Table 3 Characteristics of included studies and their findings of interest

Argalacsova et al., 2017 [25]; Czech Republic

Oncology department of a local university

Localised and advanced breast cancer patients undergoing tamoxifen therapy

(N = 258)

CYP2D6

• CYP2D6 metabolic activity classes

• Occurrence of gynaecological adverse events including hot flashes

• Time to appearance of adverse events including hot flashes

• Not specified

Comparison between CYP2D6 metabolic activity classes

• No significant difference was reported in the occurrence of gynaecological adverse events nor time to appearance of such events between UMs, EMs, IMs and PMs. (p value not reported)

Baxter et al., 2014 [26]; Canada

Personalised medicine tamoxifen clinic at a local university hospital

Breast cancer patients receiving adjuvant tamoxifen therapy

(N = 132)

CYP3A4

CYP2D6

• CYP2D6 metabolic activity classes

• CYP3A4 SNPs

• Hot flashes severity

• Hot flash severity survey

Comparison between CYP2D6 metabolic activity classes

• Genotypes of CYP2D6 that affect its metabolic activity have no correlation with hot flash severity (p = 0.76), after adjusting for the factor of concurrent intake of CYP2D6 inhibitory medications and tamoxifen.

• However, without such adjustment, IM had significantly lower hot flash severity compared to EM (p < 0.01)

The CYP3A4*22 SNP

• Compared to patients bearing the CYP3A4 wt allele, those having the CYP3A4*22 SNP are almost 9 times more likely to have zero hot flash severity scores (OR: 8.87, 95% CI; 1.78–44.14, p < 0.01)

• By comparing the two groups of patients (patients with wt CYP3A4 vs patients with CYP3A4*22 SNP) who have similar endoxifen levels, patients with CYP3A4*22 SNP are 13 times more likely to have zero hot flash severity score (OR: 13.0, p = 0.0174)

Dezentjé et al. 2014 [27]; The Netherlands

Not specified in article

Early breast cancer patients, patients to be treated with tamoxifen

(N = 742)

CYP2D6 CYP2C9 CYP2C19 CYP2B6 CYP3A5

• SNPs of CYP2D6, CYP2C9, CYP2C19, CYP2B6 and CYP3A5

• CYP2D6 metabolic activity classes

• Hot flashes occurrence

• Time to the first occurrence of hot flashes

• Adverse events case report forms

Association between CYP SNPs and hot flashes outcomes

• None of the CYP SNPs investigated (CYP2D6*3/*4/*6/*14/*41; CYP2C9*2/*3; CYP2C19*2/*17; CYP2B6*6/*6; CYP3A5*3) showed association with occurrence of hot flashes nor time to the first occurrence of hot flashes (p ≥ 0.17)

Comparison between CYP2D6 metabolic activity classes

• PMs appeared to be more likely to experience no hot flashes compared to IMs and EMs, but the difference in such likeliness between groups did not reach statistical significance (p = 0.78)

Fox et al., 2016 [28]; Australia

Not specified in article

Hormone receptor-positive breast cancer patients undergoing tamoxifen therapy

(N = 122)

CYP2D6

• CYP2D6 metabolic activity classes

• Hot flashes frequency

• Hot flashes severity

• Hot flashes diaries

Comparison between CYP2D6 metabolic activity classes

• Genotypes of CYP2D6 that affect its metabolic activity have no correlation with hot flash occurrence and severity (data not provided)

Goetz et al., 2005 [29]; USA

Mayo Clinic and North Central Cancer Treatment Group sites

Oestrogen receptor-

positive breast cancer patients. Patients to be treated with tamoxifen followed by fluoxymesterone

(N = 223)

CYP2D6

CYP3A5

• CYP2D6 SNPs and genotypes

• CYP3A5 SNPs and genotypes

• Hot flashes severity

• Patient-reported severity of hot flashes, and graded according to the National Cancer Institute Common Toxicity Criteria (version 1)

The CYP3A5*3 SNP (6986 G > A)

• No significant difference in the proportion of patients bearing the various genotypes of this variant in developing moderate or severe hot flashes (p value not reported)

o homozygous G/G: 21%

o heterozygous G/A: 25%

o homozygous A/A: 17%

• CYP3A5 SNPs have no association with severity of hot flashes among patients.

