Optimizing Postneoadjuvant Treatment in Patients With Early Breast Cancer Achieving Pathologic Complete Response.

pCR should be integrated with other prognostic factors to optimize postneoadjuvant treatments in BC.

Unveiling the Untapped Potential of Antibody Drug Conjugates in Precision Oncology.

This Viewpoint discusses cancer antigen expression and antibody drug conjugates.

Biomarkers for Antibody-Drug Conjugates in Solid Tumors.

The clinical development and then the progressive entry in clinical practice of antibody-drug conjugates (ADC) have marked a transformative advancement in the overall cancer treatment. ADCs have been extensively tested for a large number of tumors, reporting heterogeneous clinical efficacy and safety results. In some diseases, the advent of ADCs has yielded significant changes in the prognostic trajectory, portending an improvement of the survival and/or quality of life. ADCs are targeted agents, capable of delivering highly cytotoxic payloads selectively to antigen-expressing cancer cells. As such, they have been intended as perfect "bullets" to enable the promise of precision medicine, toward high-efficacy and limited-toxicity treatment options. However, only some approved ADCs are intended for the use in biomarker-selected patient populations, restricting potentially the opportunity to be more precise. Yet, key characteristics of modern ADCs might allow the activity of ADCs in tumors with heterogeneous or low expression of cancer antigens, resulting in a clinical activity that could sublimate the classic paradigm of a drug-to-target perfect match. In our review, we portrayed the current landscape of approved ADCs, reporting data of activity as related to the expression of the cancer antigens, and elucidating possible determinants of the safety and efficacy, including when used in a therapeutic sequence.

Tackling the implementation gap for the uptake of NGS and advanced molecular diagnostics into healthcare systems.

Next-generation sequencing (NGS) and liquid biopsy (LB) showed positive results in the fight against different cancer types. This paper aims to assess the uptake of advanced molecular diagnostics/NGS for quick and efficient genetic profiles of tumour cells. For that purpose, the European Alliance for Personalised Medicine conducted a series of expert interviews to ascertain the current status across member states. One stakeholder meeting was additionally conducted to prioritize relevant factors by stakeholders. Seven common pillars were identified, and twenty-five measures were defined based on these pillars. Results showed that a multi-faceted approach is necessary for successful NGS implementation and that regional differences may be influenced by healthcare policies, resources, and infrastructure. It is important to consider different correlations when interpreting the results and to use them as a starting point for further discussion.

Does Retzius-Sparing robot-assisted radical prostatectomy guarantee optimal urinary continence recovery across all ages?

The association between age at surgery and urinary continence (UC) recovery after Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) is not well established. We addressed this knowledge gap, relying on a large series of 1,417 patients treated with RS-RARP at a high-volume centre between 2010 and 2021. Multivariable logistic models, as well as LOESS plot functions were performed. The probability of immediate, as well as 12-month UC-recovery progressively declined with increasing age at surgery, and per 5-years age at surgery increase reached the independent predictor status for both immediate and 12-month UC-recovery. These findings may significantly improve the quality of patient counseling regarding RS-RARP.

Radiation therapy, tissue radiosensitization, and potential synergism in the era of novel antibody-drug conjugates.

Antibody-drug conjugates (ADCs) represent a therapeutic class of agents designed to selectively deliver cytotoxic payloads to cancer cells. With the increasingly positioning of ADCs in the clinical practice, combinations with other treatment modalities, including radiation therapy (RT), will open new opportunities but also challenges. This review evaluates ADC-RT interactions, examining therapeutic synergies and potential caveats. ADC payloads can be radiosensitizing, enhancing cytotoxicity when used in combination with RT. Antigens targeted by ADCs can have various tissue expressions, resulting in possible off-target toxicities by tissue radiosensitization. Notably, the HER-2-directed ADC trastuzumab emtansine has appeared to increase the risk of radionecrosis when used concomitantly with brain RT, as glial cells can express HER2, too. Other possible organ-specific effects are discussed, such as pulmonary and cardiac toxicities. The lack of robust clinical data on the ADC-RT combination raises concerns regarding specific side effects and the ultimate trade-off of toxicity and safety of some combined approaches. Clinical studies are needed to assess ADC-RT combination safety and efficacy.

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.

Primary malignant phyllodes tumors of the breast: A retrospective analysis from a referral center.

