Abstract Background: Dying cells play an important role in CD8+ T cell-mediated immunity. While apoptosis is mainly immunologically silent, necroptosis is immunogenic and can more efficiently initiate an adaptive immune response that could be augmented by immune checkpoint inhibition (ICI). Inhibitor of Apoptosis (IAP) proteins are key gatekeepers of how a cell dies, and frequently overexpressed in cancer. ASTX660 (tolinapant) is a triple blocker of cIAP1/2 and XIAP, sensitizing cancer cells to death ligands through ripoptosome formation, activating ‘danger’ co-stimulatory signals and dendritic cell (DC) maturation required to prime a potent antitumor response. Methods: We assessed the safety, pharmacodynamic (PD), and clinical activity of 7 days of oral ASTX660 given prior to pembrolizumab 200 mg (Q3W), in patients (pts) refractory to standard therapy. TITE-CRM was used to explore ASTX660 doses 90-180 mg. Serial paired blood and tumor samples were analyzed to interrogate the effect of ASTX660 on cell death, tumor microenvironment and host immune system. Results: 22 pts have been enrolled; median age 55 years (range 38-81); male:female 5:17; all ECOG PS ≤1; median 4.5 prior therapies. Tumor types included breast, head and neck (HN), hepatocellular, cervical, pancreatic and cholangiocarcinoma. Combination ASTX660-pembrolizumab is currently recruiting at highest dose 180 mg without any dose limiting toxicities (DLT) seen within the 6-week DLT observation period. Most common adverse events (AE) were G1-2 rash, nausea, and asymptomatic increases in amylase, lipase and transaminases; all reversible and easily manageable. Four iRECIST confirmed partial responses were seen in 10 efficacy evaluable pts treated at biologically active dose levels 120 and 150 mg (Overall response rate 40%), including 2 pts with ER+ HER2- breast cancer, 1 cervical adenocarcinoma pt (exceptional response following initial pseudoprogression) and a HN cancer pt refractory to ICI monotherapy. 3/4 responders are ongoing. Efficacy data from pts treated at highest dose level 180 mg is pending. FACS of paired blood samples from responders shows a significant rise in %CD57+/CD3+ cytotoxic effector T cells [mean 11.90% (pre-) vs 14.25% (post-ASTX660); p=.0176]. These changes were not seen in the non-responders group. Full PD from paired blood and tumour sampling will be shared at the meeting. Conclusion: ASTX660-pembrolizumab is is well-tolerated with durable antitumor responses in pts with immunologically cold tumors, providing the first clinical proof-of-concept of immunogenic cell death induction leading to effective adaptive immune response when combined with ICI. Recommended Phase 2 dose optimization and expansion cohorts in immunologically cold cancers are ongoing. Citation Format: Crescens Tiu, Wing Yau, Victoria Sanchez-Perez, Giovanni Codacci-Pisanelli, Ching Leung, Eden S. Andrews, Bristi Basu, Anna Zachariou, Toby Prout, Mona Parmar, Alison Turner, Xiaoran Lai, Zhulin Yin, Karen E. Swales, Syed Haider, Thomas Lund, Diego C. Dos Reis, Tatiany L. Silveira, Alan S. Dunlop, Ann-Marie Baker, Bora Gurel, Ana Ferreira, Claudia Bertan, Nina Tunariu, Edward W. Johnston, Alistair Ring, Tencho Tenev, Tomoko Smyth, Simone Jueliger, Udai Banerji, Johann S. de Bono, Alec Paschalis, Adam Sharp, Anna Minchom, Christina Yap, Pascal Meier, Juanita S. Lopez. Proof-of-concept and preliminary efficacy of triple IAP blockade to maximize immunogenic cell death and induce efficient adaptive immune response: First report on the ASTEROID phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT035.

Background: Cancer cases diagnosed each year are increasing, mainly because the population is ageing and, in part, due to early detection. This implies that there are more and more persons that receive medical anticancer therapies and that are interested in maintaining their quality of life. Many oncological treatments, including chemotherapy, immunotherapy, surgery, and radiotherapy, and combined therapy are associated with cutaneous toxicity and long-term side effects to different tissues and organs. This is particularly relevant when new therapies are used since these may cause new and unexpected side effects that may be short-lived but, in some cases, may become chronic or permanent. Patients often seek advice with their oncologists on what can be done and what cannot be done. Notably, many of the cutaneous side effects can be prevented or reduced by adequate interventions. Summary: The aim of this review is to highlight how oncological patients may benefit from a closer collaboration between specialists in different branches. We will focus on women with breast cancer since we think that they may derive a special benefit from this collaboration, but we will analyse other cancers in future papers. Key Messages: The working group was created to help the medical doctor in the prevention and management of all the adverse effects of the oncological treatments, supporting patients in this phase of their life, including nutritional assessment and dietary support.

