Platinum Salts Research Articles

Allergy Evaluation of Hypersensitivity to Platinum Salts and Taxanes: A Six-Year Experience

Hypersensitivity reactions (HSRs) to platinum salts (PS) and taxanes (TX) are a challenge to cancer management. Allergy evaluation based on skin tests (ST) and graded challenges can provide a diagnosis of an allergy to a suspected drug and indicate possible treatment with alternative same-class drugs. This study aimed to estimate the negative predictive value of ST in the diagnosis of HSRs to TX and PS. This multicenter study prospectively enrolled patients with a suspected HSR to PS and TX. ST were performed for chemotherapy, drugs of the same pharmacological class, and other agents (latex or cotreatments). For patients with negative ST, a graded challenge was performed by the cancer teams trained in allergy management. A total of 119 consecutive patients were included during a 6-year period. ST results were positive for 58% of the cohort: for TX in 7 patients and for PS in 62 patients. Other agents were responsible for 4.2% of cases. Skin cross-reactivity was 50% for TX and 30% for PS. A graded challenge was performed in 14 patients for TX and in 50 patients for PS. Negative predictive values (NPVs) for ST were 100% for TX and 92% for PS, with NPVs for individuals PS of 100% for cisplatin, 89% for oxaliplatin, and 87% for carboplatin. ST to PS or TX offered a high NPV, making allergy evaluation a key element in the management of patients with cancer. Graded challenges can be safely performed by oncology teams trained in anaphylaxis management.

Phase transformation induced mechanochromism in a platinum salt: a tale of two polymorphs.

Red crystals of [Pt(tpy)Cl]NO3·HNO3 show mechanochromic behaviour turning yellow when pressure is applied. The electronic character and spectroscopic signature of the red and yellow polymorphs change as a result of slipping of the molecular stacking planes in the solid state. The slippage alters the PtPt intermolecular distances from a linear stacked motif with <3.5 Å separations in the red polymorph to a less stacked motif of alternating short intradimer and long interdimer interactions in the yellow polymorph.

First-line immune-checkpoint inhibitor plus chemotherapy versus chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis.

Introduction:Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES–SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest.Methods:This meta-analysis was conducted on randomized trials comparing first-line ICI+CT versus CT alone for ES–SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis.Results:The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck et al. 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75–0.89); p < 0.00001] and PFS [0.81 (0.75–0.87); p < 0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63–0.85); p < 0.0001] or anti-PD-1 [0.76 (0.63–0.93); p < 0.006] but not for anti-CTLA-4 [0.90 (0.80–1.01), p = 0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97–1.00); p = 0.12], but responses at 12 months favored ICI+CT [4.16 (2.81–6.17), p < 0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02–1.37); p = 0.03]. Compared with CT, no ICI+CT benefit was found for ES–SCLC with brain metastases at diagnosis [HR 1.14 (0.87–1.50); p = 0.34].Conclusions:First-line ICI+CT appears to be superior to CT alone for ES–SCLC except for patients with brain metastases at diagnosis.

New catalysts for toluene oxidation technology in the liquid phase

The purpose of this study was to study the kinetics of the toluene oxidation process and establish the mechanism of the process. For the first time, catalytic systems based on platinum complexes immobilized on a polyimide film (PIP) in the toluene oxidation reaction (ArCH3) were studied. The general formula of the studied catalytic system can be represented as: ArCH3 – CH3CN – O2 – MLx/PIP, were M – Pt+4; L – Cl-; x = 2, 3. Metallization of polymer films was carried out by chemical reduction from a solution of platinum salt (0.01 M H2PtCl6). The metal concentration in the catalyst ranged from 0.1 –10−2 mol/L to 1 10−1 mol/L, while all other values of the catalytic system remained unchanged. Using the method of thermogravimetric analysis (TGA), it was found that in the temperature range 65–75 °C the catalyst samples are stable, since they do not undergo mass loss due to thermal decomposition. The presence of benzaldehyde was detected in the catalyst.