BACKGROUND: The treatment for primary malignant phyllodes tumors of the breast (B-MPT) consists of wide local excision with negative margins (≥1 cm). However, because of their rarity, prognostic factors, type of surgery and adjuvant treatments are still a matter of debate. METHODS: We conducted a single-center retrospective study to describe outcomes and prognostic factors of patients with primary B-MPT, who underwent breast surgery from January 2000 to December 2021. The primary endpoint was the cumulative incidence of any recurrence. Secondary endpoints were the cumulative incidences of distant and local recurrences. RESULTS: 131 patients were included, of whom all received surgery, 5 adjuvant anthracycline-based chemotherapy and 15 radiation therapy. After a median follow-up of 6.4 years, the cumulative incidences at 5-years of any, local and distant recurrences were of 26% (95% Confidence Interval [CI], 4-34%), 16% (95%CI, 10-24%) and 10% (95%CI, 5.3-16%), respectively. Tumor size ≥ 5 cm was associated with higher distant recurrences (p = 0.05); instead, among small tumors (<5 cm), distant recurrences were higher in those with heterologous differentiation and/or multifocal disease (p = 0.06). Type of breast surgery (mastectomy vs. lumpectomy/excision) was not found to be significantly associated with distant (p = 0.32) or local (p = 0.17) recurrence, even after controlling local recurrence incidence for negative pathologic prognostic factors (p = 0.17). CONCLUSIONS: The natural history of B-MPT is burdened by local and distant recurrences. Pathologic prognostic factors (i.e., tumor size, heterologous differentiation and multifocal disease) more than the type of wide breast surgery (mastectomy vs. lumpectomy) seem to represent the most significant prognostic factor for recurrences.

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.

Targeting HER2 heterogeneity in breast and gastrointestinal cancers.

About 20% of breast and gastric cancers and 3% of colorectal carcinomas overexpress the human epidermal growth factor receptor 2 (HER2) and are sensitive to HER2-directed agents. The expression of HER2 may differ within the same tumoral lesion (spatial intralesional heterogeneity), from different tumor locations (spatial interlesional heterogeneity), and throughout treatments (temporal heterogeneity). Spatial and temporal heterogeneity may impact on response and resistance to HER2-targeting agents and its prevalence and predictive role changes across HER2-overexpressing solid tumors. Therefore, the definition and the characterization of HER2 heterogeneity pose many challenges and its implementation as a reproducible predictive biomarker would help in guiding treatment modulation.

Neoadjuvant therapy in hormone Receptor-Positive/HER2-Negative breast cancer.

Neoadjuvant therapy is commonly used in patients with locally advanced or inoperable breast cancer (BC). Neoadjuvant chemotherapy (NACT) represents an established treatment modality able to downstage tumours, facilitate breast-conserving surgery, yet also achieve considerable pathologic complete response (pCR) rates in HER2-positive and triple-negative BC. For patients with HR+/HER2- BC, the choice between NACT and neoadjuvant endocrine therapy (NET) is still based on clinical and pathological features and not guided by biomarkers of defined clinical utility, differently from the adjuvant setting where gene-expression signatures have been widely adopted to drive decision-making. In this review, we summarize the evidence supporting the choice of NACT vs NET in HR+/HER2- BC, discussing the issues surrounding clinical trial design and proper selection of patients for every treatment. It is time to question the binary paradigm of responder vs non-responders as well as the "one size fits all" approach in luminal BC, supporting the utilization of continuous endpoints and the adoption of tissue and plasma-based biomarkers at multiple timepoints. This will eventually unleash the full potential of neoadjuvant therapy which is to modulate patient treatment based on treatment sensitivity and surgical outcomes. We also reviewed the current landscape of neoadjuvant studies for HR+/HER2- BC, focusing on antibody-drug conjugates (ADCs) and immunotherapy combinations. Finally, we proposed a roadmap for future neoadjuvant approaches in HR+/HER2- BC, which should be based on a staggered biomarker-driven treatment selection aiming at impacting long-term relevant endpoints.

GRADE Concept 7: Issues and Insights Linking Guideline Recommendations to Trustworthy Essential Medicine Lists.

OBJECTIVES: Guidelines and essential medicine lists (EMLs) bear similarities and differences in the process that lead to decisions. Access to essential medicines is central to achieve universal health coverage. The World Health Organization (WHO) EML has guided prioritization of essential medicines globally for nearly 50 years, and national EMLs (NEMLs) exist in over 130 countries. Guideline and EML decisions, at WHO or national levels, are not always coordinated and aligned. We sought to explore challenges, and potential solutions, for decision-making to support trustworthy medicine selection for EMLs from a Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group perspective. We primarily focus on the WHO EML; however, our findings may be applicable to NEML decisions as well. STUDY DESIGN AND SETTING: We identified key challenges in connecting the EML to health guidelines by involving a broad group of stakeholders and assessing case studies including real applications to the WHO EML, South Africa NEML, and a multiple sclerosis guideline connected to a WHO EML application for multiple sclerosis treatments. To address challenges, we utilized the results of a survey and feedback from the stakeholders, and iteratively met as a project group. We drafted a conceptual framework of challenges and potential solutions. We presented a summary of the results for feedback to all attendees of the GRADE Working Group meetings in November 2022 (approximately 120 people) and in May 2023 (approximately 100 people) before finalizing the framework. RESULTS: We prioritized issues and insights/solutions that addressed the connections between the EML and health guidelines. Our suggested solutions include early planning alignment of guideline groups and EMLs, considering shared participation to strengthen linkage, further clarity on price/cost considerations, and using explicit shared criteria to make guideline and EML decisions. We also provide recommendations to strengthen the connection between WHO EML and NEMLs including through contextualization methods. CONCLUSION: This GRADE concept article, jointly developed by key stakeholders from the guidelines and EMLs field, identified key conceptual issues and potential solutions to support the continued advancement of trustworthy EMLs. Adopting structured decision criteria that can be linked to guideline recommendations bears the potential to advance health equity and gaps in availability of essential medicines within and between countries.

