Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies.

As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody-drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

Immune-Related Adverse Event Likelihood Score Identifies "Pure" IRAEs Strongly Associated With Outcome in a Phase I-II Trial Population.

BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.

New Concepts in Cardio-Oncology.

Cancer and cardiovascular disease are the two major causes of morbidity and mortality in worldwide. Discovering new therapeutic agents for the management of breast cancer (BC) has increased the numbers of cancer survivors but with the risk of cardiovascular adverse events (CV-AEs). All drugs can potentially damage the cardiovascular system, with different types of clinical manifestations from ischemic myocardial disease to vasculitis, thrombosis or pericarditis. An early detection of CV-AEs guarantees an earlier treatment, which is associated with better outcomes. Cardio-oncology field enlarged its studies to improve prevention, monitoring and treatment of all cardiotoxic manifestations related to old or modern oncological agents. A multidisciplinary approach with a close partnership between oncologists and cardiologists is essential for an optimal management and therapeutic decision-making. The aim of this chapter is to review all types of cardiotoxic manifestations related to novel and old agents approved for treatment of BC patients including chemotherapy, anti-HER2 agents, cyclin-dependent kinase 4/6 inhibitors, PolyADP-ribose polymerase (PARP) inhibitors, antiangiogenic drugs and immunotherapy. We also focused our discussion on prevention, monitoring, treatment, and management of CV-AEs.

HER2-Low Breast Cancer: a New Subtype?

OPINION STATEMENT: Breast cancer (BC) guidelines subdivide the disease into three main groups, namely hormone receptor (HR)-positive HER2-negative, HER2-positive, and triple-negative BC (TNBC). The natural history of the HER2-positive subtype has changed since the introduction of HER-targeted therapies, which demonstrated benefit only in case of HER2 overexpression (IHC, score 3+) or gene amplification. Such observation may depend on direct drug inhibition of HER2 downstream signaling, which is needed for survival and proliferation in HER2-addicted BC. Clinically focused categories cannot comprehensively describe biology, as almost half of the currently defined HER2-negative BCs show some degree of IHC expression and have been recently renamed as HER2-low. Why? As technological breakthroughs enable the synthesis of antibody-drug conjugates (ADCs), target antigens may be viewed not only as a biological switch to be turned on-off by targeted drugs but also as an anchor for ADC docking and tethering. As trastuzumab deruxtecan (T-DXd) has already proven in the clinical trial DESTINY-Breast04, even fewer HER2 available receptors on cancer cells may be sufficient for a clinical benefit. So, for HR-negative HER2-low subtype (~40% of TNBCs), though only 58 patients had been enrolled in DESTINY-Breast04, the observed benefit, together with the dismal prognosis of TNBC, warrants the use of T-DXd. Notably, another topoisomerase-based ADC, sacituzumab govitecan, has already been granted approval for pretreated TNBC (ASCENT). As no head-to-head comparison has been performed, the choice relies on regulatory approvals at the time of patient assessment, critical appraisal of available evidence, and careful evaluation of possible cross-resistance with sequential use of ADCs. As for HR-positive HER2-low disease (~60% of HR-positive tumors), DESTINY-Breast04 provides solid evidence for T-DXd prioritization in either second or third treatment lines. Although the remarkable activity observed in this setting favorably compares with outcomes observed in treatment-naive patients, the ongoing DESTINY-Breast06 will clarify the role of T-DXd in this population.

Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Patients with advanced type B3 thymoma and thymic carcinoma resistant to chemotherapy have few treatment options. We report the efficacy and safety results of the combination of the anti-PD-L1 inhibitor avelumab with the anti-angiogenesis drug axitinib in patients with advanced type B3 thymoma and thymic carcinoma. METHODS: CAVEATT was a single-arm, multicentre, phase 2 trial, conducted in two Italian centres (the European Instituteof Oncology and the Humanitas Institute, Milan) in patients with histologically confirmed type B3 thymoma or thymic carcinoma, with advanced stage of disease who had progressed after at least one line of platinum-based chemotherapy. Previous treatment with an anti-angiogenesis drug was allowed but not with immune checkpoint inhibitors. Other inclusion criteria were age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, progressive disease, and presence of measurable disease according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Patients received avelumab 10 mg/kg intravenously every 2 weeks and axitinib 5 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was the centrally assessed overall response rate according to RECIST version 1.1. Patients who received at least one cycle of treatment and had at least one CT scan after treatment start at scheduled time point by protocol were judged assessable for response and were included in efficacy and safety analyses. This study is registered with EUDRACT, 2017-004048-38; enrolment is completed and follow-up is ongoing. FINDINGS: Between April 22, 2019, and June 30, 2021, 32 patients were enrolled. 27 patients had a thymic carcinoma, three a type B3 thymoma, and two a mixed type B3 thymoma and thymic carcinoma. 29 (91%) of 32 patients had stage IVB disease and 13 (41%) of 32 had been pretreated with an anti-angiogenesis drug. 11 of 32 patients had an overall response; thus the overall response rate was 34% (90% CI 21-50); no patients had a complete response, 11 (34%) had a partial response, 18 (56%) had stable disease, and in two patients (6%) progressive disease was the best response. The most common grade 3 or 4 adverse event was hypertension (grade 3 in six [19%] of 32 patients). Four (12%) of 32 patients developed serious adverse events that were new-onset immune-related adverse events, including one grade 3 interstitial pneumonitis, one grade 4 polymyositis, and two grade 3 polymyositis. There were no treatment-related deaths. INTERPRETATION: Avelumab combined with axitinib has promising anti-tumour activity and acceptable toxicity in patients with advanced type B3 thymoma and thymic carcinoma progressing after chemotherapy, and could emerge as a new standard treatment option in this setting. FUNDING: Pfizer.

Bystander effect of antibody-drug conjugates: fact or fiction?

PURPOSE OF REVIEW: Summarizing the current preclinical and clinical evidence about bystander effect of antibody-drug conjugates (ADCs) in solid tumors. RECENT FINDINGS: One of the main challenges of treating solid tumors with ADCs is the heterogeneous expression of the target antigen (Ag), which however may be overcome by the so-called bystander killing effect. This unique, but still debated, feature of certain ADCs is represented by the unintentional payload diffusion from Ag-positive tumor cells to adjacent Ag-negative tumor cells. Some pharmacological characteristics, such as a hydrophobic payload or a cleavable linker, seem to play a major role in this effect. Abundant preclinical evidence of the bystander effect has emerged, and the clinical activity of ADCs in tumors with a heterogeneous Ag expression suggests the relevance of this feature. Additional studies are required to investigate if the bystander effect is necessary for achieving a solid activity with ADCs.

Systemic Treatment of Ductal Carcinoma In Situ of the Breast.

Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer (BC), whose diagnosis significatively increased with the diffusion of BC screening programs. DCIS actually represents roughly 20% of new BC diagnoses (1). About 70% of DCIS shows positivity for hormone receptor (HR), while HER2 is overexpressed in 25-30% of the cases (2,3). Concerning the systemic approach, the only one that should be considered for HR-positive DCIS is adjuvant endocrine therapy (ET), according to NCCN guidelines (4). In fact, the excellent prognosis of this neoplasm does not justify the utilization of more aggressive treatment strategies, such as HER2- directed therapies or chemotherapy. Here we discuss the results of the most important clinical trials enrolling DCIS patients in the adjuvant and in the preoperative setting; in addition, we report the chemoprevention studies utilizing ET which demonstrated a reduction of the risk of DCIS development. On balance, the choice to undertake or not an adjuvant ET, which is often burdened by adverse events that could impact on the quality of life of the patients and on their adherence to the therapy, should be discussed with the patient, taking into account that no survival advantage has been demonstrated so far.

Adjuvant treatment of early male breast cancer.

PURPOSE OF REVIEW: Male breast cancer (MaBC) is a rare disease, and some challenges exist in its management because current treatment recommendations are extrapolated from trials that mostly excluded men. This review will revise all available data that could improve the treatment of MaBC, with a special focus on adjuvant systemic treatments. RECENT FINDINGS: To date, men with hormone receptor-positive breast cancer, who are candidates for adjuvant endocrine therapy, should be offered tamoxifen (TAM) for five years. Additional five years are possible, according to tolerance and recurrence risk. If TAM is contraindicated, a gonadotropin-releasing hormone (GnRH) agonist or antagonist and aromatase inhibitor should be proposed. Chemotherapy and targeted therapy in the other breast cancer subtypes should be used with the same indications offered to women with breast cancer. All men with breast cancer should be offered genetic counseling and germline genetic testing of cancer predisposition genes. SUMMARY: For decades, men with breast cancer have been treated suboptimally and denied the participation in clinical trials. Recently, many clinical trials started enrolling both genders, as strongly endorsed by the Food and Drug Administration. Hopefully, this turnaround will help subdue the disparities in the quality of care.