Should perioperative chemotherapy in triple negative breast cancer routinely comprise platinum salts? A vote for no

Breast cancer is the most common female neoplasm in Poland and worldwide, its mortality rate ranking second only to lung cancer. There are several biological subtypes, differing, among other parameters, as to prognosis and perioperative treatment recommendations. Triple negative breast cancer is one of the worst prognoses and systemic preoperative treatment is recommended as early as of II TNM stage. Pathological complete response (pCR) may result in an improved prognosis. Most patients respond well to standard chemotherapy and there is no need to include platinum derivatives in perioperative therapies. One should remember that platinum salts use not only increases the percentage of pCRs, but also results in an increased therapeutic toxicity; it does not, however, have an impact on disease free survival (DFS) an overall survival (OS).

Gum Kondagogu/Reduced Graphene Oxide Framed Platinum Nanoparticles and Their Catalytic Role.

This study investigates an environmentally benign approach to generate platinum nanoparticles (Pt NP) supported on the reduced graphene oxide (RGO) by non-edible gum waste of gum kondagogu (GK). The reaction adheres to the green chemistry approach by using an aqueous medium and a nontoxic natural reductant—GK—whose abundant hydroxyl groups facilitate in the reduction process of platinum salt and helps as well in the homogenous distribution of ensued Pt NP on RGO sheets. Scanning Electron Microscopy (SEM) confirmed the formation of kondagogu gum/reduced graphene oxide framed spherical platinum nanoparticles (RGO-Pt) with an average particle size of 3.3 ± 0.6 nm, as affirmed by Transmission Electron Microscopy (TEM). X-ray Diffraction (XRD) results indicated that the Pt NPs formed are crystalline with a face-centered cubic structure, while morphological analysis by XRD and Raman spectroscopy revealed a simultaneous reduction of GO and Pt. The hydrogenation of 4-nitrophenol could be accomplished in the superior catalytic performance of RGO-Pt. The current strategy emphasizes a simple, fast and environmentally benign technique to generate low-cost gum waste supported nanoparticles with a commendable catalytic activity that can be exploited in environmental applications.

1812P - Modalities of biosimilar filgrastim use in clinical practice in > 1000 patients receiving chemotherapy regimens with a rest period of ≤ 14 days: The TOPAZE study

