‘First-generation’ immune checkpoint inhibitors targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed death-ligand 1 (PD(L)1) have undoubtedly revolutionised the treatment of multiple ...cancers in the advanced setting. Targeting signalling pathways other than core inhibitory modules may strongly impact the outcome of the antitumour immune response. Drugs targeting these pathways (‘next-generation’ immune modulators, NGIMs) constitute a major frontier in translational research and have generated unprecedented scientific and financial investment. Here, we systematically reviewed published literature, abstracts from major cancer conferences and pharma pipelines to identify NGIMs that have reached clinical development. We identified 107 molecules targeting 16 pathways, which we classified into 6 groups according to function (inhibitory vs stimulatory) and cell of predominant expression (lymphoid, non-lymphoid and natural killer). We identified all registered past and ongoing clinical trials (n = 428). We summarise the preclinical rationale for these targets, extracting translationally relevant information, and review published and preliminary clinical results. Some targets like indoleamine-2,3-dioxygenase 1, lymphocyte activation gene-3 and IL15 have experienced exceptional growth of interest, measured in terms of activated studies and expected patient enrolment over time. We conclude that in this vast and rapidly changing drug development landscape, novel trial designs and better biomarker identification are necessary to optimise resource allocation
•‘Next-generation’ immune modulators (NGIMs) constitute a new field in cancer research.•We identified 107 molecules targeting 16 pathways, which we classified into 6 groups according to function (inhibitory vs stimulatory) and cell of predominant expression (lymphoid, non-lymphoid and natural killer).•We summarise the preclinical rational for these targets and all registered past and ongoing clinical trials (n = 428).
The immune system plays a dual role of host-protecting and tumor-promoting, as elegantly expressed by the ‘cancer immunoediting’ hypothesis. Although breast cancer has not been traditionally ...considered to be immunogenic, recently there is accumulating and solid evidence on the association between immune system and breast cancer. To mount an effective anti-tumor response, host immunosurveillance must recognize tumor-specific epitopes, thus defining the antigenicity of a tumor. Neoantigens are mutant cancer peptides that arise as terminal products of the expression of somatic cancer mutations. Neoantigens and major histocompatibility complex (MHC) proteins present together to effector cells of the immune system. Neoantigen vaccines have shown promising results in inducing neoantigen-specific T-cell responses. Currently, cancer vaccines are under evaluation in breast cancer to avoid recurrences in patients at high risk despite optimal standard therapy. Given the promise of a very specific long-term antitumor immune response, the development of cancer vaccines continues is of great interest. Combinations of neoantigen vaccines and other immunotherapies are also studied to evade cancer immune escape.
•Neoantigens are tumor-specific antigens resulting from somatic DNA alterations and are extremely important in predicting the efficacy of immunotherapy.•Cancer vaccines targeting neoantigens may provide the potential advantage of targeting protein sequences present in the tumoral tissue.•Different strategies are currently under investigation in breast cancer, especially in HER2 positive and triple negative, including personalized polyepitope DNA vaccines, vaccine combined with immunoadjuvant or with trastuzumab.
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•Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized non-Hodgkin lymphoma of T-cell origin.•Despite its low incidence, the increasing use of ...breast implants for cosmetic or post-mastectomy reconstruction purposes places BIA-ALC as an emerging and compelling medical challenge.•Multidisciplinary team approach is essential to well define diagnostic workup and treatment.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized non-Hodgkin lymphoma of T-cell origin. Despite the low incidence of this new disease, the increasing use of breast implants for cosmetic or post-mastectomy reconstruction purposes places BIA-ALC as an emerging and compelling medical challenge. The real BIA-ALCL pathogenesis has not been fully uncovered so far, while different putative causal factors have been proposed. Breast implants with textured surfaces seem to be associated with nearly all cases of BIA-ALCL, while the real the risk of disease development has not been well estimated so far. Late onset, persistent seroma around breast implant represents the classical clinical presentation. Most of the BIA-ALCL patients presents with localized disease, which confers an excellent prognosis. Unlike other non-Hodgkin lymphomas, surgical excision of the mass has a key role in the treatment. For patients with advanced and disseminated diseases, the treatment did not differ from other types of T-cell lymphoma. For these reasons, BIA-ALCL represents an emerging disease which requires multidisciplinary team approach to well define diagnostic workup and treatment for each patient. This review article aims to summarize available data on BIA-ALCL. First, we will outline available data on BIA-ALCL epidemiology, pathogenesis, diagnostic work-up, and treatment. Second, we will point out the potential psychological implications as well as the risk of perception distortion for women with breast implants, especially for those with previous breast cancer. Lastly, we will summarize the current national recommendations regarding textured breast implants and discuss the diagnostic-therapeutic algorithm for BIA-ALCL management.
