Rachel Lynn, MD

Globally, breast cancer is the most frequently diagnosed cancer; the lifetime incidence among women is 12%. It represents the leading cause of cancer death among women worldwide.

 To support patients with breast cancer, it is important to understand the trajectory and practical logistics of breast cancer treatment. Psychiatrists should also be aware of possible medication interactions, psychiatric or neurologic adverse effects of treatment, and signs of disease progression-issues that are the focus of this article.

The vast majority of patients (95%) with newly diagnosed breast cancer have no evidence of metastatic disease. For these patients, the treatment approach depends on the stage at presentation. In general, patients with early-stage breast cancer undergo primary surgery (lumpectomy or mastectomy) to the breast and regional nodes with or without radiation therapy (RT). Following definitive local treatment, adjuvant chemotherapy may be offered based on primary tumor characteristics, such as tumor size, grade, number of involved lymph nodes, the status of estrogen and progesterone receptors, and expression of human epidermal growth factor receptor 2. Chemotherapy may last up to 3 months, and radiation therapy generally occurs 5 days a week for 3 to 6 weeks. There are sometimes variations on these treatment schedules (such as several months of neoadjuvant chemotherapy), particularly in the context of clinical trials.

Patients with estrogen-positive breast cancer will subsequently receive endocrine therapy-tamoxifen, ovarian suppression, and/or aromatase inhibitors, depending on menopausal status-to reduce the risk of breast cancer recurrence and mortality. The recommended duration of adjuvant endocrine therapy was recently extended from 5 to 10 years, and the role of ovarian suppression has also expanded in high-risk premenopausal women. Both changes have resulted in a higher proportion of women with secondary infertility and ongoing exposure to hormonal treatments, all of which may erode quality of life and increase the risk of anxiety and mood disturbance.

Pretreatment consultation regarding fertility preservation options reduces long-term regret and dissatisfaction concerning fertility, independent of age or previous parity.

 The American Society of Clinical Oncology recommends routinely offering such consultations to all premenopausal women with breast cancer, particularly those who undergo chemotherapy, given its adverse impact on ovarian reserve.

Adverse prognostic factors in breast cancer are shown in 

. Patients with hormone-receptor–negative cancers tend to experience the majority of recurrences within the first 3 to 5 years after completing treatment, while those with estrogen/progesterone positivity remain at a low risk of recurrence (2% per year) indefinitely. In addition, human epidermal growth factor receptor 2–positive tumors are relatively more trophic to the brain than other types of breast cancer. Among patients with stage IV (metastatic) breast cancer, those with bone-only disease may experience prolonged survival, sometimes on the order of many years.

Psychiatric syndromes in breast cancer patients

Adjustment, depressive, and anxiety disorders are the most common forms of neuropsychiatric illness in patients with breast cancer (

). Risk factors include younger age, receipt of chemotherapy, hormonal disruption (amenorrhea/hot flashes), and marital discord. Symptoms appear to be most prominent at specific points in the course of the illness:

• At completion of active treatment, when patients are confronted with existential angst and fears of recurrence in the setting of less active follow-up with medical providers

• At diagnosis of recurrence or metastasis

6 Psychotherapy Questions for Medically Ill Patients

In patients with breast cancer, there is a nonlinear decline in the point prevalence of depression and anxiety in the years following diagnosis (50% in the first year; 25% in years 2 to 4; 15% in year 5), with an increase to 45% within 3 months of diagnosis of a recurrence.

 Thus, it is appropriate to reassure patients that their symptoms are likely to improve as they progress through survivorship. Although up to 80% of patients experience some PTSD symptoms related to breast cancer in the year after diagnosis, rates of acute stress disorder and PTSD after breast cancer are similar to those of the general population (2% to 4%).

Delirium, brain metastases, and leptomeningeal disease with neuropsychiatric symptoms can also occur in this population. These conditions are more often seen in patients with stage IV breast cancer, although patients with aggressive triple-negative or human epidermal growth factor receptor 2–positive tumors are also at elevated risk. Psychiatrists who are caring for a patient with high-risk breast cancer should watch for potential symptoms of CNS disease, such as headaches, vision changes/diplopia, cognitive or personality changes, and gait dysfunction.