BackgroundInternational guidelines recommend the use of granulocyte colony stimulating factors (G-CSF), such as filgrastim, to prevent chemotherapy-induced febrile neutropenia (FN) and maintain chemotherapy dose to improve clinical outcomes. However, there are no clear recommendations for regimens with a rest period (duration between two cytotoxic administrations, within one cycle or between two different cycles) of≤14 days. This study aimed to describe modalities of daily clinical use of biosimilar filgrastim in patients (pts) receiving chemotherapy regimens with a rest period of≤14 days. MethodsThis multicentre, prospective, non‐interventional study was performed in France in pts receiving biosimilar filgrastim during cytotoxic chemotherapy with rest period of≤14 days. ResultsA total of 1080 pts were enrolled, of which 953 were included in the full analysis set: 144 had lymphoma (DLBCL, N=39; Hodgkin’s lymphoma, N=105), and 809 had solid tumours (breast, N=299; lung, N=144; gastrointestinal [GI], N=366 [colorectal, N=203; pancreatic, N=106; gastric N=39; oesophageal, N=18]). The Table shows modalities of filgrastim treatment for pts receiving chemotherapy for curative intent. Similar results were reported in pts receiving chemotherapy for palliative intent. Pts with solid tumours were planned to receive filgrastim on Day 2 of treatment for ≤5 days duration. Pts with lymphoma were planned to receive filgrastim on Day ≥3 for 4–8 days duration. Of the patients receiving chemotherapy for curative intent, FN was reported in 2 pts with GI cancer, 1pt with lung cancer and 7 pts with lymphoma. ConclusionsBiosimilar filgrastim treatment in pts receiving chemotherapy with a rest period of≤14 days results in a low incidence of FN in real-world clinical practice. Editorial acknowledgementCaroline McGown of Spirit Medical Communications Ltd, supported by Sandoz. Table1812P Modalities of use of biosimilar filgrastim in patients receiving chemotherapy for curative intentTableFull group N (%)Lymphoma 144 (15.1)Solid tumours 809 (85)Subgroup (intent of chemotherapy)DLBCL (i) N=35HL (i) N=100Breast cancer (c) N=139GI cancers (c) N=126Lung cancer (c) N=58Regimen‡biw N=23m N=12biw N=100qw N=91biw N=37m N=11qw N=1biw N=120m N=5qw N=1m N=57Relative dose intensity with planned dose, % Mean (SD)97.7 (4.4)-109.5 (94.9)100.9 (21.8)97.2 (10.4)95.2 (12.6)-99.5 (24.0)96.4 (8.0)-95.1 (28.4)Patients with at least one episode of grade 4 neutropenia†Yes n (%)3 (13.0)1 (8.3)11 (11.0)02 (5.4)001 (0.8)002 (3.5)Number of patients with at least one episode of FN†Yes n (%)1 (4.3)1 (8.3)5 (5.0)00002 (1.7)001 (1.8)DLBCL: R-ACVBP; R-CHOP 14.HL: ABVD; increased-dose BEACOPP.Breast cancer: eribulin; paclitaxel weekly.Digestive cancers: simplified FolFOx4 (colorectal, gastric and oesophageal cancers); FolFlrinOx (pancreatic cancer).Lung cancer: carboplatin + paclitaxel (weekly); vinorelbine + platinum salt (carboplatin or cisplatin) 21-day cycle.biw, twice weekly regimen; c, curative; DLBCL, diffuse large B-cell lymphoma; FN, febrile neutropenia; GI, gastrointestinal; HL, Hodgkin’s lymphoma; i, induction; m, mixed regimen; N, number of patients in group; n, number of patients with event; qw, once weekly regimen; SD, standard deviation.†Note: percentages are calculated compared to completed data (i.e. not including missing data).‡The most frequently used chemotherapies in the overall study population were: Legal entity responsible for the studySandoz. FundingSandoz. DisclosureJ.M. Phelip: Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Amgen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Pierre Favre; Research grant / Funding (institution): Merck Serono. P. Souquet: Honoraria (self), Speaker Bureau / Expert testimony, Non-remunerated activity/ies: Sandoz (a Novartis company). M. Declerck: Full / Part-time employment: Sandoz. E. Nabirotchkina: Full / Part-time employment: Sandoz. O. Tredan: Non-remunerated activity/ies: Sandoz; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Lilly; Honoraria (self): Astra-Zeneca; Honoraria (self): MSD-Merck; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

842TiP - Nal-iri/lv5-fu versus paclitaxel as second-line therapy in patients with metastatic esophageal squamous cell carcinoma (OESIRI-PRODIGE 62): A FFCD multicenter, randomized, phase II study

BackgroundHalf of patients newly diagnosed with esophagus squamous cell cancer (ESCC) has a metastatic ESCC (mESCC) and half of patients with initial loco-regional disease presents disease recurrence after surgery and/or chemoradiation. Although not validated by a phase III trial, first-line palliative chemotherapy combines fluoropyrimidine with platinum salt. Patients with disease progression after platinum-based chemotherapy and good performance status may benefit from a second-line chemotherapy. Based on phase I/II trials or retrospective studies, the most commonly used regimens in second-line setting of mESCC are paclitaxel monotherapy or irinotecan monotherapy or combined with 5FU (FOLFIRI). Up to now, there is no randomized trial available. Trial designOESIRI is a multicenter, open-label, randomized phase II trial designed to evaluate efficacy and safety of nanoliposomal irinotecan (NalIRI) plus 5FU versus paclitaxel as second-line therapy in mESCC. Main inclusion criteria are histologically proven mESCC after failure of first-line platinum-based chemotherapy and WHO performance status ≤ 2. Patients initially treated by surgery and chemotherapy or definitive chemoradiation are eligible if relapse occurred less than 6 months after the end of the treatment. In the experimental arm, patients will receive, every 14 days, intravenous (IV) infusion of NalIRI (80mg/m2) followed by 5FU (2400mg/m2 over 46h). In the control arm, patients will receive at days 1, 8 and 14 of a 28 days-cycle, an IV infusion of paclitaxel (80mg/m2). The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. The clinical hypotheses are to extent the 9-months survival rate from 40% to 60%. With a one-sided type one error α of 5%, a power of 85%, a 5% rate of patients lost to follow-up, 53 patients per arm (n=106) will be randomized. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. Circulating tumor DNA will be monitored to assess its predictive value of response to treatment. Inclusions started in January 2019 and theoretical end of recruitment is January 2022. Legal entity responsible for the studyFédération Française de Cancérologie Digestive. FundingServier. DisclosureAll authors have declared no conflicts of interest.

