Asocierea dintre cancerul pulmonar și cancerul de prostată: trei cazuri studiate şi scurtă analiză a literaturii de specialitate

Introduction

The association of lung cancer with prostate cancer is little studied. On the Medscape site, we did not find any reference to this association. Starting from three concrete cases regarding this association, we tried to make a review related to the particularities of the patients who were diagnosed with these two malignant diseases.

The most frequent association of types of cancers was the following: breast; liver; head and neck; colorectal; male genital cancer – prostate; skin; female genital cancer – uterine; thyroid; lung; and female genital cancer – non-uterine. Some researchers find that second primary cancers showed specific associations that depended on the first primary cancer. Physicians should be aware of the most common combinations and the interval periods of metachronous and synchronous multiple primary cancers⁽¹⁾.

Materials and method

We analyzed the observation sheets of three patients who were treated for lung cancer and who, after approximately three years, were also diagnosed with prostate cancer. We did not have the possibility to use molecular and genetic analyses in addition to testing EGFR, ALK and PD-L1 for lung cancer.

We analyzed 10 articles provided by artificial intelligence (AI) on this topic. We tried to define the main features of the patients with this association.

Results

We analyzed three cases that had been in treatment for over five years for non-small cell lung cancer (NSCLC) in which we encountered the association: non-small cell lung cancer and, after immunohistochemical exam, adenocarcinoma. The characteristics of patients were: age between 60 and 65 years old, one patient lived in a rural area, and two patients lived in urban area. All patients were in stage IV of the disease. All were former smokers. Prostate cancer for these three patients was diagnosed in early stage. All patients had EGFR, ALK and PD-L1 negative.

We followed 10 articles selected through AI regarding the association of lung cancer with prostate cancer.

Discussion

Article 1

Prostate cancer and interstitial lung abnormality (ILA) share similar risk factors, which is men and older age. The purpose of this study was to investigate the prevalence of pre-treatment ILA among prostate cancer patients who underwent abdominal computed tomo­graphy within one year at their first visit to the urology department⁽²⁾.

Article 2

Regarding the multiplicative, additive and interactive associations of 25-hydroxyvitamin D with lung and prostate cancer, there was no epidemiological relationship of pre-diagnostic 25(OH)D concentrations with the incidence of lung cancer and prostate cancer. The respective associations of smoking and age above 50 years old with lung cancer and prostate cancer were additive rather than multiplicative⁽³⁾.

Article 3

The article analyzed the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumors. The authors discuss the current understanding of the molecular drivers of this phenomenon, emerging management strategies and open questions in the field. The histological transformation of adenocarcinomas to aggressive neuroendocrine derivatives was initially described in lung cancers harboring an EGFR mutation, and it was subsequently reported in multiple other adenocarcinomas, including prostate cancer in the presence of antiandrogens⁽⁴⁾.

Article 4

The authors report the case of a 73-year-old man with prostate cancer and rising prostate-specific antigen levels. Ga-PSMA PET/CT was performed which showed a focal lung lesion, with subsequent histological confirmation of adenocarcinoma of the lung. Incidental lung lesions on Ga-PSMA in prostate cancer patients should elicit a differential of primary lung malignancy, especi­ally if the clinical and morphological suspicion is high⁽⁵⁾.

Article 5

The article describes the case of a 63-year-old man recently diagnosed with carcinoma of the prostate (Gleason’s score 4+4), with serum prostate-specific antigen 189.2 ng/mL, who underwent Ga PSMA PET/CT scan for pre-treatment staging. The study revealed abnormal tracer uptake in the prostatic bed region, the pelvic, abdominal and mediastinal lymph nodes, and diffuse metastases to the bilateral lungs. The lung metastasis was proved to be metastatic adenocarcinoma, from the analysis of bronchoalveolar lavage⁽⁶⁾.

Article 6

This article deals with the surgical indication for pulmonary metastases of prostate cancer. The authors are in favor of at least their biopsy to eliminate other etiologies. The authors conclude that larger prospective studies are needed, the series demonstrating that surgical resection of isolated pulmonary metastases is safe and effective in selected prostate cancer patients with recurrent disease⁽⁷⁾.