PURPOSE OF REVIEWBreast cancer is a heterogeneous disease, including different subtypes with their own biology, prognosis, clinical characteristics and treatment. To date, traditional clinical and ...pathological determinants remain the main factors guiding treatment decision-making; however, the development of multigene assays improved the ability to predict the risk of recurrence in patients with early-stage breast cancer. These tools underwent an extensive independent validation and have already been partly incorporated into clinical practice.
RECENT FINDINGSThe current article summarizes current evidence for the use of the different genomic assays in clinical practice, their characteristics and validation studies. A few studies comparing available genomic assays revealed that they provide different information with a modest correlation and that they are not interchangeable; other trials are currently ongoing in this setting.
SUMMARYVariability across different gene signatures may be a challenge for the optimal management of the individual patient, hence each assay should be used for the clinical setting in which it has been validated.
Background
Peripheral blood parameters are correlated to immune‐checkpoint inhibitor efficacy in solid tumors, such as melanoma and non‐small cell lung cancer. Few data are currently available on the ...prognostic role of these immune‐inflammatory biomarkers for other solid tumors and immunotherapy combinations.
Material and Methods
From August 2014 to May 2019, 153 patients with metastatic solid tumors were enrolled in phase I clinical trials testing immunotherapy both as single agents and as combinations. Primary endpoint was to evaluate the impact of baseline blood parameters on progression‐free survival (PFS) and overall survival (OS).
Results
The most common tumor types were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Higher lactate dehydrogenase (LDH) and derived neutrophil‐to‐lymphocyte ratio (dNLR) were independently associated with reduced PFS (hazard ratio HR, 1.97; 95% confidence interval CI, 1.30–2.99; p = .001, and HR, 2.29; 95% CI, 1.39–3.77; p = .001, respectively) and reduced OS (HR, 2.04; 95% CI, 1.26–3.28; p = .004, and HR, 2.06; 95% CI, 1.12–3.79; p = .02, respectively). In the subgroup analysis, (single agent vs. combination), patients at “good” (dNLR <3 and LDH < upper limit of normal ULN) and “intermediate and poor” (dNLR >3 and/or LDH > ULN) risk had higher and lower PFS, respectively (p for interaction = .002). Conversely, patients receiving monotherapy presented statistically significant difference in OS according to the risk group, whereas this effect was not observed for those treated with combinations (p for interaction = .004).
Conclusion
Elevated LDH and dNLR are associated with poorer survival outcomes in patients treated with immunotherapy in phase I clinical trials, regardless of tumor type. These parameters represent an easy tool that might be considered as stratification factors in immunotherapy‐based clinical trials.
Implications for Practice
In this retrospective cohort study of 153 patients with metastatic solid tumors treated with immunotherapy in the context of phase I clinical trials, elevated baseline lactate dehydrogenase and derived neutrophil‐to‐lymphocyte ratio were associated with reduced survival regardless of tumor subtype. If prospectively validated, these parameters might represent low‐cost and easy biomarkers that could help patient selection for early phase immunotherapy trials and be applied as a stratification factor in randomized studies testing immunotherapy agents.
This article evaluates the effect of routine baseline blood parameters on outcomes of patients with advanced cancers treated in phase I trials testing immunotherapy agents as monotherapy or in combination.
