Keywords

Introduction

The management of patients with breast cancer is complex. Typically, physicians from multiple medical specialties are involved, including radiologists, general and plastic/reconstructive surgeons, medical oncologists, radiation oncologists, and others. However, the interactions of breast cancer and breast cancer therapy with the function of the female genital tract are often underemphasized or overlooked altogether. Oncologists are frequently uncertain of the need for or timing of gynecologic consultation, and gynecologists may be unprepared to address the needs of breast cancer patients. This is clearly an area of unmet need in breast cancer prevention, treatment, and follow-up care.

This chapter summarizes the major gynecologic issues facing women with breast cancer. It is intended to be comprehensive and is based on distinct episodes of care in the course of women at risk for and/or diagnosed with breast cancer. Screening/diagnostic issues, including familial/hereditary concerns, are addressed first, followed by the effects of breast cancer treatment on the normal female genital tract physiology. Fertility and menopause-specific gynecologic side effects of the major therapies for breast cancer are then discussed and, finally, the issues faced by women in follow-up of treatment are examined.

The authors’ intent is that this chapter serves as a useful reference for oncologists and other physicians treating breast cancer patients, as well as gynecologists, who will uniformly be faced with women affected by breast cancer in their practice. It is clear that addressing these issues will be of benefit to our patients. They deserve no less than a comprehensive assessment of the impact of this feared disease, which affects more than 10 % of our wives, mothers, sisters, and daughters.

Screening and Diagnosis

Gynecologists are in a unique position to carry out effective screening for breast cancer. Women are typically more accustomed to and comfortable with discussing, revealing, and allowing examination of their bodies by gynecologists than any other healthcare providers. Highly personal concerns (including the breasts and genital tract) are routinely included as part of the standard annual history and physical exam in the gynecologist’s office. These factors combine to give gynecologists a unique advantage in breast cancer screening, and it has been reported that gynecologists are the specialty most likely to recommend aggressive screening strategies [1].

Breast cancer is a relatively common disease with 121.9 cases per 100,000 US women. This accounts for an estimated 226,870 cases in 2012. The mortality rate of breast cancer is somewhat lower at 22.5 per 100,000, with 39,510 estimated deaths in 2012. Breast cancer is therefore the most common cancer among women and the second most common cause of cancer death in women (behind lung cancer) [2].

Both the incidence and mortality rates of breast cancer vary by ethnicity. Among US women, Caucasians have the highest risk of developing breast cancer, followed by Blacks, Hispanics, and Asians. In contrast, Black women are more likely to die from breast cancer, followed by Caucasians, Hispanics, and Asians, as shown in Table 18.1.

Table 18.1 Incidence and mortality rates by ethnicity in US women
Full size table

Breast cancer screening is typically accomplished in the United States by means of mammography. Film-based mammography has rapidly been replaced by digital mammography in the past decade, which will likely become the industry standard in the near future. Interpretation of mammograms is based on the BI-RAD system (Breast Imaging Reporting and Database), a numeric (0–6) scale for predicting the risk of malignancy from the mammographic appearance. Additional imaging techniques that may be used for screening in selected individuals include ultrasound, magnetic resonance imaging (MRI), and CT (computed tomography) scans. Ultrasound can be helpful in the evaluation of very dense breasts, particularly in young women. MRI can be more sensitive than mammography in some cases, but may miss certain cancers that mammography does not. MRI is therefore used primarily in combination with mammography, usually in women at higher risk for breast cancer based on family history or other factors. CT scans are rarely used in screening. Women with very large breasts and/or very large masses may be asked to undergo CT scan screening.

The diagnosis of breast cancer must be confirmed by a tissue sample, which may be obtained by several different methods. In general, the goal is to obtain tissue sufficient to make the diagnosis using the least invasive process. Fine-needle aspiration (FNA) is a common, clinic-based technique in which a thin (22- to 25-gauge) needle is placed percutaneously into the suspicious area. The site may be located by palpation if a mass can be felt. Image guidance, using ultrasound or mammography, is required for non-palpable lesions. In this situation, a non-hollow needle or marker may be placed to localize the area of suspicion. The clinician then uses the marker as a guide for the FNA. A syringe may be attached to the needle to aspirate a column of cells. Typically, multiple passes are taken from each area of interest. The aspirate is placed on a slide, air-dried, and then “fixed” by spraying or immersion with appropriate solutions. The slide is then stained and reviewed microscopically. The diagnosis can be made while the patient is still in the facility, allowing for counseling and treatment planning to be done at the same visit as the procedure. FNA is highly operator-dependent, requiring a skilled and experienced clinician to obtain consistent results.

