Prostate Cancer

Background

With the onset of precision oncology, findings from germline mutational analysis have been helpful in treating patients with cancer and aids in cancer prevention, early detection, and improved overall outcomes. Germline genetic testing is now part of the standard of care for certain types of patients with prostate cancer. There is a very limited body of work that investigated demographic, disease- related and social factors that may be influencing Veterans’ participation in germline genetic testing. This study helps to identify whether certain factors may be influencing decisions on participation in prostate germline testing among Veterans with prostate malignancy.

Methods

The study was conducted using retrospective chart review. Data was collected from the periods of August 1, 2022 to December 31, 2023 among Veterans with prostate cancer who met criteria for germline genetic testing. Demographic and clinical information were collected including age, race, extent of disease (high risk, very high-risk or metastatic disease), significant co-morbidities, educational level, family and personal history of cancer, travel time, germline genetic test findings, impact on treatment approaches, referral for genetic counseling, and whether Veterans agreed or declined germline genetic testing. Data was analyzed using descriptive statistics. A total of 180 charts were reviewed, with 171 meeting the criteria for inclusion. The mean age of the participants is 73, with the youngest being 55 and the oldest being 101 years old. Majority of the participants were African American (77%).

Results

Only about two percent of those who met the inclusion criteria declined to undergo testing with the one living the farthest away from the testing hospital residing 18 miles away. Those who declined testing ranged in age from 67 to 88, majority had high risk prostate cancer and no family history of malignancy, and had 0-1 serious co-morbidity. None of their educational informational was available for review.

Conclusions

Participation in germline genetic testing can be enhanced with adequate patient education and availability of accessible resources, even among patient populations that are not always well-represented in clinical research. The presence of multiple serious co-morbidities and distance from a testing facility do not seem to contribute to hesitancy in germline genetic testing participation.

Background

With the onset of precision oncology, findings from germline mutational analysis have been helpful in treating patients with cancer and aids in cancer prevention, early detection, and improved overall outcomes. Germline genetic testing is now part of the standard of care for certain types of patients with prostate cancer. There is a very limited body of work that investigated demographic, disease- related and social factors that may be influencing Veterans’ participation in germline genetic testing. This study helps to identify whether certain factors may be influencing decisions on participation in prostate germline testing among Veterans with prostate malignancy.

Methods

The study was conducted using retrospective chart review. Data was collected from the periods of August 1, 2022 to December 31, 2023 among Veterans with prostate cancer who met criteria for germline genetic testing. Demographic and clinical information were collected including age, race, extent of disease (high risk, very high-risk or metastatic disease), significant co-morbidities, educational level, family and personal history of cancer, travel time, germline genetic test findings, impact on treatment approaches, referral for genetic counseling, and whether Veterans agreed or declined germline genetic testing. Data was analyzed using descriptive statistics. A total of 180 charts were reviewed, with 171 meeting the criteria for inclusion. The mean age of the participants is 73, with the youngest being 55 and the oldest being 101 years old. Majority of the participants were African American (77%).

Results

Only about two percent of those who met the inclusion criteria declined to undergo testing with the one living the farthest away from the testing hospital residing 18 miles away. Those who declined testing ranged in age from 67 to 88, majority had high risk prostate cancer and no family history of malignancy, and had 0-1 serious co-morbidity. None of their educational informational was available for review.

Conclusions

Participation in germline genetic testing can be enhanced with adequate patient education and availability of accessible resources, even among patient populations that are not always well-represented in clinical research. The presence of multiple serious co-morbidities and distance from a testing facility do not seem to contribute to hesitancy in germline genetic testing participation.

Background

With the onset of precision oncology, findings from germline mutational analysis have been helpful in treating patients with cancer and aids in cancer prevention, early detection, and improved overall outcomes. Germline genetic testing is now part of the standard of care for certain types of patients with prostate cancer. There is a very limited body of work that investigated demographic, disease- related and social factors that may be influencing Veterans’ participation in germline genetic testing. This study helps to identify whether certain factors may be influencing decisions on participation in prostate germline testing among Veterans with prostate malignancy.

