Platinum Salts Research Articles

A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant

Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.

PARP inhibitors in HRD BRCAness breast cancer patients

Breast Cancer patients with germline Breast Cancer Gene (BRCA) mutations have a greater advantage from targeted therapy with Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi). The identification of patients with homologous recombination deficiency (HRD) tumors that may be sensitive to PARPi besides those with germline BRCA1/2 mutations remains an important point of research. There is increasing evidence demonstrating that breast tumors with BRCAness may benefit from PARPi and there are studies ongoing to identify those subtypes which may benefit the most. Pancreatic cancer with HRD non-BRCA mutations seem to have very little benefit from PARPi, but in HRD non-BRCA ovarian and prostate cancer, PARP inhibition appears to be a reasonable therapeutic target. Also, there is data showing that genomic instability caused by mutations in HRD genes, potentially makes cancer cells susceptible to chemotherapeutic drugs, such as anthracyclines or platinum salts. Widespread use of next generation sequencing could increase the role of hallmarks influencing the DNA repair system and therefore increase the therapeutic possibilities for cancer patients. In this review we evaluate the latest advances with PARPi in BRCAness Breast Cancer patients.

Pathologic complete response (pCR) to neoadjuvant treatment (NAT) with carboplatin, nab-paclitaxel and anthracycline in early and locally advanced triple-negative breast cancer (TNBC).

e12608 Background: Achieving a pCR (absence of residual invasive disease in breast and measurable disease in any of the axillary nodes sampled, ypT0/is and ypN0) after NAT correlates with improved survival. TNBC phenotype have a poor prognosis. However, it is associated with higher NAT response rates. With traditional schemes based on anthracyclines and taxanes, pCR rates of around 25-40% are obtained. Different schemes have been studied providing an increase in pCR such as using nab-paclitaxel, platinum salts, bevacizumab or dose dense (dd) anthracyclines. The purpose of the present study is to explore feasibility, toxicity and pCR of new aproach with carboplatine, nab-paclitaxel and antracycline in TNBC. Methods: Retrospective study with early and locally advanced TNBC pts, ECOG 0-1, without contraindications to antracyclines, were included. Treatment consisted of carboplatine AUC2 with nab-paclitaxel 80 mg/m2 i.v. weekly for 12 doses followed by epirubicin 90 mg/m2 (elderly pts recieved at 75 mg/m2) with cyclophosphamide 600 mg/m2 i.v., every 2 weeks (dd) or 3 weeks (if pts had G3-4 toxicity) for 4 doses. G-CSF support was allowed in pts with neutropenia G3-4. Pts with residual disease after NAT were offered capecitabine as adjuvant treatment. The primary endpoint was pCR. Results: From 02/2018 to 06/2022, 96 pts was included. Median age was 53 years (27-78). Clinical stage was I in 16 pts, II in 50 pts and III in 30 pts (N+ in 40'6%). 98% pts had tumours with a Ki67 20% or higher. 36’5% pts was premenopausal. 10 pts were germline BRCA mutated (8/10 gBRCA1, 2/10 gBRCA2) 50/96 pts (55’2%) had dd epirubicin-cyclophospamide (EC) and 44’8% pts recieved EC every 3 weeks (for G3 adverse events (AE)). pCR in pts who had dd treatment was 65’4% and 40’9% in pts with EC non-dd (p 0’016). 89’9% pts with residual disease completed adjuvant treatment with 8 cycles of capecitabine. 53/96 pts had an AE related with NAT. Neutropenia G3-4 (45’5% pts, all of them recieved dd treatment) and any grade of alopecia and mucositis (60% and 25% respectively) were the most frecuent AE reported. Pts with neutropenia G3-4 on blood test recieved G-CSF in subsequent cycles with resolution of haematological AE. All pts with dd treatment recieved G-CSF. One patient had a disease progression by radiological evaluation during the treatment. During follow-up 9 pts relapsed (1 had a pCR with NAT) and 5 pts died for progression disease. Conclusions: NAT on TNBC pts with carboplatine, nab-paclitaxel and antracycline dd is a feasible, safe and highly effective option. Even though survival analysis is not yet mature in our study, pCR has been shown to be a surrogate for overall survival. The excellent results obtained with this scheme, make it a good treatment option and could be an alternative to pembrolizumab (Keynote-522) in pts with autoinmmune diseases or immune-AE due to similar pCR.

