Prostate cancer

Diagram of a prostate tumor pressing on the urethra, which can cause urinary problems

Most cases of prostate cancer are diagnosed through screening tests, when tumors are too small to cause any symptoms.[6] As a tumor grows beyond the prostate, it can damage nearby organs causing erectile dysfunction, blood in the urine or semen, or trouble urinating – often frequent urination and slow or weak urine stream.[6] More than half of men over age 50 experience some form of urination problem,[7] typically due to issues other than prostate cancer such as benign prostatic hyperplasia (non-cancerous enlargement of the prostate).[6]

Advanced prostate tumors often metastasize to nearby bones of the pelvis and back; there they can cause fatigue, unexplained weight loss, and back or bone pain that does not improve with rest.[8] Metastases can damage the bones around them, and around a quarter of those with metastatic prostate cancer develop a bone fracture.[9] Growing metastases can also compress the spinal cord causing weakness in the legs and feet, or limb paralysis.[10][11]

Prostate cancer screening searches for tumors in those without symptoms. Screening aims to separate men with high-risk cancers who would benefit from treatment, from those whose tumors are slow-growing and unlikely to impact health.[12] This is typically done through blood tests for levels of the protein prostate-specific antigen (PSA), which are elevated in those with enlarged prostates, whether due to prostate cancer or benign prostatic hyperplasia.[13][12][14] The average person's blood has around 1 nanogram (ng) of PSA per milliliter (mL) of blood tested.[15] Those with PSA levels below average are very unlikely to develop dangerous prostate cancer over the next 8 to 10 years.[15] Men with PSA above 3 ng/mL are at increased risk; 30% will have prostate cancer, and 10% a high-grade cancer that requires treatment.[16] Those with PSA levels above 4 ng/mL are often referred for a prostate biopsy; however, even for this high risk group the majority of biopsies are negative for prostate cancer.[17] Men with higher than average PSA levels are often recommended to repeat the blood test four to six weeks later, as PSA levels can fluctuate unrelated to prostate cancer.[18] Those with elevated PSA may undergo secondary screening blood tests that measure subtypes of PSA and other blood proteins to better predict the likelihood that a person will develop aggressive prostate cancer; 4Kscore, Prostate Health Index, ExoDx Prostate Test, and SelectMDx are all available for this purpose.[19]

Several large studies have found that men screened for prostate cancer have a reduced risk of dying from the disease;[20] however, detection of cancer cases that would not have otherwise impacted health can cause anxiety, and lead to unneeded biopsies and treatments.[12] Major national health organizations offer differing recommendations, attempting to balance the benefits of early diagnosis with the potential harms of treating people whose tumors are unlikely to impact health.[12] Most medical guidelines recommend that men in good health and at high risk of prostate cancer (due to age, family history, ethnicity, or prior evidence of high blood PSA levels) be counseled on the risks and benefits of PSA testing, and be offered access to screening tests.[12] Uptake of screening varies by geography – more than 80% of men are screened in the US and Western Europe, 20% of men in Japan, and screening is rare in regions with low human development index.[20]

Diagram of a digital rectal exam.

Men suspected of having prostate cancer may undergo several tests to help assess the prostate. One common procedure is the digital rectal examination, in which a doctor inserts a lubricated finger into the rectum to feel the nearby prostate.[21][22] Tumors feel like stiff, irregularly shaped lumps against the rest of the prostate. Hardening of the prostate can also be due to benign prostatic hyperplasia; around 20–25% of those with abnormal findings on their rectal exams have prostate cancer.[23]

A diagnosis of prostate cancer requires a biopsy of the prostate. Prostate biopsies are typically taken by a needle passing through the rectum or perineum, guided by transrectal ultrasound imaging, magnetic resonance imaging (MRI), or a combination of the two.[24][22] Ten to twelve samples are taken from several regions of the prostate to improve the chances of finding any tumors.[22] Biopsies are examined under a microscope by a pathologist, who determines the type and extent of cancerous cells present. Cancers are first classified based on their appearance under a microscope. Over 95% of prostate cancers are classified as adenocarcinomas (resembling gland tissue), with the rest largely squamous-cell carcinoma (resembling squamous cells, a type of epithelial cell) and transitional cell carcinoma (resembling transitional cells).[25]

Micrograph showing a prostate cancer (conventional adenocarcinoma) with perineural invasion. H&E stain.