Methods

The study was conducted using retrospective chart review. Data was collected from the periods of August 1, 2022 to December 31, 2023 among Veterans with prostate cancer who met criteria for germline genetic testing. Demographic and clinical information were collected including age, race, extent of disease (high risk, very high-risk or metastatic disease), significant co-morbidities, educational level, family and personal history of cancer, travel time, germline genetic test findings, impact on treatment approaches, referral for genetic counseling, and whether Veterans agreed or declined germline genetic testing. Data was analyzed using descriptive statistics. A total of 180 charts were reviewed, with 171 meeting the criteria for inclusion. The mean age of the participants is 73, with the youngest being 55 and the oldest being 101 years old. Majority of the participants were African American (77%).

Results

Only about two percent of those who met the inclusion criteria declined to undergo testing with the one living the farthest away from the testing hospital residing 18 miles away. Those who declined testing ranged in age from 67 to 88, majority had high risk prostate cancer and no family history of malignancy, and had 0-1 serious co-morbidity. None of their educational informational was available for review.

Conclusions

Participation in germline genetic testing can be enhanced with adequate patient education and availability of accessible resources, even among patient populations that are not always well-represented in clinical research. The presence of multiple serious co-morbidities and distance from a testing facility do not seem to contribute to hesitancy in germline genetic testing participation.

Background

Prostate cancer is the most common non-cutaneous malignancy at the Veterans Health Administration (VHA) and every year approximately 15,000 Veterans are diagnosed and treated. Many advanced prostate cancer cases harbor genetic mutations that significantly impact prognosis, treatment decisions, and familial screening. In February 2021, the Prostate Cancer Molecular Testing Pathway (PCMTP) flow map was developed to increase appropriate genetic testing.

Methods

VHA initiated the Oncology Clinical Pathways (OCP) program to standardize cancer care for Veterans. The PCMTP was developed by a multidisciplinary team that created interactive templates within the Computerized Patient Record System (CPRS), to facilitate identification of eligible Veterans for germline and comprehensive genomic profiling (CGP). Clinical decision-making for these tests is documented as Health Factors (HF), in CPRS, allowing for assessment of pathway adherence and overall uptake.

Results

The PCMTP has achieved success, as there is over 90% compliance to molecular testing among participating Veterans which exceeds the pathway benchmark of 80%. PCMTP has been utilized at 88 VA sites, by over 700 distinct VA providers, with over 7,000 Veterans participating. This implementation has yielded over 19,200 Health Factors within CPRS.

Conclusions

The PCMTP has markedly improved the documentation and application of germline and CGP testing among Veterans diagnosed with prostate cancer. By facilitating genomic testing in appropriate patients, the PCMTP aims to enhance patient outcomes and optimize the quality of care. Prior to PCMTP establishment, assessing the prevalence of germline and CGP testing in eligible Veterans posed significant challenges. Future work will concentrate on increasing PCMTP utilization, evaluating downstream outcomes from genomic testing, including the identification of pathogenic variants, utilization of genetic counseling services, referrals to clinical trials, and the genomic impact on treatment strategies.

Background

Prostate cancer is the most common non-cutaneous malignancy at the Veterans Health Administration (VHA) and every year approximately 15,000 Veterans are diagnosed and treated. Many advanced prostate cancer cases harbor genetic mutations that significantly impact prognosis, treatment decisions, and familial screening. In February 2021, the Prostate Cancer Molecular Testing Pathway (PCMTP) flow map was developed to increase appropriate genetic testing.

Methods

VHA initiated the Oncology Clinical Pathways (OCP) program to standardize cancer care for Veterans. The PCMTP was developed by a multidisciplinary team that created interactive templates within the Computerized Patient Record System (CPRS), to facilitate identification of eligible Veterans for germline and comprehensive genomic profiling (CGP). Clinical decision-making for these tests is documented as Health Factors (HF), in CPRS, allowing for assessment of pathway adherence and overall uptake.