Association of HRD ovarian cancer by RAD51 with hot immune microenvironment: Translational analyses of MITO 16A/MaNGO-OV2 trial.

5527 Background: Homologous recombination repair (HRR)-deficient Ovarian Cancer (OvC) is sensitive to PARP inhibitors and platinum salts. Genomic HRR-deficiency (HRD) tests (i.e. Myriad MyChoice) are currently used to guide treatment selection in the maintenance setting. However, they are showing a limited predictive value, they are expensive and static, i.e. unable to capture the restoration of the HRR functionality, as a mechanism of drug resistance. Methods: We performed the functional and dynamic RAD51 test on 164 patients with high-grade serious OvC, enrolled in the MITO16A/MANGO OV2 trial and treated with first-line therapy containing carboplatin, paclitaxel, and bevacizumab. The RAD51 assay included the immunofluorescence of gH2AX (as a marker of Double Strand Breaks DNA damage), BRCA1 and RAD51 nuclear foci. Stromal Tumor Infiltrating Lymphocytes (TIL) by Immunohistochemistry, and gene expression profile were performed on the same samples. Results: RAD51 assay was informative on 70% (115/164) of the samples. On evaluable samples, median gH2AX score was 57%. BRCA1 foci by immunofluorescence were detected on 55% (49/112) of the samples; 45% (63/112) of the tumors did not show BRCA1 foci likely due to germline or somatic BRCA1 mutations, or BRCA1 promoter hypermethylation. RAD51 identified 69% (79/115) of all tumors as HRD, with a median RAD51 score of 8.8%. HRD tumors presented a statistically significantly higher TIL content than HRR-proficient ones (p = 0.03). Conclusions: Our preliminary results confirmed the feasibility of the RAD51 functional assay on primary untreated OvC. The association between HRD by RAD51 and TIL content encouraged to investigate the efficacy, in clinical trials, of the combination of PARPi and immune-checkpoint inhibitors on selected patients (i.e. HRD by RAD51 and TIL high). Gene expression profile and comparison of the HRD status by RAD51 and genomic HRD (both Myriad MyChoice and academic) and correlations with clinical outcomes will be available for the meeting.

Phase 2 study of bintrafusp alfa in recurrent/metastatic olfactory neuroblastoma.

TPS6116 Background: Olfactory neuroblastoma (ONB, esthesioneuroblastoma) is a rare malignant tumor of the nasal cavity, believed to arise from the basal cells of the olfactory neurosensory epithelium. ONB is often locally advanced at diagnosis with high rates of spread both locoregionally and systemically. Current therapy for locoregional disease is local resection with adjuvant (chemo-) radiotherapy. Actionable mutations are rare, and treatment options for recurrent or advanced, non-resectable, disease are limited and include off-label combination chemotherapy (most frequently platinum-containing) and somatostatin-directed therapies (ONB expresses somatostatin receptors). These are based on limited data, with response rates poorly characterized. Bintrafusp alfa is a first-in-class, bifunctional TGF-β “trap”/anti-PD-L1 fusion protein. Analysis of ONB has demonstrated both PD-1/PD-L1 (London et al, 2018) and TGF-β ligand expression (Romani et al, 2021). Pre-clinical and clinical data in advanced solid tumors demonstrate enhanced antitumor activity with combination PD-L1/TGF-β blockade, with responses observed independently of high PD-L1 levels (Strauss et al, 2020). Thus, combination PD-L1/TGF-β blockade in ONB is a rational approach in a setting of unmet clinical need. Methods: This study is a Phase 2 single-site, single-arm clinical trial of bintrafusp alfa (1200mg IV every 2 weeks for up to 26 doses) for patients with recurrent or metastatic ONB. Participants must co-enroll to the ONB Natural History study at the NCI (NCT4755205). Patients must not be candidates for local therapy, have received at least 1 line of systemic therapy (including a platinum salt), have RECIST 1.1 measurable disease and have adequate organ function. Prior checkpoint inhibitor therapy is permitted with patients cohorted according to checkpoint exposure; up to 21 checkpoint-naïve and 8 checkpoint-resistant patients will be enrolled. The primary objective is objective response rate by RECIST 1.1 with secondary endpoints including safety and tolerability, duration of response and overall survival; exploratory endpoints include pharmacokinetic analyses, PD-L1 and immune cell correlative analyses. The trial follows a Simon two-stage design, requiring ≥1 response in the first 12 patients. Tumor biopsy at enrollment is optional. Imaging for response assessment is planned for 8-week intervals and PET scan (preferably 68Ga-DOTATATE) will be obtained for all patients at baseline and first restaging, then on an individualized basis per radiology advice. This study is presently open at the NCI with 5 patients enrolled as of January 2023. Clinical trial registry:NCT05012098. Clinical trial information: NCT05012098 .