Next tumor samples are graded based on how much the tumor tissue differs from normal prostate tissue; the more different the tumor appears, the faster the tumor is likely to grow. The Gleason grading system is commonly used, where the pathologist assigns a number from 1 (similar to prostate tissue) to 5 (least similar) for the most common pattern observed under the microscope, then does the same for the second-most common pattern. The sum of these two numbers is the Gleason score.[25] The total scores of 2 through 5 are no longer commonly used in practice, making the lowest score 6, and the highest score 10. Scores are commonly grouped into Gleason grade groups: a score of 6 or lower is Gleason grade group 1; a score of 7 with the first number (from the most common pattern) 3 and the second number 4 is grade group 2; the reverse – first number 4, second number 3 – is grade group 3; a score of 8 is grade group 4; a score of 9 or 10 is grade group 5.[25] Higher Gleason scores and higher grade groups represent cancer cases likely to be more aggressive with worse prognosis.[25]

Extent of cancer spread is assessed by MRI or PSMA scan – a positron emission tomography (PET) imaging technique where a radioactive label that binds the prostate protein prostate-specific membrane antigen is used to detect metastases distant from the prostate.[26][22] CT scans may also be used, but are less able to detect spread outside the prostate than MRI. Bone scintigraphy is used to test for spread of cancer to bones.[26]

Staging

Main article: Prostate cancer staging

Diagram showing T1 to T3 stages of prostate cancer

After diagnosis, the tumor is staged to determine the extent of its growth and spread. Prostate cancer is typically staged using the American Joint Committee on Cancer's (AJCC) three-component TNM system, with scores assigned for the extent of the tumor (T), spread to any lymph nodes (N), and the presence of metastases (M).[27] Scores of T1 and T2 represent tumors that remain within the prostate: T1 is for tumors not detectable by imaging or digital rectal exam; T2 is for tumors detectable by imaging or rectal exam, but still confined within the prostate.[28] T3 is for tumors that grow beyond the prostate – T3a for tumors with any extension outside the prostate; T3b for tumors that invade the adjacent seminal vesicles. T4 is for tumors that have grown into organs beyond the seminal vesicles.[28] The N and M scores are binary (yes or no). N1 represents any spread to the nearby lymph nodes. M1 represents any metastases to other body sites.[28]

The AJCC then combines the TNM scores, Gleason grade group, and results of the PSA blood test to categorize cancer cases into one of four stages, and their subdivisions. Cancer cases with localized tumors (T1 or T2), no spread (N0 and M0), Gleason grade group 1, and PSA less than 10 ng/mL are designated stage I. Those with localized tumors and PSA between 10 and 20 ng/mL are desigated stage II – subdivided into IIA for Gleason grade group 1, IIB for grade group 2, and IIC for grade group 3 or 4. Stage III is the designation for any of three higher risk factors: IIIA is for a PSA level about 20 ng/mL; IIIB is for T3 or T4 tumors; IIIC is for a Gleason grade group of 5. Stage IV is for cancers that have spread to lymph nodes (N1, stage IVA) or other organs (M1, stage IVB).[27]

AJCC stage for prostate cancer.

AJCC Stage	TNM scores	Gleason grade group	PSA
Stage I	T1 or T2, N0, M0	1	<10 ng/mL
Stage IIA	T1 or T2, N0, M0	1	10-20 ng/mL
Stage IIB		2
Stage IIC		3 or 4
Stage IIIA	T1 or T2, N0, M0	3 or 4	> 20 ng/mL
Stage IIIB	T3 or T3, N0, M0		10-20 ng/mL
Stage IIIC	T1 or T2, N0, M0	5
Stage IVA	Any T, N1	Any group	Any PSA
Stage IVB	Any T, M1

The United Kingdom National Institute for Health and Care Excellence recommends a five-stage system based on disease prognosis called the Cambridge Prognostic Group, with prognostic groups CPG 1 to CPG 5.[29] CPG 1 is the same as AJCC stage I. Cases with localized tumors (T1 or T2) and either Gleason grade group 2 or higher PSA levels (10 to 20 ng/mL) are designated CPG 2. CPG 3 represents either Gleason grade group 3, or the combination of the CPG 2 criteria. CPG 4 is similar to AJCC stage 3 – any of Gleason grade group 4, PSA levels above 20 ng/mL, or a tumor that has grown beyond the prostate (T3). CPG 5 is for the highest risk cases: either a T4 tumor, Gleason grade group 5, or any two of the CPG 4 criteria.[30]

No drug or vaccine is approved by regulatory agencies for the prevention of prostate cancer. Several studies have shown 5α-reductase inhibitors to reduce the incidence of prostate cancer; however, whether they reduce disease is not clear.[31]