Results

The PCMTP has achieved success, as there is over 90% compliance to molecular testing among participating Veterans which exceeds the pathway benchmark of 80%. PCMTP has been utilized at 88 VA sites, by over 700 distinct VA providers, with over 7,000 Veterans participating. This implementation has yielded over 19,200 Health Factors within CPRS.

Conclusions

The PCMTP has markedly improved the documentation and application of germline and CGP testing among Veterans diagnosed with prostate cancer. By facilitating genomic testing in appropriate patients, the PCMTP aims to enhance patient outcomes and optimize the quality of care. Prior to PCMTP establishment, assessing the prevalence of germline and CGP testing in eligible Veterans posed significant challenges. Future work will concentrate on increasing PCMTP utilization, evaluating downstream outcomes from genomic testing, including the identification of pathogenic variants, utilization of genetic counseling services, referrals to clinical trials, and the genomic impact on treatment strategies.

Background

Prostate cancer is the most common non-cutaneous malignancy at the Veterans Health Administration (VHA) and every year approximately 15,000 Veterans are diagnosed and treated. Many advanced prostate cancer cases harbor genetic mutations that significantly impact prognosis, treatment decisions, and familial screening. In February 2021, the Prostate Cancer Molecular Testing Pathway (PCMTP) flow map was developed to increase appropriate genetic testing.

Methods

VHA initiated the Oncology Clinical Pathways (OCP) program to standardize cancer care for Veterans. The PCMTP was developed by a multidisciplinary team that created interactive templates within the Computerized Patient Record System (CPRS), to facilitate identification of eligible Veterans for germline and comprehensive genomic profiling (CGP). Clinical decision-making for these tests is documented as Health Factors (HF), in CPRS, allowing for assessment of pathway adherence and overall uptake.

Results

The PCMTP has achieved success, as there is over 90% compliance to molecular testing among participating Veterans which exceeds the pathway benchmark of 80%. PCMTP has been utilized at 88 VA sites, by over 700 distinct VA providers, with over 7,000 Veterans participating. This implementation has yielded over 19,200 Health Factors within CPRS.

Conclusions

The PCMTP has markedly improved the documentation and application of germline and CGP testing among Veterans diagnosed with prostate cancer. By facilitating genomic testing in appropriate patients, the PCMTP aims to enhance patient outcomes and optimize the quality of care. Prior to PCMTP establishment, assessing the prevalence of germline and CGP testing in eligible Veterans posed significant challenges. Future work will concentrate on increasing PCMTP utilization, evaluating downstream outcomes from genomic testing, including the identification of pathogenic variants, utilization of genetic counseling services, referrals to clinical trials, and the genomic impact on treatment strategies.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."

About 15,000 veterans are annually diagnosed with prostate cancer. Fortunately, those veterans enrolled in the US Department of Veterans Affairs (VA) Million Veteran Program (MVP) provide researchers with a deep pool of genetic data that can help identify causes, aid diagnosis, and guide targeted treatments.

More than 1,000,000 veterans have enrolled in MVP and donated their anonymized DNA to foster research. It is also one of the most genetically diverse health-related databases: 20% of participants identify as Black, 8% as Hispanic, 2% as Asian American, and 1% as Native American. 

Ethnically and racially diverse data are particularly important for advancing the treatment of underserved groups. In a 2020 review, researchers found a number of areas where Black veterans differed from White veterans, including prostate-specific antigen (PSA) levels, incidence (almost 60% higher), clinical course, and mortality rate (2 to 3 times greater). To facilitate research, the MVP developed the “DNA chip,” a custom-designed tool that tests for > 750,000 genetic variants, including > 300,000 that are more common in minority populations.