New horizons for platinum-resistant ovarian cancer: insights from the 2023 American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings.

Platinum-resistant ovarian cancer is difficult to treat and has a poor prognosis. Patients with platinum-resistant ovarian cancer have limited treatment options and often have a limited benefit from existing chemotherapeutic agents. There is a lack of contemporary effective anticancer drugs and reliable predictive biomarkers for this aggressive cancer. Recent cutting-edge research presented at the 2023 American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) Annual Meetings has provided insights into several potential therapeutic targets, such as DNA damage repair proteins, cell-cycle regulators, and immune-modulating agents. In addition, antibody-drug conjugates have provided new practice-changing results in platinum-resistant ovarian cancer. Here, we review the results of research presented at this annual event, with a focus on clinical trials investigating novel treatment approaches for platinum-resistant ovarian cancer, in addition to predictive and prognostic biomarkers for optimal patient selection, and other topics, such as real-world evidence.

Treatment optimization in early triple negative breast cancer.

INTRODUCTION: The treatment of early-stage triple-negative breast cancer (TNBC) has radically changed in recent years. Response to neoadjuvant treatment has provided prognostic information, and the achievement of a pathological complete response (pCR) is associated with improved prognosis. An exact treatment algorithm that embraces the trade-off of efficacy and toxicity in a risk-adapted manner has, however, not been consolidated. AREAS COVERED: In this review, we focused on the current treatments used for patients with early triple negative breast cancer, aiming at framing a therapeutic approach toward risk-adapted treatment optimization. We reviewed the clinical trials and other evidence at the foundation of the current clinical practice in early TNBC and identified possible areas of clinical implementation. EXPERT OPINION: In our opinion, treatment optimization will ensure improved patient-centric outcomes, with less toxicities, better long-term quality of life and risk-adapted treatment modulation. Presently, treatment modulation can be applied in some patients through de-intensification, for small TNBC, informed by novel biomarkers and based on the response to neoadjuvant treatments, especially in the case of pCR. Innovative approaches should incorporate baseline risk and cancer biology, treatment response, and post-surgery biomarkers of prognosis, to deliver risk-adapted treatments for patients with early TNBC.

Position paper of the Italian association of medical oncology on health disparities among transgender and gender-diverse people: the Assisi recommendations.

Transgender and gender-diverse individuals experience substantial health disparities across the cancer care continuum. Despite well recognized unique healthcare needs, there are barriers in accessing cancer prevention and treatment services, influenced by disadvantages in key social-economic determinants of health which result in worse clinical outcomes, as compared to the general population. The Italian Association of Medical Oncology (AIOM) acknowledges the critical relevance of this issue. The "Assisi Recommendations" here summarize the outcomes of the "AIOM Oncology Ethics Day" dedicated to gender differences in oncology and cancer care of transgender and gender-diverse people. The recommendations generated during a 2-day multidisciplinary discussion address the various aspects of cancer care experience of transgender and gender-diverse people. The promotion of research in this field, through the generation of new evidence and the collection of prospective data, has been identified as a priority action to mitigate these disparities. By acknowledging the challenges of cancer care in transgender and gender-diverse people and recognizing the need for dedicated policy and clinical recommendations, AIOM demonstrates its commitment to improving the health and well-being of all patients with cancer, regardless of their gender identity or any other personal or social circumstances, as part of health-for-all societal vision.

The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the "post-CDK4/6is" landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario.

Predicting Response to Antibody Drug Conjugates: A Focus on Antigens' Targetability.

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection.

There is no such a thing as a 'biological' basis for cancer disparities: A call to end misreporting of the ultimate determinants of health outcomes.

Improved strategies of cancer prevention and control have resulted in tangible benefits for patients with cancer. Disparities in outcome have been reported as a result of inequal access to health care. Historically, differences in health outcomes at population level have been reported according to key characteristics, including race, ethnicity and, more recently, ancestry. These population descriptors have been used to display the differences in the outcome and highlight actionable areas of health disparities, through policy and population health interventions. Yet, they have been commonly mis-intended as ultimate determinants of health outcomes, as recapitulating intrinsic biological differences. A plethora of past literature has described "biological" differences in patients belonging to a specific racial, ethnical or ancestral group, with certain cancers - commonly overlooking the social and economic contextures. The attention has ultimately focused on the existence of intrinsic differences and biological reasons, as opposed to social and economic determinants of disparities in the outcome in disadvantaged or excluded communities, thus nurturing double stigma. In our editorial, we evaluate some key roots of racial attitudes in displaying patient outcomes in oncology epidemiological studies, and call to report ultimate determinants of health - that are, primarily social and economic determinants.