Treatment of prostate cancer varies based on how advanced the cancer is, the risk it may spread, and the affected person's health and personal preferences.[32] Those with localized disease at low risk for spread are often at greater threat from treatment side effects than disease effects, and so are monitored regularly by active surveillance – repeat testing for a worsening of their disease.[33] Those at higher risk may receive treatment to eliminate the tumor – typically prostatectomy (surgery to remove the prostate) or radiation therapy, sometimes alongside hormone therapy.[34] Those with metastatic disease are additionally treated with chemotherapy, as well as additional radiation or other agents to alleviate the symptoms of metastatic tumors.[34] Throughout the treatment course, blood PSA levels are monitored to assess the effectiveness of treatments, and whether the disease is advancing.[35]

Localized disease

Men diagnosed with low-risk cases of prostate cancer often defer treatment and are instead monitored regularly for cancer progression by active surveillance.[33] Active surveillance involves monitoring the tumor for growth at fixed intervals by PSA tests (around every six months), digital rectal exam (annually), and MRI or repeat biopsies (every one to three years).[33] The goal of active surveillance is to postpone treatment, and avoid overtreatment and its side effects, given a slow-growing or self-limited tumor that in most people is unlikely to cause problems.[36] Various risk-calculating algorithms have been designed that attempt to predict a person with prostate cancer's risk of disease progression based on their clinical characteristics and test results. These include the Partin table and D'Amico risk grouping – which take into account a person's PSA levels, Gleason score, and TNM score – as well as the CAPRA score, which also considers an affected person's age and the percent of their prostate biopsies in which cancerous cells were found.[37] The NICE-endorsed Predict Prostate algorithm and webtool looks at individualized prognosis and benefit from treatment versus conservative management in non-metastatic disease.[38]

Setup for radiation therapy. The person lies flat while a radiation beam is focused on the tumor site

Those who elect to have therapy typically receive radiation therapy or a prostatectomy.[39] Radiation can be delivered by intensity-modulated radiation therapy, which allows for high doses (greater than 80 Gy) to be delivered to the prostate with relatively little radiation to other organs, or by brachytherapy, where a radioactive source is surgically placed next to the prostate.[40][41] Radiotherapy is typically given in several treatments over the course of eight to nine weeks.[42] Radiation damage to nearby organs can increase the risk of subsequent bladder cancer and cause erectile dysfunction, infertility, and gastronintestinal problems: diarrhea, bloody stools, fecal incontinence, and pain.[42] For those with relatively high-risk localized disease, combining radiation with androgen deprivation therapy improves overall survival.[40]

A surgeon performs robot-assisted surgery

Radical prostatectomy aims to surgically remove the cancerous part of the prostate, along with the seminal vesicles, and parts of the vas deferens.[43] This is typically done by robot-assisted surgery, where robotic tools inserted through small holes in the abdomen allow a surgeon to make small and exact movements during surgery.[44] This method results in shorter hospital stays, less blood loss, and fewer complications than traditional open surgery.[44] In places where robot-assisted surgery is unavailable, prostatectomy can be performed laparoscopically (using a camera and hand tools through small holes in the abdomen), or through traditional open surgery with an incision above the penis (retropubic approach) or below the scrotum (perineal approach).[45][44] The four approaches result in similar rates of cancer control.[45] Damage to nearby tissue during surgery can result in erectile dysfunction and urinary incontinence. Erectile dysfunction is more likely in those who are older or had previous erectile issues.[45] Incontinence is more common in those who are older and have shorter urethras.[45] Both for cancer progression outcomes and surgical side effects, the skill and experience of the individual surgeon doing the procedure are among the greatest determinants of success.[45]

Radiotherapy and surgery result in similar outcomes with respect to bowel, erectile and urinary function after five years.[46] Successful radiotherapy causes a drop in PSA levels due to destruction of the tumor, while prostatectomy causes PSA to drop to undetectable levels.[47] After treatment for localized prostate cancer, PSA levels are monitored regularly. Up to half of those treated will eventually have a rise in PSA levels, suggesting the tumor or small metastases are growing again.[48] People with high or rising PSA levels are often offered another round of radiation therapy directed at the former tumor site. This reduces risk for further progression by 75%.[47] Those suspected of metastases can undergo PET scanning with sensitive radiotracers C-11 choline, F-18 fluciclovine, and F-18 or Ga-68 attached to a PSMA-targeting drug, each of which is able to detect small metastases more sensitively than alternative imaging methods.[49][47]

Metastatic disease

Bone scintigraphy scan of a man with metastatic prostate cancer. Dark spots indicate metastases along the pelvis, ribs, and shoulder.