“The whole thing about understanding genetics and diversity is like a circular feedback loop,” Director of MVP Dr. Sumitra Muralidhar said in a VA news article. “The more people you have represented from different racial and ethnic backgrounds, the more we’ll be able to discover genetic variants that contribute to their health. The more we discover, the more we can help that group. It’s a complete circular feedback loop.”

In addition to veterans’ blood samples and 600,000-plus baseline surveys on lifestyle, military service, and health, the MVP has collected upwards of 825,000 germline DNA samples, which have helped inform research into prostate cancer, the most commonly diagnosed solid tumor among veterans. By mining these data, researchers have built more evidence of how genes add to risk and disease progression.

In one study preprint that has not been peer reviewed, VA researchers investigated the significance of high polygenic hazard scores. The scores are strongly associated with age at diagnosis of any prostate cancer, as well as lifetime risk of metastatic and fatal prostate cancer. However, because they’re associated with any prostate cancer, the researchers say, there is concern that screening men with high polygenic risk could increase overdiagnosis of indolent cancers.

The researchers analyzed genetic and phenotypic data from 69,901 men in the MVP who have been diagnosed with prostate cancer (6413 metastatic). They found their hypothesis to be correct: Among men eventually diagnosed with prostate cancer, those with higher polygenic risk were more likely to develop metastatic disease. 

Genetic risk scores like PHS601, a 601-variant polygenic score, can be performed on a saliva sample at any time during a person’s life, the researchers note. Thus, the scores provide the earliest information about age-specific risk of developing aggressive prostate cancer. These scores might be useful, they suggest, to support clinical decisions not only about whom to screen but also at what age.

Another study led by Stanford University researchers and published in Nature Genetics aimed to make screening more targeted, in this case prostate specific antigen screening. Estimates about PSA heritability vary from 40% to 45%, with genome-wide evaluations putting it at 25% to 30%, suggesting that incorporating genetic factors could improve screening. 

This study involved 296,754 men (211,342 with European ancestry, 58,236 with African ancestry, 23,546 with Hispanic/Latino ancestry, and 3630 with Asian ancestry; 96.5% of participants were from MVP)—a sample size more than triple that in previous work. 

The researchers detected 448 genome-wide significant variants, including 295 that were novel (to the best of their knowledge). The variance explained by genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino ancestry, and 8.6% to 15.3% for Asian ancestry, and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels.

The researchers say their study highlights how including higher proportions of participants from underrepresented populations can improve genetic prediction of PSA levels, offering the potential to personalize prostate cancer screening. Adjusting PSA for individuals’ predispositions in the absence of prostate cancer could improve the specificity (to reduce overdiagnosis) and sensitivity (to prevent more deaths) of screening.

Their findings, the researchers suggest, also explain additional variation in PSA, especially among men of African heritage, who experience the highest prostate cancer morbidity and mortality. They note that this work “moved us closer to leveraging genetic information to personalize PSA and substantially improved our understanding of PSA across diverse ancestries.”

A third study from a team at the VA Tennessee Valley Healthcare System also investigated the risk of inheriting a predisposition to prostate cancer. These researchers explored pathogenic variants using both genome-wide single-allele and identity-by-descent analytic approaches. They then tested their candidate variants for replication across independent biobanks, including MVP.

The researchers discovered the gene WNT9B E152K more than doubled the risk of familial prostate cancer. Meta-analysis, collectively encompassing 500,000 patients, confirmed the genome-wide significance. The researchers say WNT9B shares an “unexpected commonality” with the previously established prostate cancer risk genes HOXB13 and HNF1B: Each are required for embryonic prostate development. Based on that finding, the researchers also evaluated 2 additional genes, KMT2D and DHCR7, which are known to cause Mendelian genitourinary developmental defects. They, too, were nominally associated with prostate cancer under meta-analyses.