11 Platinum Speciation in Air Samples

Abstract The health effects of chloroplatinates are generally well recognised and acknowledged by regulators in both EU and USA (Platinum salt sensitivity). But what about Platinum species? Speciation is essential for valid toxicology assessments and speciation studies are lacking in this respect – it’s known that certain Platinum chloro complexes are more sensitising than others. A method for the separation of platinum chloro-complexes and their hydrolysis products has been developed. The different platinum chemical species are separated into their charged compounds in 0.07 M HCl: [PtCl4]2-, [PtCl6]2-, [PtCl3(H2O)]-, [PtCl5(H2O)]- and a zero charged/ bis-aquo compound. The separation was carried via an ion exchange chromatographic column coupled to a quadrupole ICP-MS for the detection of the different anionic platinum chloro-species. A gradient program consisting of a mixture of HCl and HClO4 was used as eluent to ensure the separation of the species. A process has been developed for the analysis of platinum species extracted from air filters in a PGM facility with JM. Although the methodology for speciation is robust, further work needs to be carried out in terms of alternative sample collection to the air filters such as bubblers as the process of sonication, drying and acid contact on the filters does adversely affect the chemical species in solution. A comparison between Platinum speciation in air filters collected form IOM samplers and bubblers will be included in this presentation. This work will generate data to help characterise different workplaces based on the types of task-based exposure.

Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy.

Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC. We evaluated the IC50 concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naïve and platinum-experienced patient-derived xenograft (PDX) models of RMC. The RMC cell lines demonstrated IC50 concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naïve and platinum-experienced PDX models of RMC (p<.01). Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.

Exposure to soluble platinum salts in precious metal refinery workers over a 17-year period.

Occupational exposure to soluble chlorinated platinum (Pt) salts, commonly called chloroplatinates, is a known cause of Pt salt sensitisation (PSS) and occupational asthma. We aimed to model inhalable soluble Pt salts exposure levels based on measurements in precious metal refineries for use in a retrospective cohort study on PSS. Five platinum refineries located in the United Kingdom (3 sites), United States, and South Africa provided time weighted average inhalable soluble Pt salts exposure data, measured in 2,982 personal air samples over a 17-year period (2000-2016). We used a Bayesian hierarchical model to estimate geometric mean (GM) exposure levels for each refinery and job title over time. The GM of measured exposure levels over all facilities was 92 ng/m3 with a geometric standard deviation (GSD) of 9.07. Facility-specific GMs ranged from 48 ng/m3 (GSD 15.3) to 242 ng/m3 (GSD 5.99). Exposure modelling showed that soluble Pt salts exposure levels declined approximately 10% per year in two of the five facilities, but there were no clear time trends in the other facilities. A priori specified exposure groups captured most of the between-jobs differences, which helps to accurately predict exposures for jobs with no measurement data available. We applied exposure modelling to estimate time, refinery, and job-specific soluble Pt salts exposures. A significant annual decline in exposure levels was observed in two of the five participating facilities. Modelled exposure levels can be linked to individual workers' job history for exposure-response analysis of PSS in an epidemiological study.

