Use of antipsychotics that increase prolactin levels is significantly associated with an increased risk for breast cancer in women with schizophrenia, new research suggests. However, at least one expert says that, at this point, clinical implications are premature.
Investigators compared data from Finnish nationwide registers on more than 30,000 women diagnosed with schizophrenia. Of those patients, 1,069 were diagnosed with breast cancer. Results showed that long-term exposure to prolactin-increasing antipsychotics was associated with a 56% increased risk of developing breast cancer in comparison with exposure of short duration. No significant association was found with cumulative exposure to prolactin-sparing antipsychotics.
“In case of planning for long-term antipsychotic [therapy], prefer non–prolactin-raising antipsychotics in females and inform patients about a potential risk to allow for informed shared decision-making,” study coauthor Christoph U. Correll, MD, professor of psychiatry and molecular medicine at Hofstra University, Hempstead, N.Y., told this news organization.
The study was published online Aug. 30, 2021, in The Lancet.
A ‘relevant contribution’
Breast cancer is 25% more prevalent among women with schizophrenia than among women in the general population. Antipsychotics have long been suspected as a potential culprit, but research results have been inconsistent, said Dr. Correll.
In addition, high concentrations of prolactin are associated with a higher risk of developing breast cancer, but most previous research did not distinguish between antipsychotics that increased prolactin levels those that did not.
Dr. Correll and colleagues “wanted to add to this literature by utilizing a generalizable nationwide sample with a sufficient large number of patients and sufficiently long follow-up to address the clinically very relevant question whether antipsychotic use could increase the risk of breast cancer.”
They also believed that grouping antipsychotics into prolactin-raising and non–prolactin-raising agents would be “a relevant contribution.”
The researchers drew on data from several large Finnish databases to conduct a nested case-control study of 30,785 women aged at least16 years who were diagnosed with schizophrenia between 1972 and 2014.
Of these patients, 1,069 received an initial diagnosis of invasive breast cancer (after being diagnosed with schizophrenia) between 2000 and 2017. These case patients were compared to 5,339 matched control patients. The mean age of the case patients and the control patients was 62 years. The mean time since initial diagnosis of schizophrenia was 24 years.
Antipsychotic use was divided into three periods: less than 1 year, 1-4 years, and ≥5 years. Antipsychotics were further divided into prolactin-increasing or prolactin-sparing drugs (for example, clozapine, quetiapine, or aripiprazole). Breast cancer was divided into either lobular or ductal adenocarcinoma.
In their statistical analyses, the researchers adjusted for an array of covariates, including previous diagnoses of other medical conditions, drugs that may modify the risk for breast cancer (for example, beta-blockers, calcium channel blockers, spironolactone, loop diuretics, and statins), substance misuse, suicide attempt, parity, and use of hormone replacement therapy (HRT).
‘Clinically meaningful’ risk
Ductal adenocarcinoma was more common than lobular adenocarcinoma (73% vs. 20% among case patients). A higher proportion of case patients used cardiovascular medications and HRT, compared with control patients.
A higher proportion of case patients had used prolactin-increasing antipsychotics for at least 5 years, compared with control patients (71.4% vs. 64.3%; adjusted odds ratio, 1.56; 95% CI, 1.27-1.92; P < .0001) in comparison with minimal exposure (<1 year) to prolactin-increasing antipsychotics.
On the other hand, a similar proportion of case patients and control patients used prolactin-sparing antipsychotics for at least 5 years (8.3 vs. 8.2%; aOR, 1.19; 95% CI, 0.90-1.58); the OR of 1.19 was not deemed significant.
Although exposure of ≥5 years to prolactin-increasing antipsychotics was associated with an increased risk for both types of adenocarcinoma, the risk was higher for lobular than for ductal disease (aOR, 2.36; 95% CI, 1.46-3.82 vs. aOR, 1.42; 95% CI, 1.12-1.80).
“Conservatively, if we subtract the 19% nonsignificantly increased odds with prolactin-sparing antipsychotics from the 56% significantly increased odds with prolactin-increasing antipsychotics, we obtain a 37% relative increase in odds,” the authors noted.
“Using a lifetime incidence of breast cancer in women in the general population of about 12%, with a somewhat higher lifetime incidence in patients with schizophrenia than the general population, this difference between prolactin-increasing versus prolactin-sparing antipsychotics in breast cancer risk upon exposure of 5 or more years would correspond to about a 4% (37% x 12%) increase in absolute breast cancer odds with prolactin-increasing antipsychotic treatment” – a difference the authors call “clinically meaningful.”
Correll noted that although the study was conducted in a Finnish population, the findings are generalizable to other populations.
Clinical implications premature?
Commenting on the study, Anton Pottegård, MScPharm, PhD, DMSc, professor of pharmacoepidemiology, department of public health, University of Southern Denmark, Odense, expressed concern that “this new study is fairly aggressive in its recommendation [that] we need to pay attention to hyperprolactinemia, as this seems to cause breast cancer.”
Dr. Pottegård, who is also the head of research, Hospital Pharmacy Funen, Odense University Hospital, who was not involved with the study, said he does not “think that the full body of the literature supports such a direct conclusion and/or direct inference to clinical practice.”
Although “this is an important study to further this work, I do not think we are at a place (yet) where it should lead to different action from clinicians,” Dr. Pottegård cautioned.
Also commenting on the study, Mary Seeman, MDCM, DSc, professor emeritus of neurosciences and clinical translation, department of psychiatry, University of Toronto, called the question of whether prolactin-increasing antipsychotics increase breast cancer risk “very complicated because the incidence of breast cancer ... is higher in women with schizophrenia than in other women.”
Dr. Seeman, who was not involved with the study, pointed to other reasons for the increased risk, including higher rates of obesity, substance abuse, cigarette smoking, stress, and sedentary behavior, all of which raise prolactin levels. Additionally, “protective factors such as pregnancies and breastfeeding are less frequent in women with schizophrenia than in their peers.” Women with schizophrenia also “tend not to do breast screening, see their doctors less often, follow doctors’ orders less rigorously, and obtain treatment less often.”
The take-home message “is to prescribe prolactin-sparing medication to women if at all possible – but until we know more, that is good advice, although not always possible because the illness for which the antipsychotics are prescribed may not respond to those particular medications,” Dr. Seeman said.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Funding was also provided to individual researchers by the Academy of Finland, the Finnish Medical Foundation, and the Emil Aaltonen foundation. Dr. Correll has been a consultant or advisor to or has received honoraria from numerous companies. He has provided expert testimony for Janssen and Otsuka; received royalties from UpToDate and is a stock option holder of LB Pharma; served on a data safety monitoring board for Lundbeck, Rovi, Supernus, and Teva; and received grant support from Janssen and Takeda. Dr. Pottegård and Dr. Seeman disclosed no relevant financial relationships.
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