We conducted a meta-analysis of randomised trials evaluating pathological complete response (pCR) and surgical outcomes after neoadjuvant systemic therapy (NST) in patients with early breast cancer ...(EBC).
The primary outcome was breast-conserving surgery (BCT) rate. Secondary outcomes were pCR rate and association to BCT. Meta-analyses were performed using random effects models that use inverse-variance weighting for each treatment arm based on evaluable patients. Point estimates are reported with 95% confidence interval (CI), and p < 0.05 was considered statistically significant.
Thirty-six studies were identified (N = 12,311 patients). We selected for the analysis 16 of 36 studies reporting both pCR and BCT for at least one treatment arm. Arms per study ranged from one to six; 42 independent units were available to evaluate the association between pCR and BCT. BCT rate ranged 5–76% across arms with an average BCT of 57% (95% CI 52–62%). Significant heterogeneity was observed among the trials (Cochrane Q = 787, p < 0.001, I2 = 97%). In the meta-regression model, BCT rates were not significantly associated with year of first patient-in (p = 0.89), grade (p = 0.93) and hormone-receptor status (p = 0.39). Clinical N-stage (p = 0.01) and human epidermal growth factor receptor (HER2) status (p = 0.03) were significantly associated with BCT. pCR rate ranged 3–60% across studies. The average pCR across all study arms was 24% (95% CI 19–29%). No association was observed between pCR rate in a study arm and the resulting BCT rate in a univariate model (p = 0.34) nor after adjusting for HER2 and clinical nodal status (p = 0.82). In the subset of 14 multi-arm studies, no significant association was seen between the differences in pCR and BCT between treatment arms (p = 0.27).
pCR does not increase BCT in patients receiving NST for EBC.
•Neoadjuvant systemic therapy (NST) achieves equivalent local recurrence, disease-free and overall survival outcomes as compared with adjuvant therapy in early breast cancer (EBC).•We conducted a meta-analysis of randomised trials evaluating pathological complete response (pCR) and surgical outcomes after NST in patients with EBC.•pCR does not increase BCT in patients receiving NST for EBC.
Dinaciclib for the treatment of breast cancer Criscitiello, Carmen; Viale, Giulia; Esposito, Angela ...
Expert opinion on investigational drugs,
09/2014, Volume:
23, Issue:
9
Journal Article
Peer reviewed
Cyclin-dependent kinases (CDK) represent attractive targets in oncology due to their key role in controlling gene transcription and cell cycle progression. Dinaciclib (MK-7965, formerly SCH727965) is ...a relatively novel CDK 1/2/5/9 inhibitor that has shown promising results in preclinical studies and an acceptable safety profile in Phase I clinical trials. It is currently under clinical evaluation for the treatment of hematological and solid malignancies, including breast cancer.
This review summarizes the current understanding of CDK's role in physiology and cancer, and the therapeutic value of blocking their pathways in breast cancer. Particularly, the article reviews the preclinical and clinical data for dinaciclib in its use for the treatment of breast cancer.
A better understanding of the molecular mechanisms underlying cell cycle dysregulation in cancer is needed in order to develop novel CDK inhibitors. Additionally, further efforts are needed to identify potential biomarkers of dinaciclib efficacy, which could allow a better selection of patients enrolled in clinical trials. Moreover, combination therapies with dinaciclib or other CDK and chemotherapy, endocrine therapy or targeted therapies might be further evaluated in breast cancer patients.
Immune Checkpoint Inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients ...significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/ neoadjuvant setting); iii) most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). In this article, we review the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.
PURPOSE OF REVIEWA burst of recent activity has surrounded the study of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors for the treatment of metastatic breast cancer. The success of these drugs in ...the metastatic setting has pushed the evaluation of these agents in early-stage disease. The use of CDK 4/6 inhibitors as neoadjuvant and adjuvant therapy is a hot topic and several studies are underway.
RECENT FINDINGSOngoing studies are exploring the addition of CDK 4/6 inhibitors to endocrine therapy in early breast cancer.
SUMMARYIdentification of the optimal treatment combinations is the goal of current research. Finding biomarkers for patients’ selection will be the goal of future research.
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