Article 7

The article highlights the importance of smoking as a risk factor in prostate cancer, and certainly highlights once again the common risk factor for lung cancer and prostate cancer⁽⁸⁾.

Article 8

This article describes another particular aspect of the presentation of prostate cancer that can have pulmonary metastases without also having bone metastases. This case highlights once again the necessity of diagnostic biopsy⁽⁹⁾.

Article 9

The article investigates the relationship between vitamin D levels and cancer incidence, including prostate and lung cancer, in older men. In conclusion, the authors reveal that vitamin D is a predictive marker in prostate cancer, but not in lung cancer⁽¹⁰⁾.

Article 10

This meta-analysis shows that systemic lupus erythematosus (SLE) patients are at an increased risk of developing cancer, particularly of the lung, bladder and liver. However, males with SLE have a decreased risk of prostate cancer⁽¹¹⁾.

From the analysis of these studies and case reports, we have drawn some remarks. Thus, from the articles studied, it emerges that this association is rare. Most authors have studied prostate cancer lung metastases, and not primary lung cancers associated with prostate cancer.

In the articles studied, the metachronous association of small cell lung cancer (SCLC) is presented, while our case series was represented by cases with non-small cell lung cancer (NSCLC).

Also, in the articles studied, it is revealed that lung cancer is usually the second cancer that appears in the evolution of patients, while our cases had a reverse sequence of appearance of the two cancers, the first being lung cancer.

A case that we selected from the recommended articles overlaps somehow our experience regarding the association: lung cancer, prostate cancer, but it concerns a patient who developed three successive cancers, and lung cancer was represented by small-cell histology. We reproduce some aspects of this article: it is a very rare case of metachronous triple cancers, including small cell carcinoma of the lung, as well as prostate and male breast cancer. It seems that this is the first documented case of this kind. A 64-year-old man was referred to hospital with left nipple retraction. He had previously undergone lobectomy of the right lung as treatment for small cell lung cancer at 57 years old, and at 61 years of age, he had undergone prostatectomy and bilateral orchiectomy for prostate cancer, histologically determined to be moderately or poorly differentiated adenocarcinoma. The physical examination identified a painless irregular hard tumor in the left breast. Needle aspiration cytology of the mass revealed adenocarcinoma. Modified radical mastectomy was performed. The histological examination revealed that the breast tumor was scirrhous carcinoma. Regarding the evolution of this case, we consider that is signification the fact that, one year and eight months after the surgical removal of the breast cancer, the patient had no recurrence of breast cancer, small cell lung cancer, or prostate cancer. The authors declare that they are unable to determine the cause of carcinogenesis in this case⁽¹²⁾.

In order to define whether there is a genetic correlation between the two cancers analyzed, we present aspects related to the genes involved in the development of lung and prostate cancer. We also discuss the epigenetic aspects described in the literature regarding these cancers.

Genetic changes driving lung cancer development

The most studied way of genes role in lung cancer is through acquired genetic mutations, known as somatic mutations. These changes occur in lung cells during a person’s life, and are not inherited from parents.

These mutations act by instructing cells to grow and divide uncontrollably. Most common mutations in the EGFR (epidermal growth factor receptor) gene can make lung cells continuously activate growth signals. Also, rearrangements or fusions involving the ALK (anaplastic lymphoma kinase) gene can produce abnormal proteins that drive cell growth.

Other frequently mutated genes include KRAS and BRAF, which are part of cell signaling pathways. PD-L1 protein can be affected too, helping cancer cells evade the immune system, these being also significant somatic alterations. Identifying these “driver mutations” is crucial for therapeutic intention⁽¹³⁾.

Genetics in prostate cancer

Variants in genes involved in DNA mismatch repair, particularly BRCA1/2, ATM, CHEK2 and NBN, have been associated with an increased risk of developing prostate cancer in men with advanced/metastatic prostate cancer in man without familial history as well as in men with familial prostate cancer.