In vitro skin permeation of potassium hexachloroplatinate and a comparison with potassium tetrachloroplatinate

Halogenated platinum salts are known respiratory sensitizers in the workplace, and occupational exposure to platinum via the respiratory system and skin has been reported. The aim of this study was to compare the permeability and skin retention of potassium hexachloroplatinate to previously published data of potassium tetrachloroplatinate. Experiments were performed using female Caucasian skin and Franz diffusion cells with the application of 0.3 mg Pt/mL in the donor solution for 24-h. After 8-h of exposure, 1.87 ng/cm2 of Pt was detected in the receptor solution with exposure to potassium hexachloroplatinate, whereas 0.47 ng/cm2 was detected with exposure to potassium tetrachloroplatinate. After 24-h of exposure the Pt retention in the skin was 1861.60 ng/cm2 and 1486.32 ng/cm2 with exposure to potassium hexa- and tetrachloroplatinate respectively. The faster rate of Pt permeation from exposure to potassium hexachloroplatinate was confirmed by the flux and permeability coefficient values. The results indicate a higher permeability and skin retention of Pt when exposed to potassium hexachloroplatinate, confirming a higher risk associated with occupational exposure to this platinum compound relative to potassium tetrachloroplatinate.

Homologous recombination deficiency in epithelial ovarian cancers: from molecular characterization to patient journey

High-grade serous ovarian carcinoma (HGSOC), the most frequent and aggressive form of epithelial ovarian cancer is characterized in half of cases by homologous recombination deficiency (HRD). This molecular alteration is defined by distinct causes and consequences. The main and most characterized cause is the presence of an alteration affecting BRCA1 and BRCA2 genes. Regarding consequences, a specific genomic instability leads to increased sensitivity to platinum salts and poly (ADP-ribose) polymerase (PARPi) inhibitors. This latter point enabled the advent of PARPi in first and second line maintenance. As such, the initial and rapid evaluation of HRD status with molecular tests is a key step in the management of HGSOC. Until recently, the range of tests offered proved to be very limited and suffered from technical and medical limitations. This has recently led to the development and validation of alternatives, including academic ones. This "state of the art" review will bring a synthesis concerning the assessment of HRD status in HGSOCs. After a brief introduction of HRD (including main causes and consequences) and of its predictive value regarding PARPi, we will discuss the limitations of current molecular tests and the existing alternatives. Finally, we will contextualize this to the situation in France, with special consideration concerning the positioning and the financial coverage of these tests, with the perspective of optimizing patient management .

Tumeurs de Bellini et carcinomes médullaires rénaux à l’ère des nouvelles thérapies

Collecting duct carcinoma (also known as Bellini tumour) and renal medullary carcinoma are two extremely rare and aggressive renal cancers. They are both less responsive to conventional treatments used in clear cell renal carcinoma. There are very few studies evaluating their optimal management and currently, at the metastatic stage, polychemotherapy based on platinum salts remains the most widely used. The emergence of new treatments such as anti-angiogenic TKIs, immunotherapy or treatments targeting specific genetic abnormalities, opens up a new field of possibilities in the management of these cancers. The evaluation of the response to these treatments is therefore essential. In this article, we will review the status of their management and the various studies that have evaluated recent treatments in these two cancers.

Predictive factors associated with pemetrexed acute toxicity

Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. Seventy-four patients were included in this study (median age: 67years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Patients

The only breast cancer (BC) subtype without targeted therapies is triple negative breast cancer (TNBC), which makes for 15–20% of incident breast cancers. TNBC is HER2 (human epidermal growth factor receptor 2) negative using clinical tests, and immunostaining reveals a negligible (1%) expression of ER and PR. It has the most dismal prognosis of all BC subtypes due to its biologically aggressive tumor, which is characterized by moderate/high grade and highly proliferating cancer cells. Although invasive ductal carcinoma is the most frequent presentation of TNBC, there are specific TNBC histologies that require special attention due to differing biology and prognosis. Patients with operable illness are increasingly receiving neoadjuvant chemotherapy, which was formerly reserved for patients with locally progressed or inflamed breast cancer, notably in TNBC patients. More people can have breast-conserving surgery (BCS) thanks to this therapeutic strategy, which also assesses how well it is working. An important prognostic factor with positive long-term results is achieving a pathological complete response (pCR). A higher pCR rate is related to the delivery of NACT regimens with platinum salts. However, at the expense of confusing treatment recommendations there is higher incidence of negative outcomes. Improvements in pathologic complete response rates and patient outcomes in the neoadjuvant setting are the main topics of clinical research.

BRCA1-methylated triple negative breast cancers previously exposed to neoadjuvant chemotherapy form RAD51 foci and respond poorly to olaparib.