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer.

Mismatch repair (MMR) analysis in breast cancer may help to inform immunotherapy decisions but it lacks breast-specific guidelines. Unlike in other neoplasms, MMR protein loss shows intra-tumor heterogeneity and it is not mirrored by microsatellite instability in the breast. Additional biomarkers can improve MMR clinical testing. Phosphatase and tensin homolog (PTEN) inactivation is an early oncogenic event that is associated with MMR deficiency (dMMR) in several tumors. Here, we sought to characterize the diagnostic utility of PTEN expression analysis for MMR status assessment in breast cancer. A total of 608 breast cancers were profiled for their MMR and PTEN status. Proteins expression and distribution were analyzed by immunohistochemistry (IHC) on tissue microarrays and confirmed on full sections; PTEN copy number alterations were detected using a real-time PCR assay. Overall, 78 (12.8%) cases were MMR-heterogeneous (hMMR), while all patterns of PTEN expression showed no intra-tumor heterogeneity. Wild-type PTEN expression was observed in 15 (18.5%) dMMR tumors (p < 0.0001). Survival analyses revealed significant correlations between MMR-proficient (pMMR), PTEN expression, and a better outcome. The positive predictive value of PTEN-retained status for pMMR ranged from 94.6% in estrogen receptor (ER)+/HER2- tumors to 100% in HER2-amplified and ER-/HER2- cases. We propose a novel diagnostic algorithm where PTEN expression analysis can be employed to identify pMMR breast cancers.

Determination of Mismatch Repair Status in Human Cancer and Its Clinical Significance: Does One Size Fit All?

The clinical management of cancers has progressed rapidly into the immunopathology era, with the unprecedented histology-agnostic approval of pembrolizumab in mismatch repair (MMR) deficient tumors. Despite the significant recent achievements in the treatment of these patients, however, the identification of clinically relevant subclasses of cancers based on the MMR status remains a major challenge. Many investigations have assessed the role of different diagnostic tools, including immunohistochemistry, microsatellite instability, and tumor mutational burden in both prognostic and therapeutic settings, with heterogenous results. To date, there are no tumor-specific guidelines or companion diagnostic tests for MMR assessment, and this analysis is often performed with locally developed methods. In this review, we provide a comprehensive overview of the current state-of-knowledge of MMR alterations in syndromic and sporadic tumors and discuss the available armamentarium for MMR pathologic characterization, from morphology to high-throughput molecular tools.

Lymphovascular invasion and extranodal tumour extension are risk indicators of breast cancer related lymphoedema: an observational retrospective study with long-term follow-up.

BACKGROUND: Breast cancer related lymphoedema (BCRL) occurs in a substantial proportion of breast cancer survivors and is a major contributor to patients' disability. Regrettably, there are no validated predictive biomarkers, diagnostic tools, and strong evidence-supported therapeutic strategies for BCRL. Here, we provide an integrative characterization of a large series of women with node-positive breast cancers and identify new bona fide predictors of BCRL occurrence. METHODS: Three hundred thirty-two cases of surgically-treated node-positive breast cancers were retrospectively collected (2-10.2 years of follow-up). Among them, 62 patients developed BCRL. To identify demographic and clinicopathologic features related to BCRL, Fisher's exact test or Chi-squared test were carried out for categorical variables; the Wilcoxon rank-sum was employed for continuous variables. Factors associated with BCRL occurrence were assessed using a Cox proportional hazards regression model. RESULTS: En-bloc dissection of the axillary lymph nodes but not the type of breast surgery impacted on BCRL development. Most of BCRL patients had a Luminal A-like neoplasm. The median number of lymph nodes involved by metastatic deposits was significantly higher in BCRL compared to the control group (p = 0.04). Both peritumoral lymphovascular invasion (LVI) and extranodal extension (ENE) of the metastasis had a negative impact on BCRL-free survival (p = 0.01). Specifically, patients with LVI and left side localization harboured 4-fold higher risk of developing BCRL, while right axillary nodes metastases with ENE increased the probability of BCRL compared to ENE-negative patients. CONCLUSIONS: Assessment of LVI and ENE should be integrated with clinical and surgical data to improve BCRL risk stratification.

