Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Peer reviewe

Disseminated Primary Uterine Hepatoid Adenocarcinoma with α-Fetoprotein Production Demonstrated on 18F-FDG PET/CT

We present the 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) findings in a 57-year-old woman with post-menopausal bleeding diagnosed with hepatoid adenocarcinoma (HAC) with a primary tumour in the uterine corpus and a highly elevated level of serum-α-fetoprotein (S-AFP) at presentation. HAC is a variant of adenocarcinoma with hepatic differentiation representing a heterogeneous group of neoplasms that morphologically and immunphenotypically resemble hepatocellular carcinoma (HCC) but are of extrahepatic origin. Microscopically, they are usually poorly differentiated adenocarcinomas proliferating in solid sheets or in a trabecular or cord-like arrangement. Primary uterine HAC is exceedingly rare with a general poor prognosis, and data is sparse and limited to case reports, making the clinical management challenging. Various primary anatomical sites have been reported in the literature, with the stomach being the most common primary site. 18F-FDG PET/CT plays an important role in staging and follow-up in many gynecological malignancies including uterine corpus cancer. To the best of our knowledge, this is the first report describing a primary uterine hepatoid adenocarcinoma with metastases to bone, vagina and lymph nodes on 18F-FDG PET/CT. By utilizing the ability of PET to detect early metabolic changes prior to visible structural changes on conventional imaging, this case illustrates a potential role of 18FDG-PET/CT in the staging of primary endometrial HAC by depicting distant metastasis that is not readily identifiable on CT alone

¹⁸F FDG PET/ CT for planning external beam radiotherapy alters therapy in 11% of 581 patients

Background: 18F-FDG PET/CT (FDG PET/CT) used in radiotherapy planning for extra-cerebral malignancy may reveal metastases to distant sites that may affect the choice of therapy. Aim: To investigate the role of FDG PET/CT on treatment strategy changes induced by the use of PET/CT as part of the radiotherapy planning. ‘A major change of treatment strategy’ was defined as either including more lesions in the gross tumour volume (GTV) distant from the primary tumour or a change in treatment modalities. Methods: The study includes 581 consecutive patients who underwent an FDG PET/CT scan for radiotherapy planning in our institution in the year 2008. All PET/CT scans were performed with the patient in treatment position with the use of immobilization devices according to the intended radiotherapy treatment. All scans were evaluated by a nuclear medicine physician together with a radiologist to delineate PET-positive GTV (GTV-PET). Results: For 63 of the patients (11%), the PET/CT simulation scans resulted in a major change in treatment strategy because of the additional diagnostic information. Changes were most frequently observed in patients with lung cancer (20%) or upper gastrointestinal cancer (12%). In 65% of the patients for whom the PET/CT simulation scan revealed unexpected dissemination, radiotherapy was given – changed (n = 38) or unchanged (n = 13) according to the findings on the FDG PET/CT. Conclusion: Unexpected dissemination on the FDG PET/CT scanning performed for radiotherapy planning caused a change in treatment strategy in 11% of 581 patients

Prospective Assessment of Fluorine-18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) for Early Identification of Checkpoint-Inhibitor-Induced Pseudoprogression

The activity of immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma is often monitored using fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans. However, distinguishing disease progression (PD) from pseudoprogression (PsPD), where increased FDG uptake might reflect immune cell activity rather than tumor growth, remains a challenge. This prospective study compared the efficacy of dual-time point (DTP) FDG-PET/CT with modified response criteria (PERCIMT) in differentiating PsPD from PD. From July 2017–January 2021, 41 patients suspected to have PsPD on an evaluation scan were prospectively included (29 evaluable). A subsequent DTP FDG-PET/CT scan was conducted within 14 days, followed by a confirmatory FDG-PET/CT scan. Additionally, PERCIMT were applied. DTP FDG-PET/CT identified 24% with PsPD and 76% with PD. Applying PERCIMT criteria, 69% showed PsPD, while 31% had PD. On follow-up, 10 patients (34%) demonstrated confirmed PsPD, while 19 (66%) exhibited PD. The sensitivity and specificity of DTP FDG-PET/CT were 20% and 74%, respectively, and for PERCIMT this was 80% and 37%, respectively. Our findings suggest limited efficacy of DTP FDG-PET/CT in distinguishing PsPD from PD in ICI-treated patients with metastatic melanoma. The use of PERCIMT could complement clinical assessment and be incorporated in multidisciplinary team conferences for enhanced decision-making

Exploring the hereditary background of renal cancer in Denmark.

BackgroundEvery year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition.MethodsThe cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue.ResultsOne start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B.ConclusionAlthough we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy

OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT