• Contemporary breast cancer treatment-associated thrombosis

  Kirwan, Cliona C; Blower, Emma L; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, University of Manchester, United Kingdom of Great Britain and Northern Ireland (2022)

  Although cancer-associated thrombosis (CAT) is relatively uncommon in breast cancer compared to other solid cancers, as breast cancer is the most commonly diagnosed cancer in women worldwide, the financial and per sonal cost of breast cancer associated thrombosis (BrCAT) is significant. This increasing risk of BrCAT over time parallels modern developments in breast cancer management. This review comprehensively reports the evidence for BrCAT in the context of modern breast cancer treatments. The risk of BrCAT is most pronounced within the first 3 months to year of diagnosis. The risk of BrCAT in creases with operating time, paralleling the increasing frequency of immediate breast reconstruction. Systemic therapies such as chemotherapy and tamoxifen have well recognised thrombogenic effects, that are exacerbated by surgery and supplementary treatments such as colony-stimulating factors, steroids, and bisphosphonates however risk assessment tools are not designed specifically for this lower-VTE risk cancer. Cyclin-dependent kinases 4 and 6 (CDK4/6) Inhibitors, used in metastatic breast cancer, with trials ongoing in early disease, appear to have a class thrombogenic effect, although there is no increase CAT risk with other breast cancer targeted therapies. Given the numerous prothrombotic treatments facing patients within the first year of diagnosis, from surgery, chemotherapy, targeted therapies and endocrine therapy, a more personalised approach considering the additive effects of each individual patient’s pathway, as well as their pre-existing risk factors, needs to be considered.
• E-cadherin loss cooperates with ras(Ha) activation to drive malignant progression in transgenic mouse skin carcinogenesis

  Zaweia, R.; McMenemy, Carol; Quinn, J.; Greenhalgh, D.; Glasgow University, Glasgow, UK (2022)

  To investigate the stage at which E-cadherin loss may drive carcinogenesis, E-cadherin expression has been investigated in mouse skin carcinogenesis driven by ras and fos activation (HK1.ras; HK1.fos), and conditional (cre/lox) PTEN knockout exclusively in the epidermis. Analysis of endogenous E-cadherin expression in stage-specific HK1.ras/fos/Δ5PTEN tumours found increased levels in papilloma basal layer keratinocytes, but following p53 loss and subsequent malignant conversion, E-cadherin expression became reduced at the invasive front of resultant, well-differentiated, squamous cell carcinomas (wdSCCs). To validate the causality of this E-cadherin loss observed in malignant progression, RU486-inducible, conditional E-cadherin knockout was introduced into regression-prone papillomas exhibited by HK1.ras mice, employing the cre/LoxP system (K14cre.ΔE-cadflx/flx). Initial observations in RU486-treated K14cre.ΔE-cadflx/flx mice found that E-cadherin ablation induced a mild hyperplasia, with some altered differentiation in basal layer and follicular keratinocytes but no tumours. In contrast, while E-cadherin loss in HK1.ras.K14cre.ΔE-cadflx/flx mice did not appear to alter HK1.ras-mediated papillomatogenesis, malignant conversion was now observed and, moreover, subsequent wdSCCs showed a rapid progression to aggressive SCC. Further analysis found that malignant conversion was associated with p53 loss, while malignant progression also implicated β-catenin activation; increased nuclear expression appeared in the invasive basal layer keratinocytes. The SCC aetiology also suggested the mechanism of tumour invasion may involve an early collective mode and later, in cooperation with β-catenin activation, this progressed to a more aggressive mode of individual cell invasion. Collectively, these data show that conditional ablation of E-cadherin cooperates with rasHa activation and p53 loss at later stages following malignant conversion of papillomas, to induce a rapid tumour progression due to cell–cell adhesion failures and β-catenin signalling.
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  Topical treatment of actinic keratoses in organ transplant recipients: a feasibility study for SPOT (Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments)