Core-needle biopsy is similar to FNA but uses a larger-bore needle and local anesthetics. Core biopsy can also be done in a clinic setting to provide immediate results. Incisional or excisional biopsies are typically done in an operating room setting, with local anesthesia and intravenous sedation. Excisional biopsy requires the surgeon to remove the mass with a margin of normal-appearing tissue around it and is considered the definitive diagnostic method. An excisional biopsy may also be considered therapeutic, if the patient desires breast conservation [3].

There has been significant recent controversy in both medical and lay communities over the current breast cancer screening guidelines. The American Cancer Society Guidelines include the following:

  • Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health.

  • Clinical breast exam (CBE) should be performed about every 3 years for women in their 20s and 30s and every year for women aged 40 and over.

  • Women should know how their breasts normally look and feel and report any breast change promptly to their healthcare provider. Breast self-exam (BSE) is an option for women starting in their 20s.

  • Some women—because of their family history, a genetic tendency, or certain other factors—should be screened with MRI in addition to mammograms.

In contrast, the U.S. Preventive Services Task Force has stated that insufficient evidence exists to demonstrate any benefit of annual mammography done between the ages of 40 and 49 or over 74, including clinical breast exams, self-breast exams, digital mammography, or MRI. They recommend biennial mammography screening beginning at age 50 and ending at age 75.

These recommendations have generated many negative responses from lay and medical spokespersons, with the major criticisms centered on the reduction in the use of mammography [4]. As of this writing, most professional societies, including the American Cancer Society and the American College of Obstetrics and Gynecology, have not made any changes in their recommendations for breast cancer screening. From a practical standpoint, eliminating annual mammography screening in favor of biennial screening between ages 50 and 74 is likely to have unintended negative consequences for women’s overall health maintenance and disease prevention. Similar to the Pap smear, women often view the mammogram as part of an annual “package” of health maintenance measures, including a visit to the primary care physician’s office. The current reality in the United States is that despite annual recommendations for these tests, many women have them done far less often. If the recommendation for that package of services is decreased from once a year to every 2 years (or an even longer gap), it seems reasonable to anticipate that many women will seek healthcare screening or maintenance even less often, if at all.

The gynecologist in practice should individualize screening strategies for each patient, taking recent reports into consideration as part of a frank discussion of the limitations of existing data. It is likely that screening recommendations will be further refined in the coming years as healthcare outcomes research becomes more robust, thereby requiring the gynecologist to review their practices on an ongoing basis.

Familial Risk and Genetic Counseling in Women with Breast Cancer

Genetic Evaluation

The risk to an American woman of developing breast cancer is 1 in 8 during her lifetime, giving the United States one of the highest rates of breast carcinoma in the world. The lifetime risk of an American woman developing breast carcinoma without a single risk factor is 1 in 17. Therefore, US healthcare providers routinely offer breast cancer screening to their patients on a regular basis. Risk factors for development of breast cancer include the following: family history of breast cancer, young age of menarche (younger than 16), age at birth of first child, earlier age of menopause, benign breast disease, radiation, obesity, oral contraceptive use, postmenopausal estrogen replacement therapy, and alcohol use. Unfortunately, risk factors only identify 25 % of women who eventually develop breast carcinoma [5].

Approximately 5–10 % of breast cancers have a familial or genetic link. Approximately 50 % of families with hereditary breast and ovarian cancer syndromes have germ line mutations in BRCA1 and BRCA2, which are responsible for approximately 3–5 % of cases of breast cancer. BRCA1 and BRCA2 are found on chromosome 17 and 13, respectively, and both function as tumor suppressor genes, which encode proteins that function in the DNA repair process. Greater than 1,200 different mutations have been reported for BRCA1, while more than 1,300 mutations have been found in BRCA2 [6]. Patients with hereditary breast cancer inherit one defective allele in BRCA1 or BRCA2 from either parent. If the second allele becomes dysfunctional or nonfunctional, the likelihood of a clinical cancer is very high. Women with BRCA2 mutations may have a lifetime risk of breast cancer as high as 85 % and a 15–20 % lifetime risk of ovarian cancer. Women with BRCA1 mutations have a similar 85 % lifetime risk of breast cancer and a 40–50 % lifetime average risk of ovarian cancer [7].

Approximately 1 in 300 to 1 in 800 individuals in the general population carry a mutation in the BRCA1 or BRCA2 gene. In certain small ancestral groups, such as the Ashkenazi Jews, French Canadians, and Icelanders, these mutations tend to occur more frequently. In the United States, it is estimated that approximately 1 in 40 Ashkenazi Jews carries mutations in the BRCA1 and BRCA2 genes [8].

