As predicted by their DNA-damaging mechanism of action, Platinum compounds are expected to be particularly active in tumours deficient of mechanisms responsible for DNA damage repair, e.g. those without active BRCA1/2 proteins.
Due to rarity of such patients, little evidence exists on the clinical activity of these drugs in BRCA1/2 mutation carriers in the metastatic setting. However, available data suggest their promising activity mostly in the neoadjuvant setting, and to a lesser degree in advanced disease.
In triple-negative breast cancer ( TNBC ), another putatively BRCA-deficient population, a relatively large amount of data from prospective studies, recently summarized in a meta-analysis, demonstrated improved pCR rates in patients whose neoadjuvant treatment included a platinum compound. However, which patients definitely benefit is not yet clear since there is also one negative GEICAM study adding Carboplatin to Epidoxorubicin - Cyclophosphamide - Docetaxel in basal-like breast cancer.
Fewer data exist for inclusion of Platinum in the treatment of metastatic disease, although the benefit in the TNBC population seems to be larger than in other breast cancer patients.
Taking available evidence into account, most of the ABC2 panel supported the inclusion of Platinum-containing regimens in the treatment of BRCA1/2 mutant patients pre-treated with anthracyclines and taxanes and demonstrated to be endocrine-resistant. ABC1-issued several recommendations for the treatment of male patients with advanced breast cancer ( ABC ) that still remain valid for ABC2.
One additional recommendation is added at this point, related to the use of aromatase inhibitors in this patient population.
There are concerns about the efficacy of these agents when used in monotherapy in male patients, due to the hypothalamic-pituitary negative feedback.
Important differences exist in the physiology of estrogen production between men and women. In men, 80% of circulating estrogens result from the peripheral aromatization of androgens, whereas 20% are directly secreted in the testicles.
Adrenals secrete less than 1% of circulating sex steroids, but precursors can undergo peripheral aromatization. So, peripheral conversion results in less than 5% of all testosterone, 80% of all dihydrotestosterone and estradiol, and nearly all of estrone ( 98% ).
Additionally, estradiol levels are 3–4 times higher in older males than in postmenopausal females.
For these reasons, and despite the lack of prospective and randomized data, the majority of panel members recommend that when an aromatase inhibitor needs to be used in male advanced breast cancer patients, a concomitant luteinizing-hormone-releasing hormone agonist or orchiectomy should be added to further down-regulate testicular function. ( Xagena )
Source: ESO ( European School of Oncology ) and ESMO ( European Society of Medical Oncology ) Guidelines, 2014