Several accomplishments have been achieved in triple-negative breast cancer (TNBC) research over the last year. The phase III IMpassion130 trial comparing chemotherapy plus atezolizumab versus ...chemotherapy plus placebo brought breast cancer into the immunotherapy era. Nevertheless, despite encouraging results being obtained in this trial, many open questions remain.
A positive overall survival outcome was achieved only in PD-L1
TNBC patients, suggesting a need to enrich the patient population more likely to benefit from an immunotherapeutic approach. Moreover, it remains unknown whether single-agent immunotherapy might be a good option for some patients. In this context, the discovery and implementation of novel and appropriate biomarkers are required. Focusing on the early onset of TNBC, neoadjuvant trials could represent excellent in vivo platforms to test immunotherapy agents and their potential combinations, allowing the performance of translational studies for biomarker implementation and improved patient selection.
The aim of our review is to present recent advances in TNBC treatment and to discuss open issues in order to better define potential future directions for immunotherapy in TNBC.
The Alps have often been considered a laboratory for architectural modernity. Buildings there were a litmus test to reveal the attitudes of 20th-century architects towards design. When Carlo Mollino ...designed a project for a Club Med hotel in Sestriere in 1973, which was neither built nor published, he was at the end not only of his career but also of an important era for architecture that had begun just after World War II and ended in the economic crisis of the early 1970s. During this time, a debate on modern architecture acquired a new and increasingly important focus on context; Alpine architecture was at the forefront. The Club Med design was the culmination of Mollino's series of reflections on modernism. In the 1950s, he conceived of buildings for a sophisticated public, and his final project was a megastructure for mass tourism. The ski-resort town of Sestriere, founded by the Agnelli family in the early 1930s, was created for the consumption of nature by the masses, just as the Agnelli family produced Fiat cars for mass consumption. It was the first resort town where rationalism, speed, mass consumption, and the dominion of man over nature were the focus of urban and architectural design. Mollino's Club Med design was for a hotel that would be a machine for tourist consumption in the mountains. The project was one of the last examples of a way of consuming the Alps that vanished in subsequent years.
Triple-negative breast cancer (TNBC) is not a unique disease, encompassing multiple entities with marked histopathological, transcriptomic and genomic heterogeneity. Despite several efforts, ...transcriptomic and genomic classifications have remained merely theoretic and most of the patients are being treated with chemotherapy. Driver alterations in potentially targetable genes, including PIK3CA and AKT, have been identified across TNBC subtypes, prompting the implementation of biomarker-driven therapeutic approaches. However, biomarker-based treatments as well as immune checkpoint inhibitor-based immunotherapy have provided contrasting and limited results so far. Accordingly, a better characterization of the genomic and immune contexture underpinning TNBC, as well as the translation of the lessons learnt in the metastatic disease to the early setting would improve patients' outcomes. The application of multi-omics technologies, biocomputational algorithms, assays for minimal residual disease monitoring and novel clinical trial designs are strongly warranted to pave the way toward personalized anticancer treatment for patients with TNBC.
Immunotherapy has revolutionized cancer treatment. Immune-checkpoint inhibitors, on balance, showed a favorable efficacy/toxicity profile with durable response in different cancer types. No ...predictive biomarker has been validated thus far to select patients who would benefit from therapy. Among the candidate predictive biomarkers, mismatch repair status of the tumor is currently one of the most promising. Indeed, tumors displaying mismatch repair deficiency or microsatellite instability showed remarkable response to immunotherapy in clinical trials. This correlation has been first reported in colorectal cancers, but similar results have been observed also in other cancer types. The possible mechanism behind this correlation may be the higher mutational load observed in mismatch repair deficient tumors, leading to neoantigens formation, recruitment of immune cells, and release of proinflammatory factors in the microenvironment. These results support an approach to treatment based on assessment of the genomic stability of the tumor besides its biologic characteristics and may change our therapeutic decision making process. However, due to the small percentage of patients with tumors displaying mismatch repair deficiency, data from clinical trials should not be considered definitive and need further confirmation.