Many women are offered the choice of either a mastectomy (with or without reconstruction) or a lumpectomy for management of early-stage breast cancer. Difficulty in navigating these and other treatment choices may be a distinct aspect of breast cancer treatment that leads to high rates of anxiety.

A major incentive for the development of breast-conserving surgery was to reduce the presumed emotional impact of radical mastectomy. However, studies have not found lumpectomy to be a psychosocial panacea-women demonstrate similar levels of depression and sexual dysfunction in the months after surgery, regardless of the specific procedure. Women who undergo lumpectomy do tend to have less body image disturbance.

 For those who undergo mastectomy, psychological distress (including depression and anxiety) is apparent immediately and 1 year after surgery, regardless of reconstruction or timing of reconstruction (immediate vs delayed).

Lymphedema-to which patients are mainly predisposed by prior axillary lymph node dissection rather than by type of breast surgery-represents an additional risk factor for depression and anxiety.

Insomnia is extremely common during breast cancer chemotherapy, particularly because of circadian rhythm disruptions, daytime inactivity, and corticosteroid tapers for nausea related to chemotherapy. It may be managed with trazodone, zolpidem, or lorazepam as needed. Note that oncology providers often prescribe lorazepam on an as-needed basis for nausea and insomnia; duplicate prescribing should be avoided.

Gabapentin may help hot flashes associated with insomnia. Melatonin may also be used for initial insomnia, particularly given some evidence that it may inhibit tumor growth.

 Although mirtazapine is an appealing option, many breast cancer patients gain considerable weight over the course of chemotherapy and adjuvant endocrine therapy, which limits the role of this medication.

For patients who present with functionally impairing depressive or anxious symptoms during chemotherapy, concurrent initiation of an antidepressant is reasonable. In addition to improving depression and anxiety, SSRIs and SNRIs (but not bupropion or mirtazapine) reduce hot flashes by approximately 50% in breast cancer survivors.

 For patients who take tamoxifen as part of their adjuvant therapy, psychiatrists must be aware of possible drug interactions in choosing an antidepressant. The research in this area is continuously evolving, and collaboration with the treating oncologist is beneficial in providing the best possible care for your patient.

Potent inhibitors of CYP P450 isoenzyme 2D6, such as paroxetine or fluoxetine, may hinder metabolism of tamoxifen into one of its most active metabolites, endoxifen (4-hydoxy-

-desmethyl-tamoxifen). Research suggests that breast cancer patients who take paroxetine have a greater risk of recurrence than those who receive no antidepressants or who take other antidepressants.

 This potential association with recurrence is not observed with other antidepressants that also inhibit isoenzyme 2D6, such as fluoxetine and bupropion.

A recent, larger study did not find an association between paroxetine use and increased risk of recurrence/mortality in patients who receive tamoxifen.

 Moreover, the discovery of new tamoxifen metabolites and the finding that other CYP isoenzymes, such as 3A4 and 2C9, are also involved in tamoxifen metabolism calls into question the relative importance of endoxifen and CYP 2D6 status in mediating the clinical effects of tamoxifen on target tissues.

Given the evolving recommendations, the best decisions regarding antidepressant therapy and tamoxifen often involve collaboration with the oncologist to allow for full consideration of breast cancer recurrence risk, severity of depressive symptoms, and effect of depressive recurrence on overall health and quality of life. 

 lists common antidepressants and their relative levels of CYP 2D6 inhibition.

Patients often attribute worsening mood symptoms to tamoxifen; however, there is limited support for this in the literature. Placebo-controlled trials of tamoxifen reveal that it does not increase rates of MDD.

 Case reports of tamoxifen-induced major depression may be confounded by chemotherapy-induced amenorrhea. Some data suggest that the same patient factors that prompt a recommendation for tamoxifen-chemotherapy and estrogen receptor positivity-are independent risk factors for depression after a diagnosis of breast cancer.

