Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in HER2-overexpressing breast cancers and, at ...present, is currently approved for patients whose tumours have this abnormality, in both the metastatic and the adjuvant setting. Several issues about its optimal use, however, are still unresolved. One of the reasons for these uncertainties lies in the absence of conclusive data about its mechanism of action and possible primary or acquired resistance mechanisms. Therefore, clinical questions such as how to optimize patient selection, how to prevent resistance to trastuzumab, or what is the optimal management of those patients whose tumours progress during treatment still await convincing answers. This review summarises the current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance and also briefly discusses their possible clinical implications.
The use of anti-HER2 monoclonal antibodies (mAbs) has improved the clinical outcome of HER2-overexpressing breast cancers (BCs). Unfortunately, often these tumors tend to relapse and, when ...metastatic, the duration of clinical benefit is limited over time and almost invariably followed by tumor progression. Alternative approaches to this essentially passive immunotherapy are therefore needed in HER2-overexpressing BC patients. As HER2 is one of the most suitable targets for active immunotherapy in BC, manipulating the immune system is a highly attractive approach.
A computer-based literature search was carried out using PubMed (keywords: breast neoplasm, HER2 vaccine, immunology); data reported at international meetings were included.
This review provides a focus on the following active vaccinal approaches under clinical investigation against HER2-overexpressing BC: (i) peptide and protein based; (ii) DNA based; (iii) whole tumor cell based; (iv) dendritic cell based. Moreover, the review discuss future challenges in the field, trying to define the best setting for the development of this innovative strategy, considering both immunological and clinical aspects of HER2 targeting.
Development of effective vaccines for BC remains a distinct challenge but is likely to become a substantial advance for patients with HER2-overexpressing BCs.
Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy but frequently cause immune-related adverse events (irAEs). Description of late-onset and duration of irAEs in the literature is ...often incomplete.
To investigate reporting and incidence of late-onset and long-lasting irAEs, we reviewed all registration trials leading to ICI’s approval by the US FDA and/or EMA up to December 2019. We analysed real-world data from all lung cancer (LC) and melanoma (Mel) patients treated with approved ICIs at the University Hospital of Lausanne (CHUV) from 2011 to 2019. To account for the immortal time bias, we used a time-dependent analysis to assess the potential association between irAEs and overall survival (OS).
Duration of irAEs and proportion of patients with ongoing toxicities at data cut-off were not specified in 56/62 (90%) publications of ICIs registration trials. In our real-world analysis, including 437 patients (217 LC, 220 Mel), 229 (52.4%) experienced at least one grade ≥2 toxicity, for a total of 318 reported irAEs, of which 112 (35.2%) were long-lasting (≥6 months) and about 40% were ongoing at a median follow-up of 369 days 194–695 or patient death. The cumulative probability of irAE onset from treatment initiation was 42.8%, 51.0% and 57.3% at 6, 12 and 24 months, respectively. The rate of ongoing toxicity from the time of first toxicity onset was 42.8%, 38.4% and 35.7% at 6, 12 and 24 months. Time-dependent analysis showed no significant association between the incidence of irAEs and OS in both cohorts (log Rank p = 0.67 and 0.19 for LC and Mel, respectively).
Late-onset and long-lasting irAEs are underreported but common events during ICIs therapy. Time-dependent survival analysis is advocated to assess their impact on OS. Real-world evidence is warranted to fully capture and characterise late-onset and long-lasting irAEs in order to implement appropriate strategies for patient surveillance and follow-up.
•Late-onset and long-lasting irAEs are underreported in immunotherapy clinical trials.•RWD is of paramount importance to complement data from ICI’s clinical trials.•Long-lasting irAEs are common events during ICI’s therapy.•Time-dependent survival analysis is advocated to assess the impact of irAEs on OS.
•PARP inhibitors have opened the era of targeted therapy in ovarian cancer;•Major therapeutic improvements have been limited to the high grade serous subtype;•The panorama of possible clinically ...actionable targets in ovarian cancer is wider.•New druggable alterations and matched drugs are under investigation.
After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.
Abstract Background Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis ...according to tumor subtype. Patients and methods 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. Results 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% ( p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 ( p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. Conclusions After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.
Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial ...cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint.
A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020 in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis.
Dostarlimab in combination with carboplatin–paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.
•RUBY compared dostarlimab + chemotherapy to chemotherapy alone in patients with primary advanced/recurrent EC.•RUBY showed statistically significant and clinically relevant improvements in OS with dostarlimab + chemotherapy.•These are clinically important results for patients with primary advanced/recurrent EC.•This represents a new standard of care for primary advanced/recurrent EC.
•The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes.•We report about a 47 years-old female affected by ...endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic.
The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes. Despite the guidelines now available, determining the pathogenicity of rare variants remains challenging, as the clinical significance of a genetic variant could be uncertain, but it may represent a disease-associated variation in the aforementioned genes. In this case report we will describe the case of a 47 years-old female affected by endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic, and a family history consistent with LS.
Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a ...favourable side effects profile and a convenient administration modality are preferred.
We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511–17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method.
The median number of previous chemotherapy lines was 5 (range 2–8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5–4.5) and 10.6 (range 8.4–12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity.
In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.
•Oral etoposide is a well-tolerated agent used in treatment of several types of neoplasms.•We retrospectively evaluated 110 pre-treated metastatic breast cancer patients receiving oraletoposide at our institution.•Oral etoposide was active and well tolerated in patients failing a median of 5 prior chemotherapy lines.•This real world study suggests that oral etoposide is a therapeutic option in pre-treated metastatic breast cancer patients.
Despite improvements in surgery and medical treatments, epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy. Aim of this study is to investigate the preclinical ...immunotherapy activity of cytokine-induced killer lymphocytes (CIK) against epithelial ovarian cancers, focusing on platinum-resistant settings. We generated CIK ex vivo starting from human peripheral blood samples (PBMCs) collected from EOC patients. Their antitumor activity was tested in vitro and in vivo against platinum-resistant patient-derived ovarian cancer cells (pdOVCs) and a Patient Derived Xenograft (PDX), respectively. CIK were efficiently generated (48 fold median ex vivo expansion) from EOC patients; pdOVCs lines (n = 9) were successfully generated from metastatic ascites; the expression of CIK target molecules by pdOVC confirmed pre and post treatment in vitro with carboplatin. The results indicate that patient-derived CIK effectively killed autologous pdOVCs in vitro. Such intense activity was maintained against a subset of pdOVC that survived in vitro treatment with carboplatin. Moreover, CIK antitumor activity and tumor homing was confirmed in vivo within an EOC PDX model. Our preliminary data suggest that CIK are active in platinum resistant ovarian cancer models and should be therefore further investigated as a new therapeutic option in this extremely challenging setting.
Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed ...at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status.
We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series.
Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. 9% vs 18%, p = 0.019 and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00–3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004–0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant.
In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.
•Hypersensitivity reactions (HSRs) to carboplatin are frequent in pretreated ovarian cancer (OC) patients (pts).•The role of BRCA mutations (mut) as a risk factor has been suggested.•We demonstrate that BRCAmut pts. have an increased risk of HSRs which is not justified by longer drug exposure only.•Receiving pegylated liposomal doxorubicin was a protective factor in our series.•The meta-analysis of literature, though results are heterogeneous, confirms the role of BRCAmut in increasing HSRs risk.
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