Breast cancer in men is rare. Its rarity has hindered the development of prospective clinical trials specifically for males.1 Although reviews of the topic suggest that the etiology, diagnosis, and treatment are similar to breast cancer in females, there are important differences to highlight for awareness.
Breast Cancer in Men Is Increasing in Frequency
Currently, the lifetime risk of breast cancer for a man is 1:1000. In the United States, male breast cancer represents 1% of all breast cancers annually, accounting for 2800 of the 300,590 expected new breast cancer diagnoses in 2023.2
Unfortunately, the annual incidence of the disease in males is rising.
Since breast cancer in males, as in females, is an age-related disease, the incidence of breast cancer rises as men get older. The average age at diagnosis for men is approximately 5 years older than for women (67 years vs 62 years).3
In addition to advancing age, risk factors in men include3:
Genetic Factors Confer a High Risk of Breast Cancer for Men
For men, the risk of breast cancer is approximately doubled by having a first-degree relative with breast cancer and mutations in BRCA1 and BRCA2 are the most clearly established risk factors.3
The Consortium of Investigators of Modifiers of BRCA1/2 accumulated data from 3184 BRCA1 and 2157 BRCA2 families anddocumented elevated risks of male breast cancer associated with pathogenic variants of BRCA1 (relative risk [RR] 4.30), especially with pathogenic variants of BRCA2 (RR = 44.0). 4
Other studies indicated that men who carry BRCA2 mutations are at an 80-fold higher risk of developing breast cancer compared with men in the general population, with breast cancer occurring in up to 1 in 10 male BRCA2 carriers.5
A study of multi-gene panel testing in 715 male breast cancer patients identified pathogenic variants in 16 breast cancer susceptibility genes, with BRCA2 and CHEK2 the most frequently mutated genes.6 However, pathogenic variants in BRCA2, CHEK2, and PALB2 were all associated with significantly increased risk.
Male patients with BRCA1/2 mutations are also at an elevated lifetime risk of prostate and pancreas cancer, among others. Carriers of a pathologic (P) and likely pathogenic (LP) BRCA1 variant have an estimated 7% to 26% cumulative lifetime risk of prostate cancer, while the cumulative lifetime risk is 19% to 61% for carriers of a P/LP BRCA2 variant. The cumulative lifetime risk of pancreatic cancer is as high as 3% for males with a P/LP BRCA1/2 variant and 2.3% for females with a P/LP BRCA1/2 variant.5
For these reasons, and because individuals with mutations have an elevated risk for other cancers, National Comprehensive Cancer Network (NCCN) guidelines recommend considering multi-gene genetic testing in all men with breast cancer.1
Finally, Klinefelter’s syndrome, a rare genetic syndrome characterized by a 47, XXY karyotype, hypogonadism, low testosterone levels, and a high ratio of estrogen to testosterone, is associated with a substantially higher risk of developing breast cancer. Males with Klinefelter’s syndrome have a cumulative risk of breast cancer of 0.9% by the age of 75 years.7
Diagnostic Considerations for Men With a Breast Lump
There are no prospective studies and only limited retrospective data to support screening mammography in men who have an elevated risk of breast cancer.8
Most men with breast cancer present with a painless mass that is subareolar and slightly eccentric to the nipple.9 Other signs can include nipple retraction, bleeding from the nipple, skin ulceration, and palpable axillary adenopathy.
Because of a lack of routine screening and the rarity of breast cancer in males, men present with larger tumors (20 mm vs 15 mm, respectively) and/or regional nodal metastases more often than women with breast cancer (42% vs 33%, respectively).3
The most common differential diagnosis is gynecomastia, which is bilateral in approximately 50% of cases.9 Breast cancer in men is rarely, if ever, bilateral at presentation.10
Because only 1% of male breast cancers occur in men who are younger than 30 years of age, the American College of Radiology recommends ultrasonography as the initial test for men younger than 25 years old, with an indeterminate palpable mass.9
For men older than 25 years or those with concerning findings on physical examination, mammography is recommended, with ultrasonography confirmation if the mammogram is inconclusive or suggests cancer. In mammograms, men do not have the same background of benign proliferative changes as women. For that reason, a circumscribed mass or round calcifications on mammography are suspicious when seen in a male.8,9
Men with suggestive lesions should undergo core biopsy for pathologic confirmation of breast cancer and to obtain tissue for immunohistochemistry and genomic assays to assess prognosis and benefit from systemic therapies.1
Histology of Breast Cancer in Males Differs From Females
Since most men with breast cancer present with clinically palpable nodules, most of their cancers are invasive carcinomas, rather than ductal carcinoma-in-situ.3 Invasive ductal carcinoma is the most common histology.