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions-notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval-and the role of real-world evidence in the process-and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework-starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients.

a Experimental Oncology, Istituto Tumori G. Paolo II, IRCCS, Bari, Italy; b Department of Medical and Surgical Sciences and Biotechnology, University of Rome la Sapienza, Latina, Italy; c Division of Medical Senology, European Institute of Oncology, IRCCS, Milan, Italy; d Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA; e Medical Oncology Department, Centre Léon-Bérard, Lyon, France Received: September 8, 2021 Accepted: September 10, 2021 Published online: September 29, 2021

Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALKinhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients.

Pregnancy and lactation represent the most effective protective elements against breast cancer; counter-intuitively breast cancer incidence shows a small but noticeable increase up to 5 years after delivery. The cumulative effect is however favourable and women show a reduction in breast cancer risk which is proportional to the total duration of lactation and to the number of full-term pregnancies.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues – notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe’s fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.

Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions. One of the paradigmatic examples is BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, development is impeded by data deficiencies, and lack of policy alignment on standards, approval – and the role of real-world evidence in the process - and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework – starting with an update to outdated recommendations.

Recent advances in biomedicine are opening the door to new approaches, and treatment and prevention are being transformed by novel medicines based on genetic engineering, innovative cell-based therapies and tissue-engineered products, and combinations of a medical device with embedded cell or tissue components. These advanced therapy medicinal products (ATMPs) hold one of the keys to making a reality of genuinely personalised medicine. There are an estimated 450 companies across the globe working on the development of gene therapies and more than 1,000 clinical trials underway worldwide, and some 20–30 new ATMPs filings are expected in Europe annually over the next 5 years. But challenges confront the sector, complicating the translation from research into patient access. Scientific, clinical development and regulatory issues are compounded by limited experience with clinical and commercial use, limited manufacturing know-how, high costs, and difficulties in accessing development funding and investment. Pricing and reimbursement and market access issues are an additional challenge, particularly in Europe, where unfamiliarity with the technology and uncertainty over the use of real-world evidence induce caution among clinicians, health technology assessment bodies and payers. There is a need for a review of the suitability of the regulatory and market access framework for these products, focused development of data, public/private partnerships, and fuller collaboration governments, doctors, insurers, patients, and pharmaceutical companies. This paper makes specific recommendations for all stakeholders, ranging from early dialogue on potential products, linking of clinical data and patient registries or standardisation of control frameworks, to a comprehensive approach to evidence generation, assessment, pricing, and payment for ATMPs.

Breastfeeding is an important aspect of mother-newborn relationship and is of great benefit for the baby. Unfortunately, many drugs taken by the mother may pass into her milk and exert an effect on the newborn. Very limited data is available and a cautionary approach is warranted especially when the woman receives anticancer treatment including chemotherapy , hormonal treatment and the recently introduced target agents as well as monoclonal antibodies. In all these conditions breastfeeding should be put on hold.More and more often physicians are faced with women that are pregnant years after the diagnosis of cancer: this has long been considered dangerous for the mother, but data show that prognosis is definitely not worse. If the woman is no longer being actively treated, breastfeeding is advisable every time it is possible, even if patients that received breast radiation may be unable to produce a sufficient amount of milk on that side.

Background Breast cancer represents the most frequent neoplasm diagnosed in women of childbearing age. When the tumour is oestrogen receptor-positive, tamoxifen is among the recommended endocrine treatments. Lactating women are advised not to breastfeed while receiving tamoxifen. However, information about tamoxifen transfer into breast milk is lacking. Methods We measured the concentration of tamoxifen and its metabolites by liquid chromatography-tandem mass spectrometry in the milk of a nursing mother that was treated for pregnancy-associated breast cancer diagnosed a few months after delivery. She was advised not to breastfeed her child and she collected milk samples for 23 days while the baby was fed with formula. Results Tamoxifen concentrations in milk increased reaching a maximum of 214 nM. The two active metabolitesZ-4-hydroxy-tamoxifen and Z-endoxifen, could not be quantified in milk the first days after tamoxifen intake, but increased over time and reached clinically significant levels after day 18. Conclusion This study demonstrates for the first time in human that tamoxifen and its metabolites transfer into milk. Since tamoxifen has a complete oral bioavailability, a long half-life (>7 days) and may interfere with the normal development of the infant, mothers should not breastfeed during tamoxifen treatment.