Genotype of the CYP2D6*4 SNP (1846 G > A)

• There is a tendency for a significantly higher proportion of patients bearing the homozygous wt and heterozygous genotype of this variant in developing moderate or severe hot flashes than those bearing the homozygous *4 allele. However, the difference did not reach statistical significance (p = 0.06).

o homozygous wt/wt: 20%

o heterozygous *4/wt: 23%

o homozygous *4/*4: 0%

Henry et al., 2009 [30]; USA

Not specified in article

Breast cancer patients starting tamoxifen treatment

(N = 297)

CYP2D6

• CYP2D6 metabolic activity classes

• Hot flashes frequency

• Hot flashes severity

• Hot flashes diaries

Comparison between CYP2D6 metabolic activity classes after 4 months of tamoxifen therapy

• Significantly higher mean weekly hot flash score (indicating hot flash severity and frequency) was reported among IMs (44.3 ± 10.2), compared to EMs (26.9 ± 8.8, p = 0.011) and PMs (20.6 ± 16.9, p = 0.038).

• EMs (p = 0.100) and PMs (p = 0.089) tend to have a higher likeliness in experiencing no hot flashes compared to IMs. Difference in such likeliness did not reach statistical significance.

• Proportion of PMs having severe or very severe hot flashes tends to be less than that of EMs and IMs (9.5% vs 29.8%, p = 0.062)

• Significantly higher hot flash frequency was also reported among IMs, compared to EMs and PMs (data and p value not reported)

Jager et al., 2013 [31]; The Netherlands

Local cancer institute

Breast cancer patients undergoing tamoxifen therapy

(N = 109)

CYP2D6

• CYP2D6 metabolic activity classes

• Hot flashes frequency

• Hot flashes severity

• Hot flashes diaries

Comparison between CYP2D6 metabolic activity classes

• There were no significant difference in hot flash frequency (p = 0.61) nor hot flash severity (p = 0.99) between EMs, IMs and PMs.

Jansen et al., 2018 [32]; Canada

Personalised medicine tamoxifen clinic at a local health sciences centre

Breast cancer patients undergoing tamoxifen therapy

(N = 410)

CYP2D6

CYP3A4

• SNPs of CYP3A4

• CYP2D6 metabolic activity classes

• Hot flashes severity

• Hot flashes surveys – Patient-reported occurrence of severe hot flashes based on 7-day recall

Comparison between CYP2D6 metabolic activity classes

• Compared to EMs, no significant differences were observed on the level of hot flashes severity among UMs (p = 0.315), IMs (p = 0.681) and PMs (p = 0.822).

The CYP3A4*22 SNP

• The CYP3A4*22 SNP has no effect on hot flashes severity among patients (p = 0.762). No association between CYP3A4*22 SNP and hot flashes severity was observed.

Joffe et al., 2012 [33]; USA

Not specified in article

Breast cancer patients starting adjuvant endocrine therapy

(N = 18)

CYP2D6

• CYP2D6 metabolic activity classes

• Occurrence of hot flashes

• Hot flashes diaries

• Skin-conductance monitor

Comparison between CYP2D6 metabolic activity classes

• No significant difference in the proportion of patients having hot flashes induced by adjuvant endocrine therapy between the EM group and IM group (p value not reported).

Johansson et al., 2016 [34]; Multi-country collaboration

Not specified in article

Oestrogen receptor and/or progesterone receptor-

positive early breast cancer patients before starting adjuvant therapy

(N = 1967)

CYP19A1

• CYP19A1 SNPs

• Occurrence / Severity of hot flashes, sweating, myalgia, joint pain and joint stiffness

• Patient-reported severity of symptoms, and graded according to Common Terminology Criteria for Adverse Events Version 3.0

Association with hot flashes

The rs10046 (C > T) SNP of CYP19A1

• A significant reduction in the odds of having early-onset severe hot flashes and sweating among patients bearing the homozygous T/T genotype for this SNP, compared to those bearing the homozygous wt and heterozygous genotype. (OR = 0.78, 95% CI 0.63–0.97; p = 0.03)

• After adjusting for confounders, reduction of such odds was still observed, but the difference did not reach statistical significance (OR = 0.83, 95% CI 0.66–1.04; p = 0.10)

The rs4646 (G > T) SNP of CYP19A1

• No significant correlation between this SNP and odds of occurrence of severe hot flashes and sweating, after adjusting for confounders (OR = 1.08, 95% CI 0.93–1.25; p = 0.30)

Association with musculoskeletal symptoms

The rs10046 (C > T) SNP of CYP19A1

• No significant correlation between this SNP and odds of occurrence of severe musculoskeletal symptoms, after adjusting for confounders (OR = 0.84, 95% CI 0.65–1.09; p = 0.18)