Tens of thousands of participants in MVP have had prostate cancer. The genetic research they participate in advances detection, prediction, and treatment for themselves and others, and science in general. The research is not only about finding causes, but what to do if the cancer develops. An “acting on MVP prostate cancer findings” study at VA Puget Sound Health Care System is testing how communicating with veterans about MVP prostate cancer results will affect their care. Those with prostate cancer will be screened to determine genetic contributions to their cancers. Those found to have a gene-based cancer diagnosis will be offered genetic counseling. Their immediate family will also be offered screening to test for inherited prostate cancer risk.

In 2016, the VA partnered with the Prostate Cancer Foundation to establish the Precision Oncology Program for Cancer of the Prostate (POPCaP). In collaboration with MVP and the Genomic Medicine Service, the program uses genetic information to individualize treatments for veterans with advanced prostate cancer. 

US Army Veteran James Perry is one of the beneficiaries of the program. First diagnosed with prostate cancer in 2001, he was initially treated with radiation therapy, but the cancer recurred and spread to his lung. The John J. Cochran Veterans Hospital in St. Louis sent a sample of Perry's lung tumor to the laboratory for genetic testing, where they discovered he had a BRCA1 gene mutation.

His oncologist, Dr. Martin Schoen, recommended Perry enroll in AMPLITUDE, a clinical trial testing the effectiveness of poly-ADP ribose polymerase inhibitors, a new class of drugs to treat hormone-sensitive prostate cancer. One year later, Perry’s lung tumor could barely be seen on computed tomography, and his PSA levels were undetectable.

"I would highly recommend enrolling in a trial," Perry told VA Research Currents. “If a veteran has that opportunity, I would encourage it—anything that is going to give you a few more days is worth it.” In the interview, Perry said he enjoyed being part of the trial because he knows he is getting the most advanced care possible and is proud to help others like himself.

"We are honored to support VA's work to improve the lives of veterans who are living with advanced prostate cancer," Vice President and National Director of the PCF Veterans Health Initiative Rebecca Levine said. "Clinical trials play a vital role in bringing new treatments to patients who need them most. Mr. Perry's experience illustrates VA's commitment to provide state-of-the-art cancer care to all veterans who need it."

The US Department of Veterans Affairs (VA) is "lowering the burden of proof" for thousands, making acute and chronic leukemias, multiple myelomas, myelodysplastic syndromes, myelofibrosis, urinary bladder, ureter, and related genitourinary cancers presumptive for service connection.

The Jan. 8 decision included Gulf War veterans, those who served in Somalia or the Southwest Asia theater of operations during the Persian Gulf War on or after Aug. 2, 1990; and post-9/11 veterans, those who served in Afghanistan, Iraq, Djibouti, Egypt, Jordan, Lebanon, Syria, Yemen, or Uzbekistan and the airspace above these locations during the Gulf War on or after Sept. 11, 2001. It also includes veterans who served at the Karshi-Khanabad (K2) base in Uzbekistan after Sept. 11, 2001.

Veterans no longer must prove their service caused their condition to receive benefits. This landmark decision allows them access to free health care for that condition.

According to the VA, these steps are also part of a comprehensive effort to ensure that K2 veterans—and their survivors—receive the care and benefits they deserve. K2 veterans have higher claim and approval rates than any other cohort of veterans: 13,002 are enrolled in VA health care, and the average K2 veteran is service connected for 14.6 conditions.

The 2022 PACT Act was the largest expansion of veteran benefits in generations. The VA then made millions of veterans eligible for health care and benefits years earlier than called for by the law. It also launched the largest outreach campaign in the history of the VA to encourage veterans to apply. 

Nearly 890,000 veterans have signed up for VA health care since the bill was signed into law, a nearly 40% increase over the previous equivalent period, and veterans have submitted > 4.8 million applications for VA benefits (a 42% increase over the previous equivalent period and an all-time record). The VA has delivered > $600 billion in earned benefits directly to veterans, their families, and survivors during that time.

The VA encourages all eligible veterans—including those with previously denied claims—to apply for benefits. To apply for benefits, veterans and survivors may visit VA.gov or call 1-800-MYVA411. 