For those with metastatic disease, the standard of care is androgen deprivation therapy, drugs that reduce levels of androgens (male sex hormones) that prostate cells require in order to grow.[50] Various drugs are used to lower androgen levels by blocking the synthesis or action of testosterone, the primary androgen. The first line of treatment is typically GnRH agonists like leuprolide, goserelin, triptorelin, or leuprolide mesylate by injection monthly or less frequently if needed.[51][50] GnRH agonists cause a brief rise in testosterone levels at treatment initiation, which can worsen disease in people with significant symptoms of metastases.[52] In these people, GnRH antagonists like degarelix or relugolix are given instead, and can also rapidly reduce testosterone levels.[52] Hormone therapy halts tumor growth in more than 95% of those treated,[53] with PSA levels returning to normal in up to 70%.[54]

Despite reduced testosterone levels, eventually nearly all prostate cancers continue to grow – typically manifested by rising blood PSA levels, and metastases to nearby bones.[55][56] This is the most advanced stage of the disease, called castration-resistant prostate cancer (CRPC). CRPC is typically treated with systemic chemotherapy alongside continued hormone therapy. The standard of care is docetaxel given every three weeks.[57] Most CRPC cases still rely on androgen signaling, and so antiandrogen drugs are often used, namely the androgen receptor antagonists enzalutamide, apalutamide, and darolutamide, as well as the testosterone production inhibitor abiraterone acetate.[55][58] Those whose cancer becomes resistant to docetaxel may receive the second-generation taxane drug cabazitaxel.[55] An alternative is the cell therapy procedure Sipuleucel-T, where the affected person's immune cells are removed, treated to more effectively target prostate cancer cells, and re-injected into the same person.[55][58]

The prognosis of diagnosed prostate cancer varies widely based on the cancer's grade and stage at the time of diagnosis; those with lower stage disease have vastly improved prognoses. Around 80% of prostate cancer diagnoses are in men whose cancer is still confined to the prostate. These men often survive long after diagnosis, with as many as 99% still alive 10 years from diagnosis.[73] Men whose cancer has metastasized to a nearby part of the body (around 15% of diagnoses) have poorer prognoses, with five-year survival rates of 60–80%.[74] Those with metastases in distant body sites (around 5% of diagnoses) have relatively poor prognoses, with five-year survival rates of 30–40%.[74]

Those who have low blood PSA levels at diagnosis, and whose tumors have a low Gleason grade and less-advanced clinical stage tend to have better prognoses.[75] After prostatectomy or radiotherapy, those who have a short time between treatment and a subsequent rise in PSA levels, or a rapid rate of PSA level increases are more likely to die from their cancers.[48] However, the prognostic models are not very accurate, and there is extensive research with aim to develop improved risk classification models.

Castration-resistant metastatic prostate cancer is incurable,[76] and kills a majority of those whose disease reaches this stage.[55]

Micrograph of prostate adenocarcinoma, acinar type, the most common type of prostate cancer. Needle biopsy, H&E stain

Prostate cancer is caused by the accumulation of genetic mutations to the DNA of cells in the prostate. These mutations affect genes involved in cell growth, replication, cell death, and DNA damage repair.[77] Changes to these genes can cause cells in the prostate to grow uncontrollably, resulting in a tumor.[78] Over time, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or bladder.[79] Eventually, tumor cells develop the ability to travel through the lymphatic system to nearby lymph nodes, or through the bloodstream to the bone marrow and (more rarely) other body sites.[80] At these new sites, the cancer cells disrupt normal body function and continue to grow. Metastases cause most of the discomfort associated with prostate cancer, and eventually can kill the affected person.[80]

Most prostate tumors begin in the peripheral zone – the outermost part of the prostate.[81] As cells begin to grow out of control, they form a small clump of disregulated cells called a prostatic intraepithelial neoplasia (PIN).[82] Some PINs continue to grow, forming layers of tissue that stop expressing genes common to their original tissue location – p63, cytokeratin 5, and cytokeratin 14 – and begin expressing genes common to cells that makeup the innermost lining of the pancreatic duct – cytokeratin 8 and cytokeratin 18.[81] These multilayered PINs also often overexpress the gene AMACR, which is associated with prostate cancer progression.[81]

