Antipsychotic Treatment in Breast Cancer Patients
Abstract
Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.
Antipsychotic drugs approved for clinical use by the U.S. Food and Drug Administration (FDA) are packaged with precautions regarding their administration to patients with established breast cancer. Because of the potential for antipsychotics to cause complications in patients with breast cancer, careful consideration is required before prescribing these agents for women with breast cancer who have a comorbid mental illness. While no clear causal link has been established between the use of antipsychotics and the risk of breast cancer, many antipsychotics are known to elevate serum prolactin levels, and a significant body of evidence supports a role for prolactin in both the pathobiology and the progression of established breast cancer (1–3). Compared with normal mammary cells, cancerous breast cells overexpress the prolactin receptor (PRLr). Prolactin supports the proliferation, survival, motility, invasion, and anchorage-independent growth (an acquired ability to grow without attachment to a basement membrane) of both estrogen receptor (ER)-positive and ER-negative breast cancer cells (4–7). We present a review of pertinent studies of tumorigenesis carried out at the cellular level involving both human and mouse models and discuss the evidence that antipsychotic agents may adversely affect women with established breast cancer. Recommendations and a rationale for treating such patients are also discussed.
Prolactin
Prolactin is a neuroendocrine hormone that is normally elevated during pregnancy and lactation. Prolactin not only is secreted by the pituitary gland, but also is produced in a variety of tissues, such as breast, lymphocytes, uterus, prostate, and placental decidua. Cells within these tissues elaborate prolactin, which functions locally by affecting the cell of origin or neighboring cells in an autocrine/paracrine fashion (4). Medical conditions such as pituitary tumor, stress, hypothalamic disorders, liver disease, and kidney disease can also elevate prolactin levels. It is well established that prolactin levels become elevated as a response to many antipsychotic drugs, with resulting side effects that may include amenorrhea, galactorrhea, osteoporosis, and loss of libido.
The secretion of prolactin by the anterior pituitary involves many feedback loops. Hypothalamic inhibition of lactotroph cells, which normally release prolactin, occurs via a dopamine-mediated portal pathway known as the tuberoinfundibular tract. Antipsychotic drugs block dopamine D2 receptors within this tract, resulting in increased serum prolactin levels.
Association of Elevated Prolactin Levels and Breast Cancer
Since the available data are correlative, the question of whether or not elevated prolactin levels actually cause breast cancer is open to discussion. The National Nurse’s Health Study, a robust prospective case-control cohort study, showed that both pre- and postmenopausal women who are in the top quartile of normal serum prolactin levels have a higher risk of developing breast cancer (8, 9). In addition, breast cancer patients with elevated prolactin levels have more rapid disease progression and a lower survival rate (10, 11). Whether prolactin plays a role in new breast cancer development in patients with a genetic or other predisposition to the disease remains to be determined.
Antipsychotic drug database studies have not demonstrated a relationship between antipsychotics and any form of newly diagnosed cancer, although one study (12) reported a 16% higher risk of breast cancer in patients taking dopamine antagonists. Another study (13) suggested that an elevated risk of breast and other cancers after the first diagnosis of schizophrenia could be attributed to nongenetic factors, such as treatment with antipsychotics. Thus, to date, no clear association between chronic administration of antipsychotics and mammary tumorigenesis has been demonstrated in clinical studies.
“Ms. A,” a 38-year-old married white woman with a history of unipolar major depression and generalized anxiety disorder, was admitted as a new patient referral to a psychiatric clinic at an academic center. She had been treated for several years with sertraline, 100 mg/day, augmented with aripiprazole, 10 mg/day. Her symptoms were well controlled, with no apparent side effects. Ms. A was seen every 4–6 months for medication refills, and she usually had no complaints. Although she presented as an anxious individual, she was generally high functioning and had a successful business career and a happy marriage. She was intelligent, highly organized, and detail-oriented. Her health had always been excellent; she exercised several times a week, had never smoked cigarettes, had no history of substance abuse, and ate a healthy diet.
Eighteen months earlier, Ms. A had found a lump on her right breast during self-examination and was subsequently diagnosed with breast cancer. She underwent a single mastectomy for a 2-cm lesion. Her breast cancer receptor status was ER+, PR+, and HER2+, indicating the presence of estrogen, progesterone, and human epidermal growth factor receptor-2 receptors. She received adjuvant chemotherapy with doxorubicin/cyclophosphamide followed by paclitaxel and trastuzumab, which resulted in hair loss and consequent feelings of shame and demoralization. Endocrine therapy with tamoxifen was recommended for a total of 5 years.
During the months following her chemotherapy, Ms. A visited her primary care physician regularly in a distressed state, upset and crying, and she complained of insomnia and loss of appetite. Her primary care physician prescribed alprazolam, 0.5 mg t.i.d., in addition to her usual regimen of sertraline and aripiprazole.
