Editorial

S. Uzan,¹ N. Chabbert-Buffet,¹ J. Gligorov,² O. Cussenot,³ E. Touboul,⁴ J. Chopier,⁵
R. Rouzier,¹ C. Coutant,1 M. Antoine ⁶

Key words: Man Cancer Breast BRCA2 Prostate

Introduction

Male breast cancer is an uncommon condition that is often diagnosed late. Most cases are observed at around 70 although this may be earlier if the patient has prostate cancer usually associated with a family history of disease.
In terms of prognosis, breast cancer in men is similar to breast cancer in postmenopausal women in that diagnosis is often late.
The diagnostic and therapeutic strategy is similar for both men and women. Nevertheless, it is worth noting that most strategic decisions are based on studies involving women.

Breast cancer affects 1 in every 100 000 men and represents less than 1% of all cases of breast cancer. Frequency varies with the geographic region but is highest in areas with endemic infectious diseases involving liver disorders that lead to relative or absolute hyperestrogenism. It is also noteworthy that increased male longevity is leading to an increase in the frequency of breast cancer.

1. Genetic factors (2).

A large number of patients have a family history of breast cancer (relative risk [RR], 2.5): 20% of men with breast cancer have a first-degree relative who has been affected by the disease. The most commonly involved genes are BRCA1, and, more particularly, BRCA2 (4% to 40% of cases of male breast cancer). Age at onset is low (52 years on average for BRCA1, 59 years for BRCA2) and the cumulative risk at 70 years is 1.2% for BRCA1 and 6.8% for BRCA2.

Other abnormalities, such as Cowden syndrome (associated with a mutation in PTEN), are also involved.

2. Lifestyle-related risk factors

The risk of male breast cancer is increased by the following factors of relative or absolute hyperestrogenism: cirrhosis (RR, 4), obesity (RR, 2), Klinefelter syndrome (RR, 20), previous mumps or cryptorchidism treated late, and antiandrogen or estrogen therapy. Exposure to radiation is also a risk factor. Gynecomastia does not appear to carry any excess risk.

Diagnosis of male breast cancer

The first sign of breast cancer is usually a lump in the breast. This is rarely painful and is sometimes associated with abnormalities of the areola mammae accompanied by inversion or retraction, discharge, and ulceration.

Paget disease of the nipple is uncommon. Enlarged axillary lymph nodes are sometimes indicative of disease, and the frequency of this sign reflects the late diagnosis.

The lack of knowledge of this condition often leads to a delay in diagnosis, which some studies place at more than 2 years. Although time to diagnosis seems to be improving, stages I and II account for 50% of cases and stages III and IV for the remaining 50%.

Histopathologically, the most common type is invasive ductal carcinoma (almost 90%).
Hormone receptors are generally positive (more than 90% of cases). It is noteworthy that positive androgen hormone receptors have been observed in more than 40% of cases. Expression of prostate-specific antigen (PSA) must also be sought, as a positive result indicates metastasis of prostate cancer.

The diagnostic procedure for male breast cancer is typical, with mammography, ultrasound, and, in some cases, magnetic resonance imaging (MRI). Cytologic analysis may also be performed: we prefer stereotactic core biopsy for the tumor itself and fine needle biopsy for axillary lymph nodes. Extension should be assessed using the same techniques and based on the same indications as in women (abdominal ultrasound, bone scan, FDG scintigraphy, tumor markers).

Treatment (3)

Surgery, consisting of radical mastectomy with axillary node dissection, is obviously the standard treatment. At the patient's request, biopsy of any potentially affected sentinel lymph node can be performed using the same procedure as in women. The rate of false negatives is the same as for women. The patient sometimes requests a conservative approach, which may be applied if the lesion is small and can be resected in sano. Radiotherapy will be recommended in this situation.

Local radiotherapy alone is reserved for the most severe cases. It can also be used to complement more conservative approaches. Chest wall radiotherapy may be necessary in node-positive patients.

The indications for chemotherapy are identical depending on the classic risk factors: lymph node involvement, tumor size, absence of hormone receptors (rare), degree and-indirectly-evaluation of proliferation, and, if necessary, HER2 status. Nevertheless, some studies show that, whatever the patient's status, chemotherapy does provide an advantage, albeit modest.

Chemotherapy regimens should include cyclophosphamide, anthracyclines, and/or taxanes, administered either sequentially or concomitantly. Addition of trastuzumab is systematic in the case of protein overexpression or amplification of HER2.

For most hormone-dependent cancers, the first-line treatment is a 5-year course of tamoxifen. There are no data on the use of aromatase inhibitors as adjuvant therapy-although they have proved to be effective for treating metastases-nor on the prolongation of antihormone treatment with an aromatase inhibitor for more than 5 years if there is initial lymph node involvement.

Management strategies for patients presenting advanced disease-particularly metastatic disease-are identical to those applied for female breast cancer, namely, systemic treatment (chemotherapy, targeted antihormone therapy, targeted antiHER2, therapy, and antiangiogenic therapy).

Breast cancer, prostate cancer, and genetic risk (4)

These two conditions are more commonly associated in patients carrying a BRCA2 mutation for whom the risk of developing prostate cancer before 60 increases by 23. A deleterious mutation in BRCA2 is observed in 2% of men with prostate cancer diagnosed before 50. At our center, we have observed 9 mutations or large rearrangements of BRCA2 in 204 men with prostate cancer diagnosed before 50 or a family history of prostate cancer with at least one case recorded before 50. Associated breast cancer was found in two men harboring a BRCA mutation.

Current recommendations for patients with a BRCA2 mutation:
(1) For breast cancer, yearly clinical breast examinations and more frequent self-examination are recommended. The issue of screening by mammogram, ultrasound scan, or indeed MRI has been raised.
(2) For prostate cancer, screening is by a yearly rectal examination and measurement of PSA from the age of 35 years. Although not well documented, the application of new diagnostic tools for aggressive cancers-dynamic MRI of the prostate or the PCA3 test (a marker that can be measured in prostatic secretions in urine after prostate massage)-seems a logical approach in this particular situation.

Hormone therapy is recommended in this context (5), as follows: If the man has prostate cancer and breast cancer requiring antiestrogen therapy, and if the prostate cancer justifies hormone therapy, chemical castration (first-choice) simultaneously reduces testosterone and estradiol levels. Addition of antiandrogenic drugs to estrogen therapy is to be avoided.

If the cancer treatment does not justify androgen deprivation therapy (follow-up of cancer treated by surgery or radiotherapy), tamoxifen is the drug of choice, as aromatase inhibitors increase physiological circulating testosterone levels, which are very harmful in the context of prostate cancer.

Conclusions
Male breast cancer remains sporadic, even when there are genetic risk factors.
On the whole, it is similar to female breast cancer in terms of diagnosis, therapy, and prognosis.
Both physicians and men should be made aware of the risk.
A European registry should be set up to provide an objective basis for prospective screening and therapeutic management.

Table 1 : Differential diagnosis between a benign mass and a suspicious mass

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2. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282-8.
3. Hayes TG. Pharmacologic treatment of male breast cancer. Expert Opin Pharmacother 2009;10:2499-510.
4. Jordan VC. A century of deciphering the control mechanisms of sex steroid action in breast and prostate cancer: the origins of targeted therapy and chemoprevention. Cancer Res 2009;69:1243-54.
5. Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 2005;23:808-15.