The rs4646 (G > T) SNP of CYP19A1

• No significant correlation between this SNP and odds of occurrence of severe musculoskeletal symptoms, after adjusting for confounders (OR = 1.11, 95% CI 0.93–1.31; p = 0.25)

Regan et al.,

2012 [35]; Multi-country collaboration

Not specified in article

Oestrogen receptor and/or progesterone receptor-

positive breast cancer patients. Patients to be treated with tamoxifen and/or letrozole

(N = 4393)

CYP2D6

• CYP2D6 metabolic activity classes

• Occurrence and severity of hot flashes or night sweats

• Patient-reported occurrence of hot flashes on case report forms, and severity was graded according to the Common Toxicity Criteria (version 2.0

Among patients receiving tamoxifen who did not undergo chemotherapy previously

• Genotypes of CYP2D6 that affect its metabolic activity are associated with the occurrence of hot flashes/night sweats (p = 0.02)

• PMs and IMs are more likely to have hot flashes/night sweats than EMs.

• Hazard ratios of developing hot flashes/night sweats:

o PM vs EM: 1.24 (95% CI: 0.96–1.59)

o IM vs EM: 1.23 (95% CI: 1.05–1.43)

Among patients receiving tamoxifen who underwent chemotherapy previously

• No association between CYP2D6 genotypes that affect its metabolic activity and hot flashes/night sweats occurrence (p = 0.81)

• Hazard ratios of developing hot flashes/night sweats:

o PM vs EM: 0.85 (95% CI: 0.47–1.54)

o IM vs EM: 1.05 (95% CI: 0.76–1.45)

Among patients receiving letrozole who did not undergo chemotherapy previously

• No association between CYP2D6 genotypes that affect its metabolic activity and hot flashes/night sweats occurrence (p = 0.72)

• Hazard ratios of developing hot flashes/night sweats:

o PM vs EM: 1.10 (95% CI: 0.85–1.44)

o IM vs EM: 0.99 (95% CI: 0.83–1.17)

Among patients receiving letrozole who underwent chemotherapy previously

• PMs and IMs tend to be more likely to develop hot flashes/night sweats than EMs. (p = 0.06)

• Hazard ratios of developing hot flashes/night sweats:

o PM vs EM: 1.94 (95% CI: 1.12–3.35)

o IM vs EM: 1.16 (95% CI: 0.81–1.64)

Ruddy et al., 2013 [36]; USA

Oncology centre at a local cancer institute

Stage I-III breast cancer patients undergoing tamoxifen therapy

(N = 99)

CYP2D6

• CYP2D6 metabolic activity classes (including a rare allele (RA) class – individuals in this class have an EM phenotype)

• Occurrence of hot flashes

• Level of bother caused by hot flashes

• Questionnaire developed based on the Breast Cancer Prevention Trial scale of menopausal symptoms

Comparison between CYP2D6 metabolic activity classes

• The proportion of patients having developed hot flashes is similar between the UM/EM/RA group and IM group. (67% vs 69%)

• The proportion of patients expressing that they are at least slightly bothered by hot flashes is similar between the UM/EM/RA group and IM group (63% vs 69%)

• The proportion of patients expressing that they are at least moderately bothered by hot flashes is similar between the UM/EM/RA group and IM group (34% vs 38%)

Wickramage et al., 2017 [37]; Sri Lanka

Hospital clinic at the National Cancer Institute in Sri Lanka

Breast cancer patients undergoing tamoxifen treatment

(N = 24)

CYP2D6

• SNPs of CYP2D6

• Occurrence of hot flashes

• Occurrence of hot flashes reported in clinical records

The CYP2D6*4 SNP (1846 G > A)

• The existence of the CYP2D6*4 SNP in patients was not associated with the occurrence of hot flashes among them (p = 0.437)

The CYP2D6*41 SNP (Combination of 2988 G > A, 2850 C > T and -1584C)

• The existence of the CYP2D6*41 SNP in patients was not associated with the occurrence of hot flashes among them (p = 0.271)

Zembutsu et al., 2017 [38]; Japan and Singapore

Multi-sites; Hospitals, cancer centres and cancer institutes in Japan and Singapore

Oestrogen receptor -positive, human epidermal growth

factor receptor 2-negative, invasive breast cancer patients undergoing tamoxifen therapy

(N = 279)

CYP2D6

• SNPs/Genotypes of CYP2D6

• Occurrence of hot flashes

• Not specified

• There was no significant difference in hot flashes occurrence between patients bearing the wt CYP2D6 and those having the CYP2D6 SNPs/genotypes investigated in this study (p = 0.25)