ES03.04 Pegargiminase to Treat Mesothelioma

ES03.04 Pegargiminase to Treat Mesothelioma

Traitements de première ligne dans les CBNPC avancés, en l’absence d’addiction oncogénique (incluant le traitement de maintenance et les anti-angiogéniques)

First-line treatment of metastatic NSCLC without oncogenic addiction remains based on chemotherapy regimen combining a platinum salt and a third generation cytotoxic drug, with similar results for the different available schedules. The improvement of chemotherapy results has been limited to non-squamous carcinoma, deriving from maintenance strategies mainly based on continuation of pemetrexed as a single agent and on addition of bevacizumab to chemotherapy. The development of immunotherapy in first-line therapy with anti-PD-1 and anti-PD-L1 is changing the first line treatment algorithm of advanced NSCLC. The anti-PD-1 pembrolizumab clearly improves the overall survival in NSCLC with PD-L1 expression in greater than 50% of tumour cells, comparatively to cytotoxic chemotherapy. Combinations of anti-PD-1/PD-L1 to platinum-based chemotherapy are superior to chemotherapy alone could become the 1st line gold-standard even though the issue of their restriction to NSCLC patients of which the tumour expresses no or low PD-L1 expression remains discussed since hyper-progression of poor prognosis are also observed in patients with highly PD-L1 expressing tumours.

500P - Are epigenetic therapies modifying sensitivity to conventional chemotherapy?

500P - Are epigenetic therapies modifying sensitivity to conventional chemotherapy?

Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer.

Immunotherapy has prompted a paradigm shift in advanced non-small cell lung cancer (NSCLC) treatment, by demonstrating superior efficacy to chemotherapy alone both in second- and in first-line setting. Novel insights on molecular mechanisms and regimens to enhance the efficacy of immunotherapy are warranted, as only a minority of patients (˜20%) respond to checkpoint blockade. Taking into account the multiple mechanisms adopted by tumor cells to evade the immune system through cancer immunoediting, the frontline combination of immune checkpoint inhibitors with chemotherapy appears to be a successful strategy as: 1) it enhances the recognition and elimination of tumor cells by the host immune system (immunogenic cell-death), and 2) it reduces the immunosuppressive tumor microenvironment. Remarkably, the immune checkpoint inhibitors pembrolizumab and atezolizumab have already been approved by the FDA in combination with chemotherapy for the first-line treatment of advanced NSCLC and many other chemo-immunotherapeutic regimens have been evaluated as an initial therapeutic approach in metastatic NSCLC. Concurrently, several preclinical studies are evaluating the molecular mechanisms underlying immunomodulation by conventional chemotherapeutic agents (platinum salts, antimitotic agents, antimetabolites and anthracyclines), unraveling drug- and dose/schedule-dependent effects on the immune system that should be exploited to achieve synergistic clinical activity. The current review provides a detailed overview of the immunobiological rationale and molecular basis for combining immune checkpoint inhibitors with chemotherapy for the treatment of advanced NSCLC. Moreover, current evidence and future perspectives towards a better selection of patients who are more likely to benefit from chemo-immunotherapy combinations are discussed.

