for patients with metastatic UC is dramatically changing through the introduction of this and other immune-checkpoint inhibitors. In this article, we provide a brief overview of these immune-checkpoint inhibitors and a comprehensive summary of the use of cytotoxic chemotherapy for metastatic urothelial cancer, including ongoing clinical trials.

Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy

Conventional cytotoxic cancer chemotherapy is often immunosuppressive and associated with drug resistance and tumor regrowth after a short period of tumor shrinkage or growth stasis. However, certain cytotoxic cancer chemotherapeutic drugs, including doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway, which activates robust innate and adaptive anti-tumor immune responses and has the potential to greatly increase the efficacy of chemotherapy. Here, we review studies on chemotherapeutic drug-induced immunogenic cell death, focusing on how the choice of a conventional cytotoxic agent and its dose and schedule impact anti-tumor immune responses. We propose a strategy for effective immunogenic chemotherapy that employs a modified metronomic schedule for drug delivery, which we term medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti-cancer activity. We also discuss strategies for combination chemo-immunotherapy, and we outline approaches to identify new immunogenic chemotherapeutic agents for drug development.

Abstract PR14: Polycomb repressive complex 2 inactivation induces primary chemotherapy resistance in T-ALL by upregulating the TRAP1 mitochondrial chaperone

Abstract The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of the outcome of cytotoxic chemotherapy for cancer. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. Here we report that mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2) and consequent downstream upregulation of the TRAP1 gene, which encodes a mitochondrial chaperone protein of the HSP90 family. In clinical samples from 47 T-ALL patients, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis, as assessed by BH3 profiling (P = 0.015). In human T-ALL cells, PRC2 depletion induced resistance to mitochondrial apoptosis induction, as assessed by caspase 3/7 activation or annexin V/PI staining, in response to multiple antileukemic drugs with distinct mechanisms of action, including dexamethasone, doxorubicin, vincristine, and asparaginase (P &amp;lt; 0.01). In mouse immature T-cell progenitors, haploinsufficiency for the PRC2 components Ezh2 or Eed was sufficient to induce resistance to mitochondrial apoptosis, as assessed by BH3 profiling analysis (P ≤ 0.01). PRC2 is a histone-modifying complex whose activity is strongly associated with transcriptional repression. We found that PRC2 represses transcription of TRAP1, a nuclearly encoded, mitochondrially localized chaperone of the HSP90 family. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation (P &amp;lt; 0.001), while pharmacologic inhibition of TRAP1 synergized with antileukemic drugs in PRC2-deficient leukemic cells. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention. This abstract is also being presented as Poster 07. Citation Format: Ingrid Aries, Triona Ni Chonghaile, Salmaan Karim, Sebastian Balbach, Melissa Burns, Gayle Pouliot, Stevenson Kristen, Donna Neuberg, Meenakshi Devidas, Loh Mignon, Stephen Hunger, Stuart Winter, David Teachey, Karen Rabin, Kimberly Dunsmore, Brent Wood, Lewis Silverman, Stephen Sallan, Peter Van Vlierberghe, Stuart H. Orkin, Anthony G. Letai, Alejandro Gutierrez. Polycomb repressive complex 2 inactivation induces primary chemotherapy resistance in T-ALL by upregulating the TRAP1 mitochondrial chaperone [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR14.

PL 04.02 Where We Are Now, and Where We Will Be in 10 years: From Asian Perspective

PL 04.02 Where We Are Now, and Where We Will Be in 10 years: From Asian Perspective

Nomograms predicting survival of patients with unresectable or metastatic gastric cancer who receive combination cytotoxic chemotherapy as first-line treatment

Some clinicopathological variables are known to influence the survival of patients with advanced gastric cancer. A comprehensive model based on these factors is needed for prediction of an individual's survival and appropriate patient counseling. A nomogram for predicting 1-year survival in patients with advanced gastric cancer in the palliative chemotherapy setting was developed using clinicopathological data from 949 patients with unresectable or metastatic gastric cancer who had received first-line doublet cytotoxic chemotherapy from 2001 to 2006 at the National Cancer Center, Korea (Baseline Nomogram). For 836 patients whose initial response to chemotherapy is known, another nomogram (ChemoResponse-based Nomogram) was constructed using the response to chemotherapy as additional variable. Nomogram performance in terms of discrimination and calibration ability was evaluated using the C statistic and Hosmer-Lemeshow-type χ 2 statistics. Two different nomograms were developed and subjected to internal validation. The baseline nomogram incorporated 13 baseline clinicopathological variables, whereas the chemoresponse-based nomogram was composed of 11 variables including initial response to chemotherapy. Internal validation revealed good performance of the two nomograms in discrimination: C statistics=0.656 (95% confidence interval, 0.628-0.673) for the baseline and 0.718 (95% confidence interval, 0.694-0.741) for the chemoresponse-based nomogram, which showed significantly better discrimination performance than the baseline nomogram (Z statistics=3.74, p<0.01). This study suggests that individual 1-year survival probability of patients receiving first-line doublet cytotoxic chemotherapy for advanced gastric cancer can be reliably predicted by a nomogram-based method incorporating clinicopathological variables and initial response to chemotherapy.