  Zeeshaan-Ul, H.; Ahmed, I.; Matin, R. N.; Homer, V.; Lear, J. T.; Ismail, F.; Whitmarsh, T.; Green, Adèle C; Thomson, J.; Milligan, A.; et al. (2022)

  Background: The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. Objectives: To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. Methods: OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. Results: Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. Conclusions: Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials.
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  Stillbirth due to SARS-CoV-2 placentitis without evidence of intrauterine transmission to fetus: association with maternal risk factors

  Konstantinidou, A. E.; Angelidou, S.; Havaki, S.; Paparizou, K.; Spanakis, N.; Chatzakis, C.; Sotiriadis, A.; Theodora, M.; Donoudis, C.; Daponte, A.; et al. (2022)

  Objectives: To describe the placental pathology, fetal autopsy findings and clinical characteristics of pregnancies that resulted in stillbirth owing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, and to identify potential risk factors. Methods: This was a prospective multicenter study of non-vaccinated pregnant women affected by coronavirus disease 2019 (COVID-19) in Greece from April 2020 to August 2021. A total of 165 placentas were examined histologically and six cases of stillbirth associated with SARS-CoV-2 placentitis were retrieved. Complete fetal autopsy was performed in three of these cases. Gross, histopathological, immunohistochemical, molecular and electron microscopy examinations were carried out in the stillbirth placentas and fetal organs. The histological findings of cases with SARS-CoV-2 placentitis were compared with those in 159 cases with maternal COVID-19 which resulted in a live birth. Regression analysis was used to identify predisposing risk factors for SARS-CoV-2 placentitis. Results: The placentas of all six stillborn cases showed severe and extensive histological changes typical of SARS-CoV-2 placentitis, characterized by a combination of marked intervillositis with a mixed inflammatory infiltrate and massive perivillous fibrinoid deposition with trophoblast damage, associated with intensely positive immunostaining for SARS-CoV-2 spike protein, the presence of virions on electron microscopy and positive reverse-transcription polymerase chain reaction test of placental tissues. The histological lesions obliterated over 75% of the maternal intervillous space, accounting for intrauterine fetal death. Similar histological lesions affecting less than 25% of the placenta were observed in seven liveborn neonates, while the remaining 152 placentas of COVID-19-affected pregnancies with a live birth did not show these findings. Complete fetal autopsy showed evidence of an asphyctic mode of death without evidence of viral transmission to the fetus. The mothers had mild clinical symptoms or were asymptomatic, and the interval between maternal COVID-19 diagnosis and fetal death ranged from 3 to 15 days. Statistically significant predisposing factors for SARS-CoV-2 placentitis included thrombophilia and prenatally diagnosed fetal growth restriction (FGR). Multiple sclerosis was seen in one case. Conclusions: SARS-CoV-2 placentitis occurred uncommonly in COVID-19-affected pregnancies of non-vaccinated mothers and, when extensive, caused fetal demise, with no evidence of transplacental fetal infection. Thrombophilia and prenatally detected FGR emerged as independent predisposing factors for the potentially lethal SARS-CoV-2 placentitis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.
• VIOLETTE: Randomised phase II study of olaparib (ola) plus ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

  Tutt, A.; Nowecki, Z.; Szoszkiewicz, R.; Im, S. A.; Arkenau, H. T.; Armstrong, Anne C; Jacot, W.; Kim, J. H.; Webster, M.; Balmana, J.; et al. (2022)

  Background: Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 in- hibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola cer or ada as 2nde3rd line in pts with mTNBC. Methods: Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1e7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1e3, 8e10 + ola 200 mg BID (ada+ola), 21- d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade 3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data. Results: Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n¼83; HR 1.02 [90% CI 0.63e1.66, P¼0.94], HRRm: n¼40; 0.54 [0.28e1.03, 0.13], non-HRRm: n¼103; 0.76 [0.50e1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n¼8) vs ola (4%, n¼2) (odds ratio 4.45; 90% CI 1.30e21.20, P¼0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade 3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented. Conclusions: Cer+ola did not improve PFS vs ola as 2nde3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.

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