Patient-derived Xenografts Reveal that Intraductal Carcinoma of the Prostate Is a Prominent Pathology in BRCA2 Mutation Carriers with Prostate Cancer and Correlates with Poor Prognosis

Risbridger, Gail P.; Taylor, Renea A.; Clouston, David; Sliwinski, Ania; Thorne, Heather; Hunter, Sally M.; Li, Jason; Mitchell, Gillian; Murphy, Declan; Frydenberg, Mark; Pook, David; Pedersen, John; Toivanen, Roxanne; Wang, Hong; Papargiris, Melissa; Lawrence, Mitchell G.; Bolton, Damien

doi:10.1016/j.eururo.2014.08.007

Cited by 122 publications

(104 citation statements)

References 30 publications

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“…The median serum PSA was 328 ng/ml (range 4.18-10 992 ng/ml). The median-submitted number of cores was six (mean 7.3, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and the median number of cancer-positive cores was six (mean 5.8, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Intraductal carcinoma of the prostate was detected in 100 (67%) patients, six with PSA levels o 20 ng/ml and the remaining 94 with PSA levels 420 ng/ml.…”

Section: Resultsmentioning

confidence: 99%

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The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation

et al. 2016

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Intraductal carcinoma of the prostate is an adverse prognostic factor in localized prostate cancer patients. However, whether it influences outcome of those patients with distant metastases discovered at initial diagnosis is unclear. Here, we evaluated whether the presence of intraductal carcinoma of the prostate in prostate needle biopsies is an adverse prognostic factor for cancer-specific survival and overall survival in such prostate cancer patients. We retrospectively enrolled 150 eligible patients. All patients received androgen-deprivation therapy and/or chemotherapy. Their age, performance status, pain, metastatic sites, clinical T stage, serum prostatespecific antigen, alkaline phosphatase, hemoglobin, Gleason score, and the presence of Gleason pattern 5 were analyzed. Primary end point was cancer-specific survival; secondary end points included prostate-specific antigen progression-free survival and overall survival. Fine and Gray's model and the Cox proportional hazards model were used as statistical tests. Intraductal carcinoma of the prostate was detected in 100 (67%) patients. At a median follow-up of 38 months, 79 patients (53%) had died of the disease and nine (6%) had died of other causes. The average time interval to cancer-related death was 28 months. On multivariate analysis, only intraductal carcinoma of the prostate was significantly associated with cancer-specific survival (P = 0.018) and overall survival (P = 0.001), and only the presence of Gleason pattern 5 was significantly associated with prostate-specific antigen progression-free survival (P = 0.026). The presence of intraductal carcinoma of the prostate was the only significant prognostic parameter for cancer-specific survival and overall survival in prostate cancer patients with distant metastasis at presentation. These results may prove useful in planning future treatments.

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Section: Resultsmentioning

confidence: 99%

“…7,12 The latest reports demonstrated that BRCA2 mutations and PTEN loss were related to intraductal carcinoma of the prostate. 13,14 Lindberg et al 15 demonstrated that prostate cancer metastasis originated from a clone derived from intraductal carcinoma of the prostate in the primary tumor.…”

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confidence: 99%

The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation

et al. 2016

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“…Review of the only available case of breast cancer in a CDH1 mutation carrier showed the carcinoma had mixed ductal and lobular features, with reduced and aberrant staining for E-cadherin in the lobular regions. Only two of the six TP53 families (families 74 and 76) fulfilled the criteria for Li and both cases showed high grade, Gleason score 9 carcinoma, and one case had IDC-P. Interestingly, these three tumours resemble prostatic adeonocarcinomas from men with germline mutations of BRCA2, which are associated with poor survival rates, 33 and suggest that further analysis of TP53 mutation status, as well as histopathology and survival analyses, would be warranted in prostatic adenocarcinoma. We identified three families with rare, evolutionarily unlikely missense mutations in the FAT or kinase domains of ATM ( p. Ala2274Thr, p.Asp2720His and p.Val2424Gly), which are predicted to confer increased risks of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families

Meeks

Feng

et al. 2015

J Med Genet

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Introduction Gene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown. Methods We performed custom-designed targeted sequencing covering the coding exons of 17 known and putative breast cancer susceptibility genes in 660 non-BRCA1/2 women with familial breast cancer. Putative deleterious mutations were genotyped in relevant family members to assess co-segregation of each variant with disease. We used maximum likelihood models to estimate the breast cancer risks associated with mutations in each of the genes. Results We found 31 putative deleterious mutations in 7 known breast cancer susceptibility genes (TP53, PALB2, ATM, CHEK2, CDH1, PTEN and STK11) in 45 cases, and 22 potential deleterious mutations in 31 cases in 8 other genes (BARD1, BRIP1, MRE11, NBN, RAD50, RAD51C, RAD51D and CDK4). The relevant variants were then genotyped in 558 family members. Assuming a constant relative risk of breast cancer across age groups, only variants in CDH1, CHEK2, PALB2 and TP53 showed evidence of a significantly increased risk of breast cancer, with some supportive evidence that mutations in ATM confer moderate risk. Conclusions Panel testing for these breast cancer families provided additional relevant clinical information for <2% of families. We demonstrated that segregation analysis has some potential to help estimate the breast cancer risks associated with mutations in breast cancer susceptibility genes, but very large case–control sequencing studies and/or larger family-based studies will be needed to define the risks more accurately.

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“…Only four patients were used, but the phenotype of BRCA2 PDXs was consistent and strikingly different to ageand stage-matched sporadic prostate cancer cases. In particular, in BRCA2 PDXs, we observed a specific and predominant pathology known as intraductal carcinoma of the prostate (IDC-P) [32]. IDC-P is a distinct pathological entity that is associated with an aggressive prostate cancer phenotype that predicts poor treatment response [33,34].…”

Section: Identification Of High-risk Features In Familial Prostate Camentioning

confidence: 96%

Patient-Derived Prostate Cancer: from Basic Science to the Clinic

Risbridger

Taylor

2016

HORM CANC

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Systems that model cancer form the backbone of research discovery, and their accuracy and validity are a key determinant to ensure successful translation. In many tumour types, patient-derived specimens are an important model of choice for pre-clinical drug development. In this review, we consider why this has been such a challenge for prostate cancer, resulting in relatively few patient-derived xenografts (PDXs) of prostatic tumours compared to breast cancers, for example. Nevertheless, with only a few patient specimens and PDXs, we exemplify in three vignettes how important new clinical insights were obtained resulting in benefit for future men with prostate cancer.

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Patient-derived Xenografts Reveal that Intraductal Carcinoma of the Prostate Is a Prominent Pathology in BRCA2 Mutation Carriers with Prostate Cancer and Correlates with Poor Prognosis

Cited by 122 publications

References 30 publications

The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation

The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation

Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families

Patient-Derived Prostate Cancer: from Basic Science to the Clinic

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