Lobular carcinomas account for approximately 12% of invasive cancers in women. Since the normal male breast lacks terminal lobules, lobular carcinoma in males is much less common, accounting for only 1% to 2% of cases.
A central review of tumor samples from 1483 men with breast cancer in the International Male Breast Cancer Program found that 99% of tumors were positive for estrogen receptor, 82% were positive for progesterone receptor, and 97% were positive for androgen receptor. Only 9% of the tumors were HER2-positive.3,11
Staging for breast cancer in men is the same as for women. As noted above, NCCN guidelines recommend that all males with breast cancer be considered for genetic testing.1
Treating Breast Cancer in Men and Women Differs Slightly—but Importantly
Women with newly diagnosed breast cancer often receive breast-conserving therapy. Most men with breast cancer undergo mastectomy, but observational studies suggest that breast-conserving surgery and radiation produce survival rates equivalent to those associated with mastectomy.3
NCCN guidelines recommend a sentinel node biopsy in males with breast cancer who have a clinically negative axilla. The indications for radiation after breast surgery are the same as for females with breast cancer.1 Similarly, NCCN guidelines suggest adjuvant chemotherapy with/without HER2-targeted therapy for males according to the treatment paradigms used for females with breast cancer.1
Data are limited regarding the use of genomic assays in males, but existing data suggests that the 21-gene assay recurrence score provides similarly valuable prognostic information and that both men and women with lower recurrence scores have low mortality from hormone receptor-positive breast cancer. Adjuvant chemotherapy can be avoided in such cases.12
In general, breast cancers in men are more likely to be endocrine sensitive and less likely to be sensitive to HER2-targeted therapies than breast cancers in women.3
The standard adjuvant endocrine therapy for men with hormone–receptor–positive breast cancer is 5 to 10 years of treatment with tamoxifen, with the duration of therapy determined by the risk of recurrence and side effects. Tamoxifen, a selective estrogen receptor modulator (SERM), has established efficacy in patients with metastatic cancer, and observational studies of adjuvant treatment with tamoxifen have also suggested a survival benefit.10
Population-based series have shown inferior survival rates when men were treated with adjuvant aromatase inhibitors as compared with tamoxifen, perhaps due to inadequate estradiol suppression when compared with postmenopausal women.1,3
For men who have intolerance or contraindications to tamoxifen, GnRH analogs, with or without an aromatase inhibitor, can overcome inadequate estradiol suppression from aromatase inhibitors and can be used as an alternative therapy.3 Biennial monitoring of bone density in men who receive adjuvant GnRH analog therapy is suggested, with conventional treatment for osteopenia or osteoporosis, if required.1
According to NCCN guidelines, treatment of metastatic breast cancer with chemotherapy, HER2-targeted agents, immunotherapy, PARP inhibitors, and secondary endocrine therapy in males is similar to therapy in females, with the caveat that, when an aromatase inhibitor is used, concurrent GnRH analogs are required.1
CDK4/6 inhibitors in combination with endocrine therapy, mTOR inhibitors, and PIK3CA inhibitors have not been evaluated in prospective clinical trials in males. However, these agents can be used, based on extrapolation of data from studies comprised largely of females.
Alan Lyss, MD, was a medical oncologist in academic and community practice in St Louis, Missouri, from 1982 to 2020. In his practice, he was consistently engaged in clinical research. The focus of Dr Lyss’ medical writing since 2020 has been the clinical applicability of recently reported oncology research.
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Clinically significant prostate cancer is found in a “non-negligible” number of men who have screening PSA levels of 1.8 or higher but less than 3.0 ng/mL, according to recent study findings. It remains unclear, however, if a delay in the diagnosis of these cancers until PSA levels rise to 3.0 ng/mL would lower the likelihood of cure.
The findings are from the population-based Göteborg-2 screening study. Among 17,974 participants, 6006 men with a median age of 55.9 years were included in the current analysis. Of these, 82% had a PSA level less than 1.8 ng/mL, 11% had a PSA level of 1.8 or higher but less than 3 ng/mL (low-PSA group; median PSA 2.1 ng/mL), and 6.3% had a PSA level of 3 or higher but less than 10 ng/mL (high-PSA group; median PSA 3.9 ng/mL). Another 0.5% had a PSA level of 10 ng/mL or higher. Patients in the low-PSA group were recommended to undergo magnetic resonance imaging (MRI). Men with positive MRI findings had 4 targeted biopsies from each MRI-visible lesion.
Prostate cancer was found in 64 patients (41%) with positive MRI findings in the low-PSA group, the investigators reported in European Urology. Of these, 33 (21%) had Gleason 6 tumors (insignificant cancer) and 31 (20%) had Gleason 7 or higher tumors (significant cancer). In the high-PSA group, prostate cancer was detected in 61 patients (56%), including 26 (24%) with Gleason 6 tumors and 35 (32%) with Gleason 7 or higher tumors.
“These results are in-line with previous knowledge of prostate cancer incidence at low PSA levels” said study corresponding author Fredrik Möller, MD, of Skövde Hospital in Skövde, Sweden.
He added, “Our study indicates that MRI could be used as a selection tool to reduce prostate cancer overdiagnosis at lower PSA values, but would lead to a large increase in MRI [use]. We hope our future planned study comparing PSA cutoff of 3 ng/mL to a PSA cutoff of 1.8 ng/mL will show robust evidence regarding the benefits and harms of a lower PSA cutoff as an indication for MRI.”
Due to the limited sensitivity and specificity of PSA screening, it has been proposed that MRI be part of first-line screening for prostate cancer. However, the high costs, limited availability, and large inter-reader variability are significant barriers.
The main strength of the current study is its large, population-based design with a relatively high participation rate. “The results should therefore be generalizable to a screening situation,” Dr Möller said. “The main limitations are the relatively young age group and results that are based on a single screening round and lack follow-up so far.”
Despite the strengths of the study, an important question remains as to whether the lead time in diagnosing these cancers (PSA 1.8 or higher versus PSA 3-10 ng/mL) has a major impact on outcomes, said Aly-Khan Lalani, MD, an assistant professor in the department of oncology at McMaster University in Hamilton, Ontario, Canada, who was not involved with the study.
“The larger point is that population-based screening, with rational guidance of when to leverage adjunctive tests and thereby risk stratify patients, will help ensure the most patients who warrant treatment are caught early,” Dr Lalani said. “By balancing this concept and also limiting overdiagnosis or excessive invasive testing, we can seek to provide survival benefits for our patients.”
Michael Whalen, MD, an associate professor of urology and chief of urologic oncology at George Washington University in Washington DC, noted that the number of positive MRI findings in the low-PSA group (25%) was surprisingly quite similar to the rate of positivity in the high PSA (3-10 ng/mL) group (31%). “However, significant cancer detection rates in the low-PSA group were about half of that in the high PSA group,” Dr Whalen said.
He pointed out that 37,887 men were invited to participate in the study, but only 17,806 opted to do so and 6006 were included in the current analysis. “Compared to other screening trials, this number is actually very low. The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial included about 182,000 men, and the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial in the United States included about 76,000 men. “Thus, the generalizability of the findings may be limited,” Dr Whalen said.
The study had a high biopsy compliance rate, so disease detection rates should be accurate, Dr Whalen said. Also, there was pathologic consensus from 3 different experienced uropathologists. “Although racial demographics were unpublished, it is likely predominately a Caucasian population,” he said. “How the lower PSA threshold of 1.8 ng/mL applies to a population with a higher proportion of African American men is unclear. Also, the influence of family history on acceptable PSA threshold was not explored.”
In a meeting of the Oncologic Drugs Advisory Committee (ODAC), the committee of 11 members unanimously voted that the potential benefits of ciltacabtagene autoleucel (cilta-cel) outweigh its risks for its proposed indication.1
The US Food and Drug Administration (FDA) convened the meeting on March 15, 2024, to obtain committee input on the results of the CARTITUDE-4 trial (ClinicalTrials.gov Identifier: NCT04181827).