About 15% of Triple-Negative-Breast-Cancer (TNBC) present silencing of the BRCA1 promoter methylation and are assumed to be Homologous Recombination Deficient (HRD). BRCA1-methylated (BRCA1-Me) TNBC could, thus, be eligible to treatment based on PARP-inhibitors or Platinum salts. However, their actual HRD status is discussed, as these tumors are suspected to develop resistance after chemotherapy exposure. We interrogated the sensitivity to olaparib vs. carboplatin of 8 TNBC Patient-Derived Xenografts (PDX) models. Four PDX corresponded to BRCA1-Me, of which 3 were previously exposed to NeoAdjuvant-Chemotherapy (NACT). The remaining PDX models corresponded to two BRCA1-mutated (BRCA1-Mut) and two BRCA1-wild type PDX that were respectively included as positive and negative controls. The HRD status of our PDX models was assessed using both genomic signatures and the functional BRCA1 and RAD51 nuclear foci formation assay. To assess HR restoration associated with olaparib resistance, we studied pairs of BRCA1 deficient cell lines and their resistant subclones. The 3 BRCA1-Me PDX that had been exposed to NACT responded poorly to olaparib, likewise BRCA1-WT PDX. Contrastingly, 3 treatment-naïve BRCA1-deficient PDX (1 BRCA1-Me and 2 BRCA1-mutated) responded to olaparib. Noticeably, the three olaparib-responsive PDX scored negative for BRCA1- and RAD51-foci, whereas all non-responsive PDX models, including the 3 NACT-exposed BRCA1-Me PDX, scored positive for RAD51-foci. This suggested HRD in olaparib responsive PDX, while non-responsive models were HR proficient. These results were consistent with observations in cell lines showing a significant increase of RAD51-foci in olaparib-resistant subclones compared with sensitive parental cells, suggesting HR restoration in these models. Our results thus support the notion that the actual HRD status of BRCA1-Me TNBC, especially if previously exposed to chemotherapy, may be questioned and should be verified using the BRCA1- and RAD51-foci assay.

Optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma-a retrospective, international, multicentric AGEO study.

The optimal treatment strategy after first-line induction therapy in advanced HER2-positive oeso-gastric adenocarcinoma (OGA) remains challenging. Patients treated with trastuzumab (T) plus platinum salts and fluoropyrimidine (F) as first-line chemotherapy between 2010 and 2020 for HER2-positive advanced OGA at 17 academic care centers in France, Italy, and Austria were included. The primary objective was the comparison of F + T vs T alone as maintenance regimen in terms of progression-free survival (PFS) and overall survival (OS) after a platinum-based chemotherapy induction + T. As secondary objective, PFS and OS between patients treated with reintroduction of initial chemotherapy or standard second-line chemotherapy at progression were assessed. Among the 157 patients included, 86 (55%) received F + T and 71 (45%) T alone as a maintenance regimen after a median of 4months of induction chemotherapy. Median PFS from start of maintenance therapy was 5.1months in both groups (95% CI 4.2-7.7 for F + T and 95% CI 3.7-7.5 for T alone; p = 0.60) and median OS was 15.2 (95% CI 10.9-19.1) and 17.0months (95% CI 15.5-21.6) for F + T and T alone, respectively (p = 0.40). Of 112/157 patients (71%) receiving systemic therapy after progression under maintenance, 26/112 (23%) were treated with a reintroduction of initial chemotherapy + T and 86/112 (77%) with a standard second-line regimen. Here, median OS was significantly longer with the reintroduction (13.8 (95% CI 12.1-19.9) vs 9.0months (95% CI 7.1-11.9); p = 0.007) as confirmed by multivariate analysis (HR 0.49; 95% CI 0.28-0.85; p = 0.01). No additional benefit of adding F to T monotherapy as a maintenance treatment could be observed. Reintroduction of initial therapy at first progression may be a feasible approach to preserve later treatment lines.