Ms. A gradually accepted her cancer condition. She attended support groups and consulted a therapist. She is now being seen with her husband as a new patient in our clinic because she wanted another opinion regarding her medications. With the new diagnosis of breast cancer and additional health care expenses, she became concerned that the insurance copayment for aripiprazole plus the additional cancer expenses would be unaffordable. Ms. A researched her insurance plan’s drug formulary and discovered that risperidone was less expensive than aripiprazole on her plan. She also learned of the hormonal effects of antipsychotic drugs by reading the drug package inserts, and she now seeks information about the safety of the antipsychotic medication she was receiving.
After gathering Ms. A’s records and interviewing the patient, the treating psychiatrist determined that by continuing to use antipsychotic drugs, Ms. A ran the risk of elevated prolactin levels. Ms. A’s receptor typing was not an issue, since prolactin promotes breast cancer cell growth regardless of receptor status. Her depression was found to be similar to her previous depressive episodes and not just demoralization from a cancer diagnosis. Therefore, other treatment options were discussed, including increasing the dosage of sertraline, augmenting with another type of medication, replacing sertraline with another antidepressant, adding psychotherapy, and trying ECT. Eventually the patient did well on a combination of sertraline, 200 mg/day, and clonazepam, 0.5 mg b.i.d., without the need for augmentation with an antipsychotic. This was a lower-cost regimen and helped reassure the patient. She also responded well to cognitive therapy, education about her treatment, and the development of an alternative treatment plan should her condition worsen. After several months, the clonazepam was successfully tapered off.
Role of the Prolactin Receptor in Breast Cancer
Prolactin action is mediated by the PRLr, which is a member of the cytokine receptor superfamily (14). Overexpression of the PRLr is observed in more than 95% of human breast cancers and occurs in both ER-positive and ER-negative cancers (15). Loss of the PRLr in breast cancer cells results in a dramatic reduction in ER and progesterone receptors (PR), revealing another mechanism through which the PRLr may regulate breast cancer growth (i.e., through regulation of estrogen and progesterone action) (16). Many genes that are activated by PRLr in breast cancer cells are associated with tumorigenesis and cell proliferation (17). Lacking intrinsic kinase activity, the PRLr mediates its function through associated kinases such as Jak2, Src/Fyn, Tec, Nek3, AKT, and Raf/MAPK (1–3); all of these pathways have been implicated in the pathogenesis of breast cancer. Activation of these kinases induces the phosphorylation and activation of latent transcription factors such as Stat3 and Stat5 (18, 19). The PRLr and other receptors, such as epidermal growth factor receptor (EGFr), ER, and integrin receptors, are known to play a role in breast cancer (20). Recent evidence also indicates that the PRLr has a direct nuclear function as a transcriptional coactivator that coordinates the actions of Stat5 and the nucleosome-binding protein HMGN2 on the prolactin-driven Stat5-responsive promoter chromatin (16, 21).
Prolactin and Tumorigenesis in Mouse Models
Prolactin promotes mammary cancer in rodent models. Warning labels accompanying FDA-approved antipsychotic drugs caution physicians that chronic administration of these drugs has been associated with an increase in mammary neoplasms in rodents. This warning is based on findings predominantly from models in which the effects of prolactin are determined in mammary cells that are genetically similar to human breast cancer cells. Two types of transgenic models are used to study the effects of prolactin in mice. The “gain of function” approach forces the overexpression of a gene during early cell development in order to determine whether cancer develops as a result. The “loss of function” approach entails the elimination of a gene using homologous recombination; an existing gene is replaced by one that is nonfunctioning. The resulting gene “knockout” method is well established in murine experimentation. Prolactin transgenic mice develop a mix of ER-positive and ER-negative mammary tumors that are histologically similar to human breast tumors (22, 23). When prolactin transgenic mice are crossed with established models of murine mammary tumorigenesis, tumor development is accelerated (24). Conversely, loss of the PRLr-associated Jak2/Stat5 pathway results in delayed tumorigenesis in existing mouse models of mammary carcinoma (3, 25). Data from both of these models thus support an important role for prolactin/PRLr pathways in the pathogenesis and progression of mammary cancer in rodents.
Effect of Antipsychotics on Prolactin Levels
The potential of antipsychotic drugs to cause prolactin elevation has been well documented in the literature and is included on all product labeling. Although recent controlled investigations are somewhat lacking for first-generation antipsychotics, several studies have reported twofold to tenfold increases in plasma prolactin levels in some patients. The effects of second-generation antipsychotics have been much better documented over the past two decades, given their recent approvals and their established role as first-line treatment agents. The elevations in serum prolactin levels associated with each agent can be compared from different studies to give us an estimation of the possible risks accompanying their use. Table 1, compiled from available data on FDA-approved antipsychotic drugs (26–33), presents the relative effects of commonly prescribed antipsychotics on prolactin levels.