The trial data served as the primary evidence for a supplemental Biologics Licensing Application submitted by Janssen Biotech, Inc. for CARVYKTI (cilta-cel) for the treatment of relapsed or refractory multiple myeloma (MM) in adults who have received at least 1 line of therapy and are refractory to lenalidomide.2 Participants who had received 1 to 3 prior lines of therapy for MM were randomly assigned to receive cilta-cel or standard care.
Unmet Need
Based on data from the phase 1b/2 study CARTITUDE-1 (ClinicalTrials.gov Identifier: NCT03548207), cilta-cel is currently approved in the United States for the treatment of relapsed or refractory MM in adults who have received 4 or more prior lines of therapy.3
In the presentation from Janssen Biotech, Inc., Irene Ghobrial, MD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, outlined the current unmet need for the use of CAR-T therapy as early treatment in MM.
Dr Ghobrial cited data showing that 85% of multiple myeloma patients were unable to receive treatments beyond the third line of therapy. This underscores the need for administering effective treatments earlier in the disease course. “Initial treatment is the best chance for deep and durable remissions,” she said.
Additionally, T-cells become exhausted with disease progression. Administering CAR-T therapy earlier in the disease course, when T-cells are less exhausted, is associated with better long-term outcomes, Dr Ghobrial noted.
The current standard care for MM patients is continuous treatment, which contributes to “added toxicity and added burden for the patient,” said Dr Ghobrial. A one-and-done treatment such as cilta-cel early in the disease course creates the opportunity for patients to achieve remission without having to undergo continuous, burdensome treatments.
Trial Data
Jordan Schecter, MD, vice president of research and development for the Janssen Pharmaceutical Companies of Johnson & Johnson, presented data from CARTITUDE-4 at the meeting.1
Cilta-cel was associated with significant and meaningful PFS improvement compared to the standard care arm, and this finding was consistent across subgroups. Median PFS was not reached in the cilta-arm, while it was 11.8 months for the standard care arm.
Additionally, 85% of patients in the cilta-cel arm obtained a response, compared with 67% patients in the standard care arm.
Dr Schecter addressed an increased risk for early death in the cilta-cel arm. “The only period in which we see more deaths in the experimental arm versus standard of care arm is between 0 and 3 months,” he stated. Before 3 months, there were 7 deaths in the cilta-arm and 1 death in the standard care arm.
Dr Schecter noted that a cause for the disparity in early deaths prior to receiving treatment was disease progression in the cilta-cel arm, and not cilta-cel toxicity. For example, 6 out of the 7 deaths prior to 3 months were in patients randomized to cilta-cel, but who progressed prior to infusion with cilta-cel. Additionally, he noted that between 3 and 6 months, the OS curves began to balance and then trended towards fewer deaths in the cilta-cel arm.
“The depth and durability of response observed with cilta-cel is something not observed with any other modality and is important for long-term outcomes such as progression-free survival and of course, overall survival,” said Dr Schecter.
"
The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits.
FDA Concerns
The FDA raised concerns over the lower overall survival (OS) in the first 10 months of treatment in the cilta-cel arm compared to the standard care arm. In the first 10 months of treatment, 14% of patients died in the cilta-cel arm, whereas 12% died in the standard care arm.
Additionally, 4.8% of patients in the cilta-cel arm died prior to receiving CAR-T therapy and 0.5% of patients in the standard care arm died before treatment.
“One might consider that since the subject did not receive cilta-cel, there is no treatment causality,” said Helkha Peredo-Pinto, MD, a clinical reviewer for the FDA, during the meeting. “However, it is [a] consequence of proceeding to receive treatment in the investigation arm. In this case, [the] CAR-T product, therefore, is relevant to the subject outcome.”
The FDA noted that it is the responsibility of Janssen Biotech, Inc. to demonstrate or prove that a more adequate bridging therapy regimen has the capacity to prevent death or early progression of disease. Additionally, the FDA stated that data are too immature to draw a conclusion about the OS benefit of cilta-cel.
“It represents a challenge for the agency to make a conclusive regulatory decision based solely on a speculative assessment of the benefit-risk profile rather than robust scientific evidence,” Dr Peredo-Pinto said.
Discussion
Based on the trial data, the FDA proposed 2 questions for the committee to discuss. These included:
Whether the results of the CARTITUDE-4 trial are sufficient to support a positive risk-benefit assessment of cilta-cel for the proposed indication; and
Whether the risk of early death associated with cilta-cel treatment is acceptable in the context of the PFS benefit.