Combined chemotherapy and allogeneic human Vγ9Vδ2 T lymphocyte-immunotherapies efficiently control the development of human epithelial ovarian cancer cells in vivo

ABSTRACTEpithelial ovarian cancer (EOC) represents 5% of human gynecologic cancers in the world, is heterogeneous and highly invasive with a dismal prognosis (5 year-survival rate <35%). Diagnosis of EOC is frequently made at advanced stages and, despite aggressive treatments combining surgery and chemotherapy, fatal relapse rapidly occurs and is accompanied by a peritoneal carcinosis. In this context, novel therapeutical advances are urgently required. Adoptive transfer(s) of immune effector cells, including allogeneic human Vγ9Vδ2 T lymphocytes, represent attractive targets for efficiently and safely tracking tissue-invading tumor cells and controlling tumor dissemination in the organism. Our study describes the establishment of robust and physiological orthotopic model of human EOC in mouse, that includes surgical resection (ovariectomy) and chemotherapy, which are ineluctably accompanied by a fatal peritoneal carcinosis recurrence. Through a complementary set of in vitro and in vivo experiments, we provide here a preclinical proof of interest of the antitumor efficiency of adoptive transfers of allogeneic human Vγ9Vδ2 T lymphocytes against EOC, in association with surgical debulking and standard chemotherapies (i.e., taxanes and platinum salts). Moreover, our results indicate that chemo- and immunotherapies can be combined to improve the antitumor efficiency of immunotherapeutic lines. Altogether, these results further pave the way for next-generation antitumor immunotherapies, based on local administrations of human allogeneic human Vγ9Vδ2 T lymphocytes, in association with standard treatments.

Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis.

Different neoadjuvant chemotherapies are available for triple-negative breast cancer (TNBC). Here, we performed a network meta-analysis to evaluate the pathological complete response (pCR) benefit and safety of treatment regimens. Pairwise and Bayesian network meta-analyses were performed to compare direct and indirect evidence, respectively. Twenty-three studies involving 12 regimens namely standard chemotherapeutic agents, bevacizumab (B)-, platinum salts (P)-, B plus P (BP)-, poly(ADP-ribose) polymerase inhibitors (Pi)-, P plus Pi (PPi)-, capecitabine (Ca)-, gemcitabine (Ge)-, zoledronic acid (Za)-, everolimus (E)-, P plus E (PE)-, and gefitinib (G)-containing regimens. The results showed that P-, B-, PPi-, and Za-containing regimens achieved higher pCR than standard chemotherapeutic agents. BP-containing regimens had a better pCR than B-containing regimens. In indirect comparisons, Za-, BP-, P-, and B-containing regimens were the top four strategies with the highest probability for pCR. Benefit-risk analysis showed that B-containing regimens had the highest acceptability of being the best treatment for better pCR achievement with fewer SAEs. The addition of P, B, BP, PPi, and Za to standard chemotherapeutic agents enhanced the pCR, but a balance between efficacy and safety should be carefully considered. B-containing regimens might be the best choice for neoadjuvant chemotherapy due to its better efficacy and tolerability.

Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer.

The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression.

Homologous recombination DNA repair defects in PALB2-associated breast cancers

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors.

Breast cancer (BC) is the most frequent oncologic cause of death among women and the improvement of its treatments is compelling. Platinum salts (e.g., carboplatin, cisplatin, and oxaliplatin) are old drugs still used to treat BC, especially the triple-negative subgroup. However, only a subset of patients see a concrete benefit from these drugs, raising the question of how to select them properly. Therefore, predictive biomarkers for platinum salts in BC still represent an unmet clinical need. Here, we review clinical and preclinical works in order to summarize the current evidence about predictive or putative platinum salt biomarkers in BC. The association between BRCA1/2 gene mutations and platinum sensitivity has been largely described. However, beyond the mutations of these two genes, several other proteins belonging to the homologous recombination pathways have been linked to platinum response, defining the concept of BRCAness. Several works, here reviewed, have tried to capture BRCAness through different strategies, such as homologous recombination deficiency (HRD) score and genetic signatures. Moreover, p53 and its family members (p63 and p73) might also be used as predictors of platinum response. Finally, we describe the mounting preclinical evidence regarding base excision repair deficiency as a possible new platinum biomarker.