We compared 2-[fluorine-18] fluoro-2-deoxy-D-glucose PET-CT and contrast-enhanced computed tomography (CECT) in 62 consecutive patients with newly diagnosed Hodgkin Lymphoma (HL), aiming to provide evidences that may spare CECT from the staging procedures of HL patients. Among a total of 1448 nodal sites examined, disease involvement was detected in 232 (16%) and 280 (19.3%) nodal areas by CECT and PET-CT, respectively (P < 0.01). Sensitivity of CECT in detecting disease involvement ranged from 0% for internal mammary region (7 cases) and Waldayer's ring (1 case) to 100% for mediastinum. A total of 248 extranodal areas were examined. CECT and PET-CT identified disease involvement in 19 (7.7%) and 25 (10.1%) extranodal areas, respectively (P=n.s). Compared to PET-CT, CECT detected a lower number of cases with bone and/or bone marrow involvement (P=0.05), whereas no differences were detected at the level of lung. By contrast, CECT identified liver lesions in four patients versus three identified by PET-CT. In comparison to CECT, PET-CT upstaged 6 patients (9.7%) and downstaged 1 patient (1.6%). We showed that PET-CT modified treatment strategy in five (8.1%) cases not only as a result of stage advancement (2 cases) but also of a different prognostic stratification in patients with localized disease (3 cases), due to the better sensitivity in detecting nodal involvement. In conclusion, our data, confirm the superiority of PET-CT in detecting disease involvement at diagnosis of HL, and further supports the possibility to replace CECT with PET-CT in the initial staging of HL.

Any disease occurring in pregnancy creates a dilemma of treating the patient but causing potential harm to the unborn child. 1 Lancet HaematologyTo treat, or not to treat: the dilemma for pregnant women. Lancet Haematol. 2018; 6: e58 Summary Full Text Full Text PDF Scopus (1) Google Scholar In the Lancet Haematology, Charlotte Maggen and colleagues 2 Maggen C Dierickx D Lugtenburg P et al. Obstetric and maternal outcomes in patients diagnosed with Hodgkin lymphoma during pregnancy: a multicentre, retrospective cohort study. Lancet Haematol. 2019; (published online Sept 26)https://doi.org/10.1016/S2352-3026(19)30195-4 Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar describe the findings from their retrospective cohort study, which suggest that women diagnosed with Hodgkin lymphoma during pregnancy can be successfully treated during pregnancy with no harm to the unborn child. Obstetric and maternal outcomes in patients diagnosed with Hodgkin lymphoma during pregnancy: a multicentre, retrospective, cohort studyOccurrence of preterm contractions or preterm rupture of membranes was higher in patients with Hodgkin lymphoma receiving antenatal treatment compared with those who did not initiate treatment during pregnancy. Maternal survival did not differ between pregnant and non-pregnant patients with Hodgkin lymphoma, suggesting that antenatal chemotherapy or deferral of treatment until postpartum in selected patients can be considered, with regular obstetric follow-up to safeguard foetal growth. Full-Text PDF

Should we rename low risk cancers?1 Words will not solve our problems, but they may help. Cancer has been defined as “the emperor of all maladies” and its name raises panic, which is by definition irrational and, as stated in …

•The possibility that hormonal contraception may increase cancer risk is a relevant topic for fertile women.•Recent papers showed a statistically significant increase in breast cancer even with “modern” low-dose formulations.•It is important to note that this increase was numerically very small.•Hormonal contraception is associated with a reduction in ovarian cancer and considering the global risks and benefits the balance is favourable.•Counselling may be the optimal circumstance to encourage the woman to adopt life style habits that may reduce cancer risk.

Treatment of cancer during pregnancy has been extensively studied, but few data are available about the management of women with cancer diagnosed during breastfeeding.

The possibility that the use of hormonal contraceptives may increase the risk of breast cancer has been raised since many years. In the past this hypothesis has been dismissed on the basis that available data were generally derived from "old" studies in which relatively high hormone doses had been used. The recent publication of two studies that analysed data from women receiving low-dose hormonal contraception and showed a statistically significant increase in breast cancer contradicts this reassuring belief. The topic however is not settled, since different results were obtained in other studies and since hormonal contraception (HC) also has unquestionable positive effects such as a decrease in ovarian and in endometrial cancer. The aim of the present paper is to provide evidence that may help gynaecologists and oncologists in discussing with their patients the use of HC. Even if cancer phobia is a strong reason for not using or limiting HC, patients must be informed that notwithstanding the slightly increased breast cancer risk, the overall cancer risk may still be lower than non-users. Proper counselling may help the woman choose the most suitable contraception in the different phases of her life and on the basis of other conditions that may increase cancer risk such as overweight, smoking or family history.