Some committee members mentioned that the imbalance in early OS seemed to be a case of front-loaded risk, and that providers should be encouraged to inform patients of this before treatment.
“The curves really remind me of transplant related toxicities that are high early on,” said Mary Kwok, MD, clinical associate professor at the University of Washington School of Medicine.
Additionally, some members mentioned that cilta-cel is an important consideration for early treatment because it would allow patients periods of nontreatment and a higher quality of life.
“We can’t understate the ability of individuals to have this period of nontreatment that allows them higher quality of life — that the data did support — and moving into a disease-free state,” Susan Lattimore, RN, a nonvoting member of the committee and consumer representative, stated during the meeting.
“The sense of the panel’s discussion here has been that there are issues upfront, but they are small, and perhaps balanced by the long-term benefits,” said Ravi Madan, MD, chair of ODAC, during the meeting. Dr Madan also noted that bridging therapy and protecting patients against infection are areas for further research and development to optimize cilta-cel treatment.
The American Society of Clinical Oncology (ASCO) has released guidelines for the use of cannabis and cannabinoids in adults with cancer. The guidelines were published in the Journal of Clinical Oncology, and a related Q&A article was published in JCO Oncology Practice.1,2
The guidelines note that cannabis and/or cannabinoids are increasingly being used by cancer patients, but data to support the efficacy and safety of these products remain limited.
The guidelines recommend that clinicians facilitate conversations with patients about their interest in or current use of cannabis and/or cannabinoids to prevent side effects or drug-drug interactions.
Cannabis and cannabinoids should not be used to augment or replace cancer treatment, but they may improve chemotherapy-induced nausea and vomiting when other guideline-recommended options have been exhausted.
Recommendations and Evidence
Health systems and clinicians should provide adult cancer patients with educational resources on cannabis and/or cannabinoids to enable communication and shared decision-making between patients and clinicians (good practice statement).1
Clinicians should routinely and without judgment ask adult cancer patients if they are interested in cannabis and/or cannabinoids, and, if so, provide guidance or resources (based on a good practice statement).1 This recommendation is based on data that suggest anywhere from 20% to more than 40% of adults with cancer may use cannabis products.2
If patients are using cannabis and/or cannabinoids outside of recommendations or evidence-based indications, clinicians should educate patients on recommended use and seek to minimize harm (good practice statement).1 Serious side effects of cannabis products include tachycardia, orthostatic hypotension, severe confusion, and paranoia, which may be more prominent in older adults or those naïve to cannabis and/or cannabinoids.2
Clinicians should advise patients against using cannabis and/or cannabinoids in place of cancer-directed treatment (a strong recommendation based on very low-quality evidence).1
Likewise, cannabis and/or cannabinoids should not be used to augment the effects of cancer therapies, unless being studied as part of a clinical trial (a weak recommendation based on very low quality evidence).1 This is based on a lack of data regarding potential drug-drug interactions in the cancer setting and the impact of these interactions on cancer treatment outcomes.2 In addition, studies have suggested that cannabis and/or cannabinoids may worsen immunotherapy outcomes, including progression-free survival and overall survival, although more data are needed.
If patients are receiving cancer treatments that are moderately or highly likely to cause nausea and vomiting and the patients experience symptoms that are refractory to standard antiemetic treatments, their antiemetic regimen can be augmented with dronabinol, nabilone, or a quality-controlled oral 1:1 THC:CBD extract (weak recommendations based on low- to moderate-quality evidence.1
Unless they are enrolled in a clinical trial, adults with cancer should not take 300 mg or more of oral CBD daily to manage symptom burden (a weak recommendation based on low-quality evidence). This is due to a lack of proven efficacy and the risk of reversible liver enzyme abnormalities, which were observed in a study of adults and children without cancer.
Oral cannabis products have a variable onset from 30 minutes to 2 hours, and effects may last from 5 to 8 hours, so dose stacking should be avoided to prevent side effects.
The guidelines also note that there is insufficient evidence to recommend for or against cannabis and/or cannabinoids in managing cancer treatment-related toxicities or symptoms, including pain, aside from the aforementioned clinical settings or in a clinical trial setting.1
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