| Antipsychotic | Patients With Prolactin Levels >ULN (%) | Estimated Range of Prolactin Elevation | Recommendation in Patients With Breast Cancer |
|---|---|---|---|
| Risperidone | 45–87 | 45 to >100 ng/mL | Avoid |
| Paliperidone | 45–87 | 45 to >100 ng/mL | Avoid |
| Haloperidol | 34–75 | 28–50 ng/mL | Avoid |
| Olanzapine | 30–47 | 23–34 ng/mL | Caution |
| Iloperidone | 26 | 20–32 ng/mL | Caution |
| Lurasidone | 5–8 | ≥5×ULN | Caution |
| Ziprasidone | <5 | Minimal | Preferred |
| Asenapine | <5 | Minimal | Preferred |
| Quetiapine | <5 | Minimal | Preferred |
| Clozapine | <5 | Minimal | Preferred |
| Aripiprazole | <1 | May lower prolactin | Preferred |
In general, first-generation antipsychotics cause significant elevations in serum prolactin levels. Of the second-generation drugs, risperidone and its separately marketed active metabolite, paliperidone, raise prolactin levels the most. This is because these two drugs cross the blood-brain barrier poorly, and as a result, serum concentrations of risperidone and paliperidone must be higher than those of other antipsychotics in order to achieve CNS levels sufficient to exert their therapeutic effects. The pituitary is located outside the blood-brain barrier, and therefore the effect of these drugs on D2 receptors is greater (30, 33). A number of second-generation antipsychotics appear to have minimal effects on serum prolactin levels. Aripiprazole may even lower prolactin levels because of its partial agonist effect on the dopamine receptor (28, 33). Therefore, in the case of Ms. A, switching from aripiprazole to risperidone would not be deemed advisable.
Treatment Considerations
Clinicians routinely administer antipsychotic drugs to patients suffering from both a mental illness and breast cancer. However, many clinicians and their patients may be unaware of the potentially harmful effects that may be associated with the use of such drugs in this patient population. The widespread acceptance and clinical use of antipsychotics to treat a diverse array of mental conditions—bipolar disorder, major depression, autism spectrum disorders, tic disorders, dementia, and schizophrenia, as well as various off-label uses—may pose an unforeseen risk in patients with established breast cancer.
In the absence of controlled studies, it is difficult to predict how a particular antipsychotic might affect the prognosis for a woman with breast cancer. In fact, the role of serum prolactin levels is not currently an established predictor in the management of breast cancer. However, blocking the prolactin receptor has been identified as an important area of potential treatment for breast cancer (34). Considering the precautions that accompany antipsychotic drugs, and given the current available research data, a prospective study to determine the potentially harmful effects of such drugs would be considered unethical by most standards. Hence, we have combined relevant preclinical research data, FDA precautions, and some epidemiological evidence from the fields of cellular pathology, pharmacology, oncology, and psychiatry to help inform the practicing physician about the possibility of harmful side effects accompanying the use of antipsychotics in patients with breast cancer.
As with any case, clinicians must weigh the potential benefits and risks of treatment and nontreatment. It is advisable that the oncologist, psychiatrist, and other relevant clinicians be involved together with the patient (or possibly the family and guardian) to arrive at an informed decision. The duration of antipsychotic treatment, the severity and type of mental illness, potential effects on serum prolactin levels, ethical considerations, and breast cancer staging may all require careful consideration.
Since prolactin appears to promote breast cancer development irrespective of receptor status, breast cancer receptor typing is not a factor when it comes to making the decision of whether or not to prescribe an antipsychotic. All women with intraductal breast cancers should be assumed to have an elevated risk of prolactin-related progression of the disease if they are treated with antipsychotic medication.
Additionally, other risks of these drugs, such as metabolic side effects, may play a yet unknown role in breast cancer survival rates. For example, insulin resistance, genetics, parity, diet, smoking, dyslipidemia, abdominal obesity, and hypertension are all associated with a higher incidence of breast cancer (35, 36). Increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cancer cell proliferation and survival. After adjustment for body mass index, women with higher adiponectin levels were found to have a 65% lower risk for breast cancer than women in a control group (35). Clozapine and olanzapine have been reported to decrease levels of adiponectin (37). The effect, if any, of these parameters on breast cancer risk or recurrence requires further investigation.
Patients with severe psychotic illnesses such as schizophrenia are often treated with depot formulations to enhance treatment adherence. The risk of seriously exacerbating a psychotic condition by avoiding or discontinuing antipsychotic treatment may outweigh the risk of elevating levels of prolactin by administering an antipsychotic. Similarly, treatment of a delirious or agitated patient may require the relatively safer short-term use of an antipsychotic. It is recommended that serum prolactin levels be monitored in these patients to assess possible risk and to guide treatment. Switching drugs or adding dopamine agonists may also be options. Women being treated with a prolactin-elevating antipsychotic should be cautioned about the risk of unintentional pregnancy as a result of possible changes in libido and fertility after switching drugs and should be advised to consider using reliable contraception (38).
The availability of alternative classes of drug that do not elevate prolactin levels should also be carefully considered. For example, an acutely manic patient with psychosis may initially be treated aggressively with several medications, including an antipsychotic, and then placed on a less aggressive regimen of one or two non-antipsychotic mood stabilizers (lithium, anticonvulsants). In the case of Ms. A, a completely different drug regimen, with reduced potential to elevate prolactin levels, was found to be an effective means of treating her mental condition.
This case also highlights the need for the development of antipsychotic drugs that are not associated with such deleterious side effects, as well as the need for advocacy to ensure that the currently available antipsychotics that are relatively safer for breast cancer patients are covered by health insurance plans.
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