Abstract P4-01-08: Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis

Abstract Background: Approximately 5% of breast cancer patients carry a deleterious germline BRCA1/2 mutation, which leads malignant cells to be deficient in the repair of DNA double-strand breaks via homologous recombination. The poly(adenosine diphosphate–ribose) polymerase (PARP) enzymes are important on DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Methods: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. PubMed, Embase, and Cochrane databases were searched for papers up to June 26, 2022. Data extraction from published reports and quality assessment were performed under Cochrane recommendations. Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of &amp;lt; 0.05 was considered statistically significant. The software Review Manager 5.3 was selected for conducting the statistical analysis. The primary endpoint of interest was progression-free survival (PFS). Results: Out of 2069 database results (487 on PubMed; 1376 on Embase; and 206 on Cochrane), 42 studies were selected for full review, and 4 RCTs, with a total of 249 patients, were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53-0.97; p = 0.03]. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR = 0.68; 95% CI, 0.52-0.89; p = 0.005]. A subgroup analysis containing only the three randomized trials with PARPi monotherapy confirmed the central tendency favoring PARPi over physicians’ choice of single-agent chemotherapy in patients with prior platinum-therapy; however, because of small numbers and wide confidence interval it was not statistically significant [HR = 0.72; 95% CI, 0.51-1.01; p = 0.06]. Conclusions: Our findings suggest that PARPi are associated with longer PFS in patients with advanced breast cancer and previous exposure to platinum therapy, decreasing the concerns about cross-resistance between the drug classes. Nonetheless, more extensive studies are still necessary to investigate the efficacy of PARPi in patients with prior platinum exposure and truly platinum-resistant disease. Progression-free survival of included studies Citation Format: Alice D. Marinho, Beatriz Mella S. Pessoa, Gabriela R. Brandao, Caroliny H. Da Silva, Pedro A. Reis, Ana Carolina M. Comini, Felipe Batalini. Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-08.

Abstract P2-26-23: Transcriptomic modification induced by the first cycle of neoadjuvant chemotherapy impacts response to treatment in triple negative breast cancer (TNBC)

Abstract Background Despite adequate neoadjuvant chemotherapy, TNBC remains poor prognosis. Non-responding patient have 25-40% risk of relapse at 5 years. pCR is therefore currently considered as a major goal in TNBC and new tools of early prediction of residual disease should be identified. TransTep is a phase 2 monocentric clinical trial which aims to identify transcriptomic profile of triple-negative cancer cells associated with early tumor chemoresistance, as identified by FDG PET after the first course of neoadjuvant chemotherapy. Twenty patients were included between January 2015 and October 2017, with stage II or III of the UICC classification (except stage T4d). All patients received neoadjuvant chemotherapy with anthracyclines and taxanes sequentially, none of them had a dose-dense chemotherapy. Six patients obtained metabolic response (Delta SUV &amp;lt; -30%) after one cycle of anthracycline. Methods Total RNA was extracted from biopsies (HES &amp;gt; 30%) and used to prepare libraries thanks to TruSeq RNA library Prep kit (Illumina) and sequenced on NextSeq500 device. Results Transcriptomic expression analysis between tumors before chemotherapy and tumors after one course of chemotherapy showed that tumors showing a significant decrease of their Delta SUV (←30%) had a much higher gene expression variation than tumors with a Delta SUV &amp;gt;-30%. These tumors presented, after one course of chemotherapy, a decrease of cell cycle, DNA replication and Fanconi anemia pathway related genes, while they harbored an increase of genes belonging to immunity related pathways such as natural killer cell mediated toxicity, TH17 cell differentiation, or chemokine signaling pathway. As patients had a surgery after neoadjuvant chemotherapy, we had Chevalier tumor response. As observed with FDG PET data, patients with a good response according to Chevalier (class 1) criteria presented a much higher transcriptomic modification after one course of chemotherapy. Patients with a little gene expression modification were classified as Chevalier 3. When we focused on pathways impacted by chemotherapy in tumors classified as Chevalier 1, we observed a significant decrease of cell cycle, DNA replication and DNA repair pathways related gene after one course of chemotherapy, whereas a high number of genes belonging to immunity related genes (NK cells, antigen processing and presentation, or chemokine signaling pathway) were increased. Conclusion Our results tend to indicate that transcriptomic tumor response after one course of chemotherapy could forecast final response to treatment. Moreover, it seems that one cycle of anthracycline-based chemotherapy is able to get hot some breast tumors, and that this tumor warming could be a marker of good response to the full treatment. In the following months, we will test whether transcriptomic could predict progression free survival and/or overall survival of patients. We will also look for the best early marker of response between PET FDG and tumor transcriptomic modifications. Based on these results, a new trial will be organized. A therapeutic adaptation depending on the transcriptomic or metabolic data will be proposed to increase pCR rate and prognosis of patients. Moreover, with years and therapeutic innovations, patient managment obviously evolves. This was recently the case with a new standard of care in triple negative breast cancer with combination of platinum salt and immunotherapy. Therefore, a new trial, similar to TRANSTEP, will be carried out with this new standard of care. Citation Format: Isabelle Desmoulins, David Chardin, Corentin Richard, Laurent Arnould, ALEXANDRE COCHET, Olivier Humbert, Romain Boidot. Transcriptomic modification induced by the first cycle of neoadjuvant chemotherapy impacts response to treatment in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-23.