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The finalization of the Human Genome Project in 2003 paved the way for a deeper understanding of cancer, favouring a faster progression towards “personalized” medicine. Research in ...oncology has progressively focused on the sequencing of cancer genomes, to better understand the genetic basis of tumorigenesis and identify actionable alterations to guide cancer therapy. Thanks to the development of next-generation-sequencing (NGS) techniques, sequencing of tumoral DNA is today technically easier, faster and cheaper. Commercially available NGS panels enable the detection of single or global genomic alterations, namely gene mutation and mutagenic burden, both on germline and somatic DNA, potentially predicting the response or resistance to cancer treatments. Profiling of tumor DNA is nowadays a standard in cancer research and treatment. In this review we discuss the history, techniques and applications of NGS in cancer care, under a “personalized tailored therapy” perspective.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and now represent the mainstay of treatment for many tumor types, including triple-negative breast cancer and two agnostic ...registrations. However, despite impressive durable responses suggestive of an even curative potential in some cases, most patients receiving ICIs do not derive a substantial benefit, highlighting the need for more precise patient selection and stratification. The identification of predictive biomarkers of response to ICIs may play a pivotal role in optimizing the therapeutic use of such compounds. In this Review, we describe the current landscape of tissue and blood biomarkers that could serve as predictive factors for ICI treatment in breast cancer.
The integration of these biomarkers in a “holistic” perspective aimed at developing comprehensive panels of multiple predictive factors will be a major step forward towards precision immune-oncology.
•Most breast cancer (BC) patients receiving ICIs do not derive substantial benefit.•PD-L1 is an unsatisfactory predictive factor for ICI benefit in metastatic BC.•Several promising tissue and blood biomarkers may inform tailoring of ICIs in BC.•A comprehensive integration of different biomarkers is key for precision immunology.
Nausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at ...evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd.
Data from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square.
A total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%;
= 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (
= 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (
= 0.022) and vomiting decreased from 47% to 13% (
= 0.046).
The NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.
As most erb‐b2 receptor tyrosine kinase 2 (HER2)‐positive breast cancer (BC) patients currently receive dual HER2‐targeting added to neoadjuvant chemotherapy, improved methods for identifying ...individual response, and assisting postsurgical salvage therapy, are needed. Herein, we evaluated the 41‐gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre‐ and 166 post‐treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico‐pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER‐positive specimens but not in ER‐negative counterparts. Among ER‐positive BC patients not achieving a pCR, those with TRAR‐low scores in surgical specimens showed a trend for lower distant event‐free survival. In conclusion, in HER2‐positive/ER‐positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti‐HER2‐based neoadjuvant therapy and to assist treatment escalation and de‐escalation strategies in this setting.
TRAR‐low score is an independent predictor of pathological complete response (pCR) to anti‐HER2 agents in patients with HER2‐positive and ER‐positive breast cancer of the NeoSphere study. The higher risk of relapse observed in these patients likely depends on modification by treatment of tumor proliferation and ER activity. TRAR is a promising tool to assist escalation and de‐escalation of anti‐HER2‐based treatment strategies.
Adjuvant chemotherapy recommendations for ER+/HER2- early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to ...discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2- eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2- eBC.
Targeting the microenvironment in solid tumors Belli, Carmen; Trapani, Dario; Viale, Giulia ...
Cancer treatment reviews,
April 2018, 2018-Apr, 2018-04-00, 20180401, Volume:
65
Journal Article
Peer reviewed
•Tumor microenvironment (TME) gets specific modifications during cancer progression.•Targeting different components of TME may overcome drug resistance.•It is advantageous to target genetically ...stable TME containing non-tumor cells.
Tumorigenesis is a complex and dynamic process involving different cellular and non-cellular elements composed of tumor microenvironment (TME). The interaction of TME with cancer cells is responsible for tumor development, progression and drug resistance. TME consists of non malignant cells of the tumor such as cancer associated fibroblasts (CAFs), endothelial cells and pericytes composing tumor vasculature, immune and inflammatory cells, bone marrow derived cells, and the extracellular matrix (ECM) establishing a complex cross-talk with tumor. These interactions contribute towards proliferation and invasion of the tumor by producing growth factors, chemokines and matrix-degrading enzymes. ECM is a complex system containing macromolecules with distinctive physical, biochemical and biomechanical properties. During tumorigenesis this system is deregulated favoring the generation of tumorigenic microenvironment enhancing tumor-associated angiogenesis and inflammation.
An important step of anticancer treatment is the identification of the biological alterations present in TME in order to target these key molecular players. Multitargeted approaches, providing a simultaneous inhibition of TME components, may offer a more efficient way to treat cancer. In this manuscript we overview the function of each components of TME and the treatments targeting the key players.
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