The US Department of Veterans Affairs (VA) is "lowering the burden of proof" for thousands, making acute and chronic leukemias, multiple myelomas, myelodysplastic syndromes, myelofibrosis, urinary bladder, ureter, and related genitourinary cancers presumptive for service connection.

The Jan. 8 decision included Gulf War veterans, those who served in Somalia or the Southwest Asia theater of operations during the Persian Gulf War on or after Aug. 2, 1990; and post-9/11 veterans, those who served in Afghanistan, Iraq, Djibouti, Egypt, Jordan, Lebanon, Syria, Yemen, or Uzbekistan and the airspace above these locations during the Gulf War on or after Sept. 11, 2001. It also includes veterans who served at the Karshi-Khanabad (K2) base in Uzbekistan after Sept. 11, 2001.

Veterans no longer must prove their service caused their condition to receive benefits. This landmark decision allows them access to free health care for that condition.

According to the VA, these steps are also part of a comprehensive effort to ensure that K2 veterans—and their survivors—receive the care and benefits they deserve. K2 veterans have higher claim and approval rates than any other cohort of veterans: 13,002 are enrolled in VA health care, and the average K2 veteran is service connected for 14.6 conditions.

The 2022 PACT Act was the largest expansion of veteran benefits in generations. The VA then made millions of veterans eligible for health care and benefits years earlier than called for by the law. It also launched the largest outreach campaign in the history of the VA to encourage veterans to apply. 

Nearly 890,000 veterans have signed up for VA health care since the bill was signed into law, a nearly 40% increase over the previous equivalent period, and veterans have submitted > 4.8 million applications for VA benefits (a 42% increase over the previous equivalent period and an all-time record). The VA has delivered > $600 billion in earned benefits directly to veterans, their families, and survivors during that time.

The VA encourages all eligible veterans—including those with previously denied claims—to apply for benefits. To apply for benefits, veterans and survivors may visit VA.gov or call 1-800-MYVA411. 

The US Department of Veterans Affairs (VA) is "lowering the burden of proof" for thousands, making acute and chronic leukemias, multiple myelomas, myelodysplastic syndromes, myelofibrosis, urinary bladder, ureter, and related genitourinary cancers presumptive for service connection.

The Jan. 8 decision included Gulf War veterans, those who served in Somalia or the Southwest Asia theater of operations during the Persian Gulf War on or after Aug. 2, 1990; and post-9/11 veterans, those who served in Afghanistan, Iraq, Djibouti, Egypt, Jordan, Lebanon, Syria, Yemen, or Uzbekistan and the airspace above these locations during the Gulf War on or after Sept. 11, 2001. It also includes veterans who served at the Karshi-Khanabad (K2) base in Uzbekistan after Sept. 11, 2001.

Veterans no longer must prove their service caused their condition to receive benefits. This landmark decision allows them access to free health care for that condition.

According to the VA, these steps are also part of a comprehensive effort to ensure that K2 veterans—and their survivors—receive the care and benefits they deserve. K2 veterans have higher claim and approval rates than any other cohort of veterans: 13,002 are enrolled in VA health care, and the average K2 veteran is service connected for 14.6 conditions.

The 2022 PACT Act was the largest expansion of veteran benefits in generations. The VA then made millions of veterans eligible for health care and benefits years earlier than called for by the law. It also launched the largest outreach campaign in the history of the VA to encourage veterans to apply. 

Nearly 890,000 veterans have signed up for VA health care since the bill was signed into law, a nearly 40% increase over the previous equivalent period, and veterans have submitted > 4.8 million applications for VA benefits (a 42% increase over the previous equivalent period and an all-time record). The VA has delivered > $600 billion in earned benefits directly to veterans, their families, and survivors during that time.

The VA encourages all eligible veterans—including those with previously denied claims—to apply for benefits. To apply for benefits, veterans and survivors may visit VA.gov or call 1-800-MYVA411.