Clinical outcomes of adapted hypofractionated radiotherapy for bladder cancer in elderly patients.

To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split-course hypofractionated radiotherapy (RT) for non-metastatic muscle-invasive bladder cancer (MIBC) in elderly patients. We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non-metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio-chemotherapy (platinum salt and 5-fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split-course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end-point was overall survival (OS). Secondary end-points included other survivals outcomes and safety. A total of 122 patients were identified, with a median (range) follow-up of 51.1(0.5-210.8)months. In all, 83.5% of patients completed radio-chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer-specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio-chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%. Bifractionated split-course hypofractionated RT with concomitant chemotherapy regimen appears to be well-tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.

Clinical Utility of Genomic Tests Evaluating Homologous Recombination Repair Deficiency (HRD) for Treatment Decisions in Early and Metastatic Breast Cancer

Breast cancer is the most frequently occurring cancer worldwide. With its increasing incidence, it is a major public health problem, with many therapeutic challenges such as precision medicine for personalized treatment. Thanks to next-generation sequencing (NGS), progress in biomedical technologies, and the use of bioinformatics, it is now possible to identify specific molecular alterations in tumor cells-such as homologous recombination deficiencies (HRD)-enabling us to consider using DNA-damaging agents such as platinum salts or PARP inhibitors. Different approaches currently exist to analyze impairment of the homologous recombination pathway, e.g., the search for specific mutations in homologous recombination repair (HRR) genes, such as BRCA1/2; the use of genomic scars or mutational signatures; or the development of functional tests. Nevertheless, the role and value of these different tests in breast cancer treatment decisions remains to be clarified. In this review, we summarize current knowledge on the clinical utility of genomic tests, evaluating HRR deficiency for treatment decisions in early and metastatic breast cancer.

Evaluation of 8% Capsaicin Patches in Chemotherapy-Induced Peripheral Neuropathy: A Retrospective Study in a Comprehensive Cancer Center.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is often painful and can arise during or after the end of oncological treatments. They are mostly induced by platinum salts, taxanes, and immunotherapies. Their incidence is estimated between 19 and 85%. They can require a chemotherapy dose reduction or early termination. The European Society for Medical Oncology (ESMO) recommends high-concentration capsaicin patch (HCCP) in second line for the treatment of painful CIPN. This treatment induces a significative pain relief but only shown by low-powered studies. The objective of this study was to evaluate efficacy and tolerability of HCCP applications in CIPN. Methods: This monocentric observational retrospective real-world-data study of the CERCAN cohort took place in the Western Cancer Institute's Anaesthesiology and Pain Department at Angers, France. Independent pain physicians completed the CGIC (Clinician Global Impression of Change) for each patient who benefited from HCCP applications for painful CIPN starting from 1 January 2014 to 22 December 2021, based on the collected data after every patch application. Results: A total of 57 patients (80.7% women) was treated with HCCP for painful CIPN, and 184 applications were realized, consisting of 296 sessions. CGIC found an important or complete pain relief for 61 applications (33.2%, corresponding to 43.9% patients). We found less efficacy for platinum-salts-induced CIPN compared to others (p = 0.0238). The efficacy was significatively higher for repeated applications when HCCP was used in second line compared to third line (p = 0.018). The efficacy of HCCP was significatively higher starting the third application (p = 0.0334). HCCPs were mainly responsible for local adverse events found in 66.6% patients (65.1% burning or painful sensation, 21.1% erythema). Conclusion: HCCP applications in painful CIPN induce an important pain relief with a global satisfying tolerability.