Genomic Features of Lung-Recurrent Hormone-Sensitive Prostate Cancer

Abstract

PURPOSE Pulmonary involvement is rare in metastatic hormone-sensitive prostate cancer (mHSPC) that recurs after treatment for localized disease. Guidelines recommend intensive systemic therapy, similar to patients with liver metastases, but some lung-recurrent mHSPC may have good outcomes. Genomic features of lung metastases may clarify disease aggression, but are poorly understood since lung biopsy is rarely performed. We present a comparative assessment of genomic drivers and heterogeneity in metachronous prostate tumors and lung metastases. METHODS We leveraged a prospective functional imaging study of 208 biochemically recurrent prostate cancers to identify 10 patients with lung-recurrent mHSPC. Histologic diagnosis was attained via thoracic surgery or fine-needle lung biopsy. We retrieved clinical data and performed multiregion sampling of primary tumors and metastases. Targeted and/or whole-exome sequencing was applied to 46 primary and 32 metastatic foci. RESULTS Unusually for mHSPC, all patients remained alive despite a median follow-up of 11.5 years. Several patients experienced long-term freedom from systemic treatment. The genomic landscape of lung-recurrent mHSPC was typical of curable prostate cancer with frequent PTEN, SPOP, and chromosome 8p alterations, and there were no deleterious TP53 and DNA damage repair gene mutations that characterize aggressive prostate cancer. Despite a long median time to recurrence (76.8 months), copy number alterations and clonal mutations were highly conserved between metastatic and primary foci, consistent with intrapatient homogeneity and limited genomic evolution. CONCLUSION In this retrospective hypothesis-generating study, we observed indolent genomic etiology in selected lung-recurrent mHSPC, cautioning against grouping these patients together with liver or bone-predominant mHSPC. Although our data do not generalize to all patients with lung metastases, the results encourage prospective efforts to stratify lung-recurrent mHSPC by genomic features.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer

“…14,15,16 Additionally, studies have shown that underlying biology could be more important analysis is muddled by the aggregation of "visceral" disease even though the biology and prognosis of these sites may differ depending on sites of metastasis. 19…”

“…Missing information on some variables such as tumor stage or M‐Stage at presentation should be noted. Further, our analysis is muddled by the aggregation of “visceral” disease even though the biology and prognosis of these sites may differ depending on sites of metastasis 19 …”

A case of repeat oligoprogressive castration‐resistant prostate cancer treated with pulmonary metastasectomy

“…Fonseca et al. reported the results of an analysis of 10 cases of metastatic castration‐sensitive prostate cancer that recurred after radical treatment, in which biopsy or resection of the lung metastases was performed 10 . They found that recurrent lung metastases did not contain the deleterious mutations in TP53 and DNA damage‐repair genes that characterize aggressive cancer, and that copy number changes and clonal mutations were highly conserved between metastases and primary lesions.…”

“…Fonseca et al reported the results of an analysis of 10 cases of metastatic castration-sensitive prostate cancer that recurred after radical treatment, in which biopsy or resection of the lung metastases was performed. 10 They found that recurrent lung metastases did not contain the deleterious mutations in TP53 and DNA damage-repair genes that characterize aggressive cancer, and that copy number changes and clonal mutations were highly conserved between metastases and primary lesions. This report suggests that selected metastatic castration-sensitive prostate cancer with recurrence in the lung may have different biological features than metastatic cancers with aggressive features, although these patients were carefully selected based on their clinical course and underwent biopsy or resection for lung metastases.…”

Prostate Cancer Lung Metastasis: Clinical Insights and Therapeutic Strategies

“…Historically, the genomic features of lung metastasis were poorly explored in the literature apart from two case series that investigated the genomics of lung metastasis on metastatic hormone sensitive PCa (mHSPC) patients [56,60]. Shenderoev et al identified 16 mHSPC patients with plenty of variations in mismatch repair (MMR) genes, homologous recombination deficit (HRD) genes, PI3K pathway genes, Wnt signaling pathway genes, and TP53 mutations [56].…”