Targeting DNA repair in breast cancer

Targeting of DNA repair is an important therapeutic approach in breast cancer, particularly for BRCA1/2 associated breast cancers and those characterized by a “BRCAness” phenotype including those with “triple negative” subtype. Various assays and scores have been developed to evaluate degree of homologous recombination deficiency in the hope that this would aid in predicting for susceptibility to DNA repair targeting agents, and yet, presence of a germline mutation in BRCA1/2 remains the strongest predictor for therapeutic efficacy of such agents. Pre-clinical studies suggested increased sensitivity to agents that damage DNA in a way that interferes with DNA replication forks and which subsequently require DNA repair by homologous recombination, such as platinum salts, and this data was further confirmed clinically. Recently published phase III data favor the use of PARP inhibitors amongst patients with BRCA1/2 associated advanced breast cancer. Novel chemotherapeutic agents targeting DNA damage repair are under evaluation as well as further combinations of PARP inhibitors with immuno-therapeutics and other biological agents.

Abstract 295: Synergism between oxaliplatin or irinotecan with the PARP inhibitor niraparib in a preclinical model of KRAS/BRAF mutated colorectal cancer is associated with MSI status

Abstract DNA damage response (DDR) is crucial in a variety of tumors and several new drugs that interfere with this mechanism are already available or in advanced clinical testing. RAS-MAPK pathway activation, induced by either RAS or BRAF mutation, is a frequent feature of colorectal cancers (CRCs) and is strongly associated to mitotic stress and dependency upon DDR. Among the drugs used for CRC, oxaliplatin and irinotecan are known to induce DNA damage in form of single or double strand breaks (SSB/DSBs) and thus require active DDR systems in cancer cells to be tolerated. The poly-ADP-Ribose Polymerase (PARP) inhibitor Niraparib (MK-4827) is an FDA-approved orally bioavailable drug with strong PARP1-trapping activity, a feature ofted associated with synergism in combination with platinum salts, while synergism with other DNA damaging agents is independent of the PARP1-trapping activity. We tested the activity of niraparib used in combination with oxaliplatin or irinotecan (in the form of its active metabolite SN38) in a panel of 8 KRAS or BRAF mutated CRC cell lines (LOVO, HCT15, SW1116, LS1034, SW948, WiDr, SW480, HCT116) with different microsatellite and CIMP status. Combination index (CI) analysis was performed in order to evaluate the synergism between niraparib and the chemotherapeutics. Cell cycle distribution and apoptosis assays were performed in order to further characterize the effects of the combinations. The combination between niraparib and oxaliplatin resulted synergistic in 6 out of 8 cell lines, with strong synergism (CI &amp;lt; 0,5) in 2 cell lines, while the combination between niraparib and irinotecan (SN38) resulted synergistic in 7 out of 8 cell lines, with strong synergism in 5 cell lines and very strong synergism (CI &amp;lt; 0,1) in 3 cell lines. Interestingly, the only non-synergistic cell line to the combination with irinotecan is also non-synergistic to the combination with oxaliplatin; on the other hand, the cell lines that exhibit strong synergism to the combination with irinotecan do not present strong synergism to the combination with oxaliplatin and vice versa. Moreover, all the microsatellite instable (MSI) cell lines tested resulted synergistic for the two combinations. Finally, the synergistic combinations showed an increased induction of apoptosis and cell cycle arrest compared to non-synergistic combinations. Taken together, these data investigate the combination between the PARP inhibitor niraparib and the antiproliferative agents oxaliplatin and irinotecan in KRAS/BRAF mutated CRC cell lines, showing how MSI status predicts good synergism with the drug combinations, while MSS status is not a good predictor of synergism. Further studies are needed to identify better predictive biomarker beyond MSI status, in order to optimize the use of these combinations for future development. Citation Format: Pietro Paolo Vitiello, Davide Ciardiello, Claudia Cardone, Giulia Martini, Valentina Belli, Nunzia Matrone, Luca Poliero, Carola Borrelli, Pasquale Vitale, Nicoletta Zanaletti, Teresa Troiani, Davide Melisi, Fortunato Ciardiello, Erika Martinelli. Synergism between oxaliplatin or irinotecan with the PARP inhibitor niraparib in a preclinical model of KRAS/BRAF mutated colorectal cancer is associated with MSI status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 295.