“A review by Pritchard et al., of 692 men with mCRPC, revealed a germline DNA repair-gene variant in 11.8% of all men, across 16 genes including BRCA1/2, ATM, CHEK2, PALB2 and RAD51D. These men were unselected for age at diagnosis or family history status. In men with localized prostate cancer, a lower frequency of germline DNA repair gene variant of 4.6% was found (however, when specifically grouping men by NCCN risk criteria, 2% of men with low-intermediate risk had germline variants in DNA repair genes)”. Patients who carry germline variants in BRCA2 with metastatic prostate cancer have superior responses to PARP inhibition and platinum chemotherapy. This aspect justifies the emerging importance of knowing a patient’s variant status, especially in advanced or metastatic disease.

Nicolosi et al. performed a cross-sectional study of 3607 men with prostate cancer, unselected for family history, age or disease stage referred to clinical genetics for germline testing between 2013 and 2018. They found that 17.2% of men carried pathogenic germline variants, of which 30.7% were BRCA1/2 variants, 4.5% were due to HOXB13, 14.1% CHEK2, and 9.6% due to ATM⁽¹⁴⁾.

In an analysis of a European cohort of men with a family history of prostate cancer in the United Kingdom Genetics Prostate Cancer Study (UKGPCS), 7.3% of prostate cancer patients with a positive family history (of three cases of prostate cancer) were found to carry a pathogenic germline variant. The most frequent variant was BRCA2 (28.57% of all variants) and, importantly, there was a significant association between genetic variant carrier status and nodal and metastatic disease^(15-17).

Epigenetic factors in lung cancer

Epigenetic mechanisms, including DNA methylation (DNAm), histone modifications and microRNA expression, play a crucial role in cancerogenesis. Changes in DNAm patterns can lead to affecting some cellular genes, playing an important role in the development and progression of lung cancer. MicroRNAs and exosomes have also emerged as reliable biomarkers for lung cancer.

The epigenetic factors can provide valuable information about early diagnosis and treatment assessment. In particular, abnormal hypermethylation of gene promoters and its effects on tumorigenesis, as well as its roles in the some signaling pathway, have been extensively studied. Epigenetic drugs were approved in the treatment of lung cancer and have shown promise in the treatment. These drugs target the aberrant epigenetic modifications that could have an intervention in the development and progression of disease. Several factors have been identified as drug targets in non-small cell lung cancer⁽¹⁸⁾.

Epigenetic factors in prostate cancer

Epigenetic alterations, including changes in DNA methylation, histone modifications and nucleosome remodeling, result in abnormal gene expression patterns that contribute to prostate tumor initiation and continue to evolve during the course of disease progression. Epigenetic modifications are responsible for silencing tumor-suppressor genes, activating oncogenic drivers and driving therapy resistance, and thus have emerged as promising targets for antineoplastic therapy in prostate cancer. In this review, we discuss the role of epigenetics in prostate cancer with a particular emphasis on clinical implications. We review how epigenetic regulators crosstalk with critical biological pathways, including androgen receptor signaling, and how these interactions dynamically control prostate cancer transcriptional profiles. Because of their potentially reversible nature, the restoration of a “normal” epigenome could provide a basis for innovative therapeutic strategies in prostate cancer. We highlight how particular epigenetic alterations are emerging as potential diagnostic and prognostic biomarkers and/or targets for the treatment of advanced prostate cancer⁽¹⁹⁾.

Conclusions

The association of lung cancer with prostate cancer is rare. There are no may cases described in medical literature.

The core driver mutations and actionable targets are distinct between lung and prostate cancer.

There is limited overlap in certain pan-cancer susceptibility genes (e.g., TP53, TERT, DNA repair genes) and circadian pathway genes, but these do not translate into major clinical similarities in genetic testing or targeted therapy selection for most patients.

In our experience, the patients had first lung cancer (NSCLC) and secondly prostate cancer, with a survival from the diagnosis of metastatic lung cancer of five years and more.

The second cancer was prostate cancer, also with a good evolution determined by early diagnosis.

Data from literature and the studies reveal the importance of genetical tests for assessing the disease prognosis and the selection of therapy.

The epigenetics of both cancers are similar and could be diagnosed by biopsy. The treatment must also take into account the epigenetic aspects.   

Corresponding author: Alexandru-Călin Grigorescu E-mail: alexgrigorescu2004@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.