Despite the lack of group data, tamoxifen may contribute to depressive symptoms in a subgroup of patients who are sensitive to hormonal fluctuations, including those with histories of premenstrual dysphoric disorder and/or postpartum depression. Interestingly, tamoxifen is a protein kinase C inhibitor, similar to lithium and valproate, and has antimanic effects.

Psychiatrists play a critical role in devising treatment regimens that will increase the likelihood of tolerating adjuvant endocrine therapy. If depressive symptoms are temporally correlated with tamoxifen use and resolve after discontinuation-and in addition do not respond to concomitant antidepressant therapy-coordination with the oncologist can help determine whether it might be appropriate to consider a switch to aromatase inhibitors in postmenopausal women, or to an ovarian suppression agent plus an aromatase inhibitor in premenopausal women. There are no relevant drug/drug interactions between antidepressants and aromatase inhibitors/ovarian suppression agents. However, some patients may continue to experience mood lability while they take ovarian suppression agents and/or aromatase inhibitors.

Psychotherapy is a crucial component of psychiatric care for patients with breast cancer. Cancer is a life-transforming diagnosis and a traumatic stressor that presents numerous immediate threats, including:

• Treatments that often seem worse than the disease itself

Whenever possible, supportive therapy should be incorporated into medication management visits for breast cancer patients. Unfortunately, early hopes that group therapy might prolong survival in patients with metastatic breast cancer have not been conclusively borne out.

 Still, a recent randomized clinical trial that tested a group-based psychological intervention in patients with regional breast cancer found that patients in the intervention group had significantly reduced risks of breast cancer recurrence and death.

Overall, 5% to 10% of women with breast cancer have genetic mutations, primarily BRCA1 and BRCA2, which are inherited in an autosomally dominant fashion; the rate approaches 20% in women with a family history of breast cancer. BRCA positivity may lead to emotional turmoil, given the need to consider more extensive surgery (bilateral mastectomy and prophylactic oophorectomy) and guilt over potential transmission to children. However, BRCA mutations do not appear to increase the overall risk of psychiatric disorders in patients with breast cancer.

Male breast cancer represents 0.5% to 1% of all breast cancer diagnoses; up to 15% of men with breast cancer harbor a BRCA mutation. Men may experience increased psychological distress because of the strong association between breast cancer and female gender. Furthermore, aspects of their medical care-such as questionnaires asking about menstrual functioning and clinical trials that exclude males-may heighten these feelings. Telephone or on-line support groups offer promise in combating isolation among male breast cancer patients.

Because of the high prevalence of breast cancer in the general population-with potentially further increases in the risk of worse outcomes as a result of mental illness-virtually every practicing psychiatrist will at some point treat a patient with a breast cancer diagnosis or recurrence. Adjustment, anxiety, and depressive disorders are the most common neuropsychiatric illnesses across the stages of the disease. Cognitive disorders due to brain metastases, leptomeningeal disease, and delirium warrant consideration in the setting of advanced cancer. A working knowledge of the practical logistics of breast cancer treatment, communication with the patient’s oncology treatment team when feasible, and encouragement of adjunctive therapy (including group therapy) are critical strategies to facilitate patients’ adjustment to this life-altering diagnosis.

The authors acknowledge the Academy of Psychosomatic Medicine (APM) for helping to bring this article to fruition. The APM is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions. More information on the APM can be found at 

Dr. Meyer is Staff Psychiatrist at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital and is Assistant Professor of Psychiatry, Harvard Medical School, Boston, MA. Dr. Lynn is Staff Psychiatrist and Assistant Professor in the department of psychiatry at the University of Texas (UT) MD Anderson Cancer Center and Adjunct Assistant Professor at Baylor College of Medicine and McGovern Medical School at UT Health Science Center of Houston. The authors report no conflicts of interest concerning the subject matter of this article.

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Articles

To support patients with breast cancer, psychiatrists should be aware of possible medication interactions, psychiatric or neurologic adverse effects of treatment, and signs of disease progression--issues that are the focus here. 

Rachel Lynn, MD

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Breast Cancer: What Psychiatrists Need to Know