Checkpoint inhibition for early-stage hormone receptor-positive breast cancer.

INTRODUCTION: Most patients with breast cancer have early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease. Even though the prognosis for most of these patients is good, there is a need to identify patients at risk for poor outcomes and to develop strategies to mitigate this risk. AREAS COVERED: The addition of immunotherapy to standard neoadjuvant chemotherapy represents a promising option for select patients with HR-positive early breast cancer. Three randomized clinical trials have shown favorable results to date. In this review, we discuss the findings of I-SPY2, CheckMate 7FL (NCT04109066), and KEYNOTE-756 (NCT03725059). EXPERT OPINION: Despite the promising results of these trials, there are unanswered questions that need to be considered before incorporating neo/adjuvant immunotherapy in the treatment paradigm of early-stage HR-positive breast cancer. One example of an unanswered question is patient selection. Because the regimens used in these protocols are associated with long-term toxicities, identifying the patients who are more likely to derive a benefit from these agents, such as through the use of biomarkers, is critical. A second example is the optimal integration of adjuvant therapies that improve invasive disease-free survival, such as abemaciclib and ribociclib, which are not safely administered concurrently with immunotherapy.

Cardiotoxicity of Agents Used in Patients With Breast Cancer.

Cancer and cardiovascular diseases are the two major causes of mortality, morbidity, and disability worldwide. The improvement in effective therapeutic options for the management of breast cancer (BC) has led to an increased number of BC survivors, who can experience long-term toxicities from cancer treatments. Adverse events including cardiovascular toxicities must be considered in light of effectiveness of recently approved drugs for BC treatment, including elacestrant, tucatinib, neratinib, olaparib, the immune checkpoint inhibitors, trastuzumab deruxtecan, or sacituzumab govitecan. Many cancer drugs affect the cardiovascular system with a range of clinical manifestations. Prompt diagnosis and treatment as well as a multidisciplinary approach involving a cardio-oncologist is optimal for management of these cardiovascular events.

Advancing equitable and personalized cancer care: Novel applications and priorities of artificial intelligence for fairness and inclusivity in the patient care workflow.

Patient care workflows are highly multimodal and intertwined: the intersection of data outputs provided from different disciplines and in different formats remains one of the main challenges of modern oncology. Artificial Intelligence (AI) has the potential to revolutionize the current clinical practice of oncology owing to advancements in digitalization, database expansion, computational technologies, and algorithmic innovations that facilitate discernment of complex relationships in multimodal data. Within oncology, radiation therapy (RT) represents an increasingly complex working procedure, involving many labor-intensive and operator-dependent tasks. In this context, AI has gained momentum as a powerful tool to standardize treatment performance and reduce inter-observer variability in a time-efficient manner. This review explores the hurdles associated with the development, implementation, and maintenance of AI platforms and highlights current measures in place to address them. In examining AI's role in oncology workflows, we underscore that a thorough and critical consideration of these challenges is the only way to ensure equitable and unbiased care delivery, ultimately serving patients' survival and quality of life.

Risk of thromboembolic events in patients with metastatic solid tumors treated with PARP inhibitors: A systematic review and meta-analysis of phase 3 randomized controlled trials.

BACKGROUND AND SCOPE: Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized cancer treatment in recent years. These drugs present a favorable safety profile, even though the potential risk of thromboembolic events (TEs) during their use has not been addressed yet. In addition, PARPi have been involved in an active scientific debate regarding non-oncologic indications, particularly during the Coronavirus Disease 2019 pandemic, including potential anti-thromboembolic effect. METHODS: To clarify whether patients treated with PARPi for metastatic solid tumors are either at increased or decreased risk of TEs, we conducted a systematic review of the literature and meta-analysis, including all phase 3 randomized controlled trials (RCTs) which investigated PARPi in this setting. Search was conducted through Medline, EMBASE, Pubmed, SCOPUS and Google Scholar in February 2023, including the proceedings of the principal oncology meetings of the last 10 years, with no time restriction. For each included study, frequencies of TEs in experimental and control arm were collected. RESULTS: Our search identified 2,369 reports, of which 20 were lastly selected. A total of 4,946 patients were included, across 12 different RCTs. The meta-analysis did not demonstrate either an increased or a reduced risk in TEs in patients treated with PARPi for metastatic disease (OR 1.50, range: 1.00-2.24; 95% CI; P = 0.050), with low heterogeneity and low publication bias. CONCLUSION: Although our research did not confirm either increased or decreased risk of TEs for PARPi use, no safety alerts emerged. Thromboembolic risk assessment models should always be integrated in daily clinical routine, to identify high-risk patients.

