18 November, 2019: 

a comment on Climacteric Editor's Choice "Benefit-risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer"

Summary

Breast cancer patients treated with endocrine therapies can suffer severe climacteric vasomotor and psychological symptoms as a consequence of the anti-estrogenic effects; hence, treatment adherence can be compromised. To determine if these symptoms can be treated with specific herbal medications, the authors of the present paper reviewed the benefit-risk profile of a standardized extract of isopropanol Cimicifuga racemosa (iCR) REMIFEMIN®, and a higher dose iCR preparation in a fixed combination with Hypericum perforatum (HP/iCR) REMIFEMIN PLUS®, in women surviving breast cancer, treated or not with tamoxifen (TMX) or aromatase inhibitors. The review is based on a systematic literature search (1997 - April 2018) analyzing clinical studies in breast cancer patients, as well as experimental data on biological effects in breast cancer cells, in animal models of breast cancer, in human breast cancer tissue, and studies on the metabolism of endocrine therapies. The authors concluded that there is a favorable benefit/risk profile of both herbal medicinal products, that could offer a non-hormonal therapeutic option for these women [1].

Commentary

Knowledge of the efficacy and safety of phytopharmaceutical treatment options for climacteric symptoms is much needed, especially for women undergoing endocrine treatment for breast cancer. Ruan and colleagues analyzed data on Remifemin® (iCR) and Remifemim Plus® (HP/iCR), standardized registered phytopharmaceuticals produced in Germany by Schaper & Brümmer GmbH–Co.KG, with certified quality of manufacturing [1]. These specific extracts were already reviewed in 2013, with results distinguishing them from other CR preparations [2]. In 2012, a Cochrane Systematic Review had concluded that there was insufficient evidence to support the use of black cohosh for menopausal symptoms [3]. However, a later review reported a significant efficacy of black cohosh on vasomotor symptoms and on psychological climacteric symptoms [2]; this review was based on 9 clinical studies, of which two were double-blinded placebo-controlled (Remifemin® (n=304 women 12-week duration), and Remifemin Plus® (n=301 and 16-week duration)), another was blinded versus tibolone, and the others were open versus low-dose transdermal estradiol. Ruan and colleagues state this is Oxford Level 1 evidence of efficacy [1].

The present review [1] describes a few small studies in patients on tamoxifen or raloxifene treatment or no treatment, showing variable to poor results of efficacy on symptoms. The authors concluded that tamoxifen may affect efficacy and suggested that higher doses of the phytopharmaceuticals should be administered to these patients, following the observation of a better response to increasing doses of or switching to the combined formulation with HP [1].

Furthermore, two retrospective studies have suggested a protective role of CR on breast cancer [1]: a population-based case-control study in the USA reported significantly less breast cancer in black cohosh users; another study, a big pharmacoepidemiological retrospective cohort study (18,861 breast cancer survivors, 1,102 treated with iCR or iCR/HP) led by the producers of the specific products reported better disease-free survival in breast cancer patients using iCR in Germany. More rigorous research is needed to verify this effect.

The annulment of all estrogen activity on estrogen-sensitive organs is fundamental in breast cancer survivors and there should be no interference with adjuvant antiestrogen therapy on behalf of concomitant pharmacological therapy, including phytochemicals. The key phytoconstituents of Cimicifuga racemosa (CR) are triterpene glycosides, phenolic acids, and Nω-methylserotonin; the latter is hypothesized as having the effect of reducing vasomotor symptoms [4,5]. CR does not contain phytoestrogens. As reviewed [1], the extracts do not influence hormone plasma levels, breast cell proliferation, breast mammographic density, or endometrial thickness. iCR preclinical data mostly show favorable effects: no stimulation of tumor growth, antiproliferative effects/induction of apoptosis, enhancement of the antineoplastic effects of TMX. Nevertheless, a particular mouse cancer model showed an increase in lung metastases with the use of this phytochemical [6]. Hence, The European Medicines Agency Committee on Herbal Medicinal Products in 2018 specified that these preclinical controversial data call for precaution, and stated that “Influence on breast cancer or other hormone-depending tumors cannot be excluded”, and that “adequate tests on genotoxicity, carcinogenicity and reproductive toxicity have not been performed”, therefore these patients “should not use CR preparations without medical advice”[7].