Prostate cancer that has metastasized to the bone

Particularly large PINs can eventually grow into tumors. This is commonly accompanied by large-scale changes to the genome, with chromosome sequences being rearranged or copied repeatedly. Some genomic alterations are partiuclarly common in early prostate cancer, namely gene fusion between TMPRSS2 and the oncogene ERG (up to 60% of prostate tumors), mutations that disable SPOP (up to 15% of tumors), and mutations that hyperactivate FOXA1 (up to 5% of tumors).[81]

Metastatic prostate cancer tends to have more genetic mutations than localized disease.[83] Many of these mutations are in genes that protect from DNA damage, such as p53 (mutated in 8% of localized tumors, more than 27% of metastatic ones) and RB1 (1% of localized tumors, more than 5% of metastatic ones).[83] Similarly mutations in the DNA repair-related genes BRCA2 and ATM are rare in localized disease but found in at least 7% and 5% of metastatic disease cases respectively.[83]

The transition from castrate-sensitive to castrate-resistant prostate cancer is also accompanied by the acquisition of various gene mutations. In castrate-resistant disease, more than 70% of tumors have mutations in the androgen receptor signaling pathway – amplifications and gain-of-function mutations in the receptor gene itself, amplification of its activators (e.g. FOXA1), or inactivating mutations in its negative regulators (e.g. ZBTB16 and NCOR1).[83] These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease.[83] Similarly, deletions of the tumor suppressor PTEN are harbored by 12–17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors.[83] Less commonly, tumors have aberrant activation of the Wnt signaling pathway via disruption of members APC (9% of tumors) or CTNNB1 (4% of tumors); dysregulation of the PI3K pathway via PI3KCA/PI3KCB mutations (6% of tumors) or AKT1 (2% of tumors).[83]

Age-standardized death from prostate cancer per 100,000 inhabitants in 2004.[84]

  no data

  <4

  4–8

  8–12

  12–16

  16–20

  20–24

  24–28

  28–32

  32–36

  36–40

  40–44

  >44

Prostate cancer is the second-most frequently diagnosed cancer in men, and the second-most frequent cause of cancer death in men (after lung cancer).[2][5] Around 1.2 million new cases of prostate cancer are diagnosed each year, and 350,000 men die of the disease.[2] One in eight men are diagnosed with prostate cancer in their lifetime, and around one in forty die of the disease.[5] Rates of prostate cancer rise with age. Due to this, prostate cancer rates are generally higher in parts of the world with higher life expectancy, which also tend to be areas with higher gross domestic product and higher human development index.[2] Australia, Europe, North America, New Zealand, and parts of South America have the highest incidence. South Asia, Central Asia, and sub-Saharan Africa have the lowest incidence of prostate cancer; though incidence is increasing in these regions at among the fastest rates in the world.[2] Prostate cancer is the most diagnosed cancer in men in over half of the world's countries, and the leading cause of cancer death in men in around a quarter of countries.[85]

Prostate cancer is rare in those under 40 years old.[86] The overwhelming majority of cases are diagnosed in those over 60 years,[2] with the average person diagnosed at 67.[87] The average person who dies from prostate cancer is 77.[87] Only a minority of prostate cancer cases are ever diagnosed. Autopsies of men who died at various ages have shown cancer in the prostates of over 40% of men over age 50. Incidence rises with age, and nearly 70% of men autopsied at age 80–89 had cancer in their prostates.[88]

A tumor in the prostate was first described in 1817 by the English surgeon George Langstaff, following the autopsy of a man who had died at age 68 with lower-body pain and urinary issues.[99][100] In 1853, London Hospital surgeon John Adams described another prostate tumor from a man who had died with urinary issues; Adams had a pathologist examine the tumor, providing the first histologically confirmed case of a cancerous tumor in the prostate.[99][101] The disease was initially thought to be uncommon as it was rarely distinguished from other causes of urinary obstruction.[102] An 1893 report found only 50 cases described in the medical literature.[103] Around the turn of the 19th century, prostate surgery to relieve urinary obstruction became more common, allowing surgeons and pathologists to examine the removed prostate tissue. Two studies around the time found cancer in as many as 10% of surgical specimens, suggesting prostate cancer was a fairly common cause of prostate enlargement.[103]