Evolving treatment landscape of immunotherapy in breast cancer: current issues and future perspectives.

Immune checkpoint inhibitors (ICIs) deeply changed the treatment landscape of breast cancer (BC). In particular, anti-programmed-death (ligand) 1 antibodies were approved for the treatment of triple-negative breast cancer (TNBC), both in first line for metastatic disease and in neoadjuvant setting, on the basis of a demonstrated improvement of the survival outcomes. In light of these results, current clinical trials aim at improving this benefit investigating novel combinations and strategies, at exploring the role of ICIs beyond TNBC, and at better selecting the patients in order to spare non-responders from avoidable toxicities. This narrative review aims at summarizing and discussing the evolving landscape of immunotherapeutic treatments for BC, highlighting the current challenges and the future perspectives.

Future potential targets of antibody-drug conjugates in breast cancer.

Metastatic breast cancer (BC) remains an incurable disease. Besides endocrine and targeted agents, chemotherapy is still a relevant therapeutic option for this disease. Recently, antibody-drug conjugates (ADCs) have shown to overcome the lack of tumor specificity and systemic toxicity typically associated with traditional chemotherapies, thus improving the therapeutic index. To effectively exploit this technological breakthrough, identification of optimal target antigens (Ags) is of utmost importance. To make the ideal target, differential expression of target Ags between healthy and cancer tissues, as well as specific mechanisms of ADC internalization after Ag-antibody interaction are required. Therefore, several in silico strategies to identify and characterize new promising candidate Ags have been developed. If initial in vitro and in vivo positive data are documented, thus providing a biological rationale for further Ag investigation, early phase clinical trials are designed. In BC, these strategies have already led to the development of effective ADCs, namely trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), primarily targeting HER2 and TROP-2. However, promising new Ags are currently under investigation, with encouraging results especially coming from targeting HER3, FRα, Tissue Factor, LIV-1, ROR1-2, and B7-H4. In this review, we describe the landscape of emergent and future potential targets (i.e., other than HER2 and TROP-2) investigated in BC for ADC development. Predominant target expression, function, preclinical rationale, potential clinical implication, as well as preliminary clinical trial results are provided.

Artificial intelligence in cancer research and precision medicine: Applications, limitations and priorities to drive transformation in the delivery of equitable and unbiased care.

Artificial intelligence (AI) has experienced explosive growth in oncology and related specialties in recent years. The improved expertise in data capture, the increased capacity for data aggregation and analytic power, along with decreasing costs of genome sequencing and related biologic "omics", set the foundation and need for novel tools that can meaningfully process these data from multiple sources and of varying types. These advances provide value across biomedical discovery, diagnosis, prognosis, treatment, and prevention, in a multimodal fashion. However, while big data and AI tools have already revolutionized many fields, medicine has partially lagged due to its complexity and multi-dimensionality, leading to technical challenges in developing and validating solutions that generalize to diverse populations. Indeed, inner biases and miseducation of algorithms, in view of their implementation in daily clinical practice, are increasingly relevant concerns; critically, it is possible for AI to mirror the unconscious biases of the humans who generated these algorithms. Therefore, to avoid worsening existing health disparities, it is critical to employ a thoughtful, transparent, and inclusive approach that involves addressing bias in algorithm design and implementation along the cancer care continuum. In this review, a broad landscape of major applications of AI in cancer care is provided, with a focus on cancer research and precision medicine. Major challenges posed by the implementation of AI in the clinical setting will be discussed. Potentially feasible solutions for mitigating bias are provided, in the light of promoting cancer health equity.

Sustained Improvement in the Management of Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocation: Where Are We Running?

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.