The combination of CR with HP has the objective of improving psychological symptoms. The key phytoconstituents in HP are hypericin and hyperforin: the first is a reuptake inhibitor of the neurotransmitters serotonin, norepinephrine, dopamine, GABA [5], the second has a dopaminergic effect. HP also contains rutoside, a flavonoid glycoside, and quercetin, a flavonol aglycone, both with low bioavailability. Flavonoids should be avoided in women with breast cancer and, in particular, in women being treated with TMX due to possible antagonism. It is of vital importance to know more about the possible action of HP on estrogen-sensitive organs. The EMA/HMPC indicates that the amounts of flavonoids in HP preparations should be declared [8]. TMX is metabolized mainly via CYP2D6 and CYP3A4 into its active metabolite endoxifen; the inhibition of these enzymes could interfere with efficacy. CR has no known interactions with CYP(P450) activity. In HP, the hyperforin constituent may induce CYP3A4 [9] and enhance metabolism to endoxifen, though very slightly. Flavonoids/flavonols have inhibiting effects on CYP2C9 and CYP3A4; thus, the flavonoid rutin constituent and the flavonol quercetin in HP could interfere with TMX metabolism [9]. Aromatase inhibitors, anastrozole, and letrozole do not seem to have significant interactions with HP. Exemestane is mainly metabolized by CYP3A4 to less potent metabolites; nevertheless, the induction by HP is slight and the interaction would not be relevant. In conclusion, it is not possible to categorically state whether there is a favorable benefit/risk profile of both phytopharmaceuticals in breast cancer patients.

Comprehensive everyday experience judged as good in terms of efficacy and tolerability of these products [1], needs to be evidenced with rigorous data analysis. Cimicifuga racemosa seems to be safe considering that it has no estrogenic action and it does not interact with CYP (P450) activity. There is reason and the necessity to conduct further research with black cohosh in breast cancer survivors.

Paulina Villaseca

Centro de Excelencia en Biomedicina de Magallanes (CEBIMA) Universidad de Magallanes – Pontificia Universidad Católica de Chile

References

1. Ruan X, Mueck AO, Beer AM, Naser B, Pickartz S. Review. Benefit-risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer patients. Climacteric 2019;22(4):339-347.
   https://www.ncbi.nlm.nih.gov/pubmed/30626212
2. Beer AM, Neff A. Differentiated evaluation of extract-specific evidence on Cimicifuga racemosa’s efficacy and safety for climacteric complaints. Evid Based Complement Alternat Med 2013;2013: 860602
   https://www.ncbi.nlm.nih.gov/pubmed/24062793
3. Leach MJ, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD007244.
   https://www.ncbi.nlm.nih.gov/pubmed/22972105
4. Chen SN, Fabricant DS, Lu ZZ, Fong HHS, Farnsworth NR. Cimiracemosides I-P, new 9,19-cyclolanostane triterpene glycosides from Cimicifuga racemose. J Nat Prod 2002;65(10):1391-7.
   https://doi.org/10.1021/np0200818
5. Powell SL, Gödecke T, Nikolic D, et al. In vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as a potential active constituent. J Agric Food Chem 2008;56(24):11718-26.
   https://www.ncbi.nlm.nih.gov/pubmed/19049296
6. Davis VL, Jayo MJ, Ho A, et al. Black cohosh increases metastatic mammary cancer in transgenic mice expressing c-erbB2. Cancer Res 2008;68:8377–83.
   https://www.ncbi.nlm.nih.gov/pubmed/18922910
7. European Union Herbal Monograph on Cimicifuga racemosa (L.) Nutt., rhizoma EMA/HMPC/48745/2017.
   https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-cimicifuga-racemosa-l-nutt-rhizome-revision-1_en.pdf
8. Community Herbal Monograph on Hypericum Perforatum L., Herba (Well-Established Medicinal Use). Doc Ref: EMA/HMPC/101304/2008.
   https://www.ema.europa.eu/en/documents/herbal-monograph/final-community-herbal-monograph-hypericum-perforatum-l-herba-well-established-medicinal-use_en.pdf
9. NIH. US National Library of Medicine. National Center for Biotechnology Information. PubChem. Hyperforin.
   https://pubchem.ncbi.nlm.nih.gov/compound/441298