For much of the 20th century, the primary therapy for prostate cancer was surgery to remove the prostate. Perineal prostatectomy was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.[104][105] Young's method became the widespread standard, initially done primarily to relieve symptoms of urinary blockage.[104] In 1931 a new surgical method, transurethral resection of the prostate, became available, replacing perineal prostatectomy for symptomatic relief of obstruction.[103] In 1945, Terence Millin described a retropubic prostatectomy approach, which provided easier access to pelvic lymph nodes to assist in staging the extent of disease, and was easier for surgeons to learn.[104] This was improved upon by Patrick C. Walsh's 1983 description of a retropubic prostatectomy approach that avoided damage to the nerves near the prostate, preserving erectile function.[104][106]

Radiation therapy for prostate cancer was used occasionally in the early 20th century, with radium implanted into the urethra or rectum to reduce the tumor size and associated symptoms.[107] In the 1950s the advent of more powerful radiation machines allowed for external beam radiotherapy to reach the prostate. By the 1960s, this was often combined with hormone therapy to improve the potency of therapy.[107] In the 1970s, Willet Whitmore pioneered an open surgery technique where needles of Iodine-125 were placed directly into the prostate. This was improved upon by Henrik H. Holm in 1983 by using transcrectal ultrasound to guide the implantation of radioactive material.[107]

The observation that the testicles (and the hormones they secrete) influence prostate size was made as early as the late 18th century via castration experiments in animals. However, occasional experimentation over the next century bore mixed results, likely due to the inability to separate prostate tumors from prostates enlarged due to benign prostatic hyperplasia. In 1941, Charles B. Huggins and Clarence V. Hodges published two studies using surgical castration or oral estrogen to reduce androgen levels and improve prostate cancer symptoms. Huggins was awarded the 1966 Nobel Prize in Physiology or Medicine for this discovery, the first systemic therapy for prostate cancer.[108][109] In the 1960s, large studies showed estrogen therapy to be as effective as surgical castration at treating prostate cancer, but that those on estrogen therapy were at increased risk of suffering blood clots.[108] Through the 1980s, Andrzej W. Schally's studies of GnRH led to the development of GnRH agonists, which were found to be as effective as estrogen without the increased risk of clotting.[108][110] Schally was awarded the 1977 Nobel Prize in Physiology or Medicine for his work on GnRH and prostate cancer.[108]

Systemic chemotherapy for prostate cancer has been studied since the 1950s, with clinical trials failing to show benefits in most people who receive the drug.[111] In 1996, the US Food and Drug Administration approved the systemic chemotherapy mitoxantrone for those with castration-resistant prostate cancer based on trials showing that it improved symptoms even though it failed to enhance survival.[112] In 2004, docetaxel was approved as the first chemotherapy to increase survival in those with castration-resistant prostate cancer.[112] After additional trials in 2015, docetaxel use was extended to those with castration-sensitive prostate cancer.[113]

Prostate cancer screening and awareness have been widely promoted since the early 2000s by Prostate Cancer Awareness Month in September and Movember in November.[114] Analyses of internet searches and social media posts suggest neither event changes the level of prostate cancer interest or discussion, in contrast to the more established Breast Cancer Awareness Month.[114][115] A light blue ribbon is used to promote prostate cancer awareness.

Prostate cancer is a major topic of ongoing research, with the U.S. National Cancer Institute (NCI, the world's largest funder of cancer research) spending $209 million on prostate cancer research in 2020 – the sixth highest among cancer types.[116] Despite high gross spending, prostate cancer research funding is relatively low for the number of deaths it causes. The NCI spends around $5,700 per prostate cancer death, considerably lower than for brain cancer ($21,000 per death), breast cancer ($13,000 per death) or cancer as a whole ($11,000 per death).[117] A similar trend holds for private nonprofit organizations. Annual revenues of prostate cancer-focused nonprofits rank sixth among cancer types, but prostate cancer nonprofits have lower revenue than would be expected for the number of cases, deaths, and potential years of life lost.[118]

Research into prostate cancer relies on a number of laboratory models to test aspects of the disease. Several prostate immortalized cell lines are widely used, namely the classic lines DU145, PC-3, and LNCaP, as well as more recent cell lines 22Rv1, LAPC-4, VCaP, and MDA-PCa-2a and −2b.[119] Research requiring more complex models of the prostate uses organoids – clusters of prostate cells that can be grown from human prostate tumors or stem cells.[120] Modeling tumor growth and metastasis requires a model organism, typically a mouse. Researchers can either surgically implant human prostate tumors into immunocompromised mice (a technique called a patient derived xenograft),[121] or can induce prostate tumors in mice either with chemical exposure or genetic engineering.[122] These genetically engineered mouse models typically use a Cre recombinase system to disrupt tumor suppressors or activate oncogenes specifically in prostate cells.[123]

• Prostate cancer at Curlie