Abstract 3504: Mutation analysis of ovarian carcinoma patients presenting optimal response to neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NAC) followed by interval debulking does not present inferior results to those of primary cytoreduction and offers the opportunity to evaluate chemo-sensitivity in vivo. Pathological response scores (CRS) have been shown to correlate with outcome with a complete or near-complete CRS (CRS3) predicting improved progression-free survival. Approximately 20% of ovarian cancers present BRCA1/2 mutations, which predict a better response to platinum salts. Our proposal is to determine the prevalence of BRCA mutations or other homologous recombination (HR) alterations among patients with a CRS3 after NAC. Methods: We performed a retrospective analysis of clinical, pathological, and sequencing data of patients who experienced a complete or near-complete response to platinum based NAC. For patients with wild-type (WT) sequencing and with tumor samples available, somatic analysis based on Next Generation Sequencing (NGS) with a large panel of genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CCNE1, CDK12, CHEK2, PALB2,RAD51C, RAD51D, TP53), including specific non-coding regulatory regions of BRCA1, BRCA2 and RAD51C, was also performed. We present preliminary data on the 1st cohort analysed at the time of abstract submission. Results: A total of 33 patients were identified who demonstrated CRS3 post-NAC. Tumors were in majority EC IIIc (57%) and grade II-III serous ovarian carcinoma (90%). Median overall survival (m OS) of the entire cohort was 55 months (IC95% 36-74). To date, germline and/or somatic analyses were available on 23 pts. The prevalence of pathogenic BRCA1/2 variants is higher than expected in this cohort of patients presenting a CRS3. In total, 7 of 23 patients (30%) had a germline (4) or somatic pathogenic (3) BRCA variant. In addition, among the 16 BRCA1/2 WT pts subjected to further HR NGS analysis, the following cases of alterations were identified: one ATM nonsense mutation (c.2465T&amp;gt;G; p.Leu822*), one pathogenic mutation of CDK12 gene (c.3G&amp;gt;A;p.Met1?), one likely pathogenic variant located on BRCT domain of BRCA1 (c.5165C&amp;gt;T p.Ser1722Phe), two 3'UTR BRCA2 variants of uncertain significance (VUS) (c.*14C&amp;gt;T; c.*72A&amp;gt;G), and one BRIP1 VUS (c.2932G&amp;gt;C, p.Gly978Arg). Further, one BRCA WT case presented an unexpected CCNE1 amplification. Conclusion: HGOC patients presenting with a pCR are enriched for BRCA germline and/or somatic BRCA mutations. In addition, among the small subset of BRCA WT pCR tumors, a deleterious ATM and CDK12 mutation were identified. This prevalence can be underestimated in a context of pCR since somatic screening is impossible on the debulking material. Somatic BRCA1/2 and complete HR sequencing on the initial biopsy is recommended to identify additional pts with exclusive somatic mutations. More complete data on this cohort will be presented. Citation Format: Etienne Rouleau, Elizabeth Santana dos Santos, Francilette Maela, Ludovic Lacroix, Aurélie Auguste, Patricia Pautier, Philippe Morice, Catherine Genestie, Alexandra Leary. Mutation analysis of ovarian carcinoma patients presenting optimal response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3504.