Routine obstetrical and gynecologic practice should include evaluating a patient’s risk for hereditary breast and ovarian cancer syndromes. Screening should involve questions regarding personal and family history of breast and ovarian carcinomas. Directed screening and prevention strategies may reduce morbidity and mortality from breast cancer by identifying individuals with inherited risk. Genetic risk assessment is recommended for women with greater than a 20–25 % chance of having an inherited predisposition to breast and ovarian cancer.

The following criteria are associated with a risk of being a carrier of a genetic predisposition to breast/ovarian cancer of approximately 20 %. Genetic risk assessment is recommended for these individuals:

  1. 1.

    Women with a personal history of both breast and ovarian cancers

  2. 2.

    Women with ovarian cancer and a first-degree relative (mother, sister, daughter) or two second-degree relatives ( grandmother, granddaughter, aunt, niece) with breast cancer

  3. 3.

    Women with premenopausal breast cancer or both ovarian cancer and breast cancers

  4. 4.

    Women with ovarian cancer and of Ashkenazi Jewish descent

  5. 5.

    Women with breast cancer at age 50 or younger or a first- or second-degree relative with ovarian cancer or male breast cancer at any age

  6. 6.

    Women of Ashkenazi Jewish descent in whom breast cancer was diagnosed at age 40 or younger

  7. 7.

    Women with a first- or second-degree relative with known BRCA1 or BRCA2 mutation

Evaluating Family History

Both breast and ovarian cancer-predisposing genes can be transmitted through either parent. Of note, families with few female relatives may underrepresent female cancer. In such cases, it may be reasonable to consider genetic counseling in the setting of breast cancer at or before age 50.

Issues Arising During Genetic Counseling

Genetic counseling for breast/ovarian cancer risk should include a discussion of possible outcomes of testing. Options in terms of surveillance, chemoprevention, and risk-reducing surgery should be discussed prior to testing. Psychological implications of test results must also be considered. The cost of genetic testing may be discussed during the genetic counseling session as this may influence the decisions of patients and family members. Another important aspect to discuss includes current legislation regarding genetic discrimination and the privacy of genetic information [9].

Genetic testing ideally begins with a family member already affected by breast or ovarian cancer. Since mutations are found along the entire length of both BRCA1 and BRCA2, full sequencing of both genes is recommended. During genetic testing, if a specific mutation is identified in an affected individual, a single-test site may be utilized for other family members. Certain ethnic groups are at increased risk of specific genetic mutations. BRCA1 and BRCA2 mutations are more often found in Ashkenazi Jewish, French Canadian, Icelandic, Netherlandic, and Swedish populations. Genetic testing for common mutations among these groups may be utilized as well.

If no mutations are found, patients should be counseled that they could still carry an unidentified mutation, an undetectable mutation in BRCA1 or BRCA2, or their family cancer history could be a result of random chance (no inherited predisposition). Management of women with a strong family history of breast cancer who have tested negative for BRCA mutation must be individualized, but may include many of the same discussions.

Risk-reduction strategies for women at high cancer risk due to BRCA mutations include surveillance, chemoprevention, and surgery. Secondary to the high risk of ovarian and fallopian tube cancer in individuals with BRCA1 and BRCA2 mutations, periodic screening for CA 125 and transvaginal ultrasonography is recommended beginning between age 30 and 35 or 5–10 years earlier than the age of first diagnosis of ovarian cancer in the family. Recommended surveillance also includes clinical breast examination and annual mammography as well as annual breast MRI beginning at age 25 or at the earliest age of onset in the family.

MRI has the greatest sensitivity for the detection of breast cancer. The combination of MRI, mammography, and breast exams has the greatest sensitivity in detecting breast cancer in high-risk BRCA mutation carriers.

Prophylactic Mastectomy

Women with BRCA1 or BRCA2 mutations may be offered bilateral total prophylactic mastectomy, starting at around age 35 or 5–10 years before the age of the youngest affected relative. Prophylactic (or preventive) mastectomy is effective in reducing the risk of breast cancer by approximately 90 % [10].

Reconstruction of the breasts may be done via a variety of methods, often at the same time as the mastectomy. Implants, typically filled with saline, can be placed under the chest muscles. The size of the reconstructed breast is determined by the amount of saline in the implant. Saline injections can be made at 1- to 2-week intervals, allowing the skin to slowly expand in accommodation. Alternatively, autologous tissue flaps can be used for reconstruction. Skin, muscle, and fat can be moved from the patient’s back, buttocks, or (most commonly) abdomen to the site of the breast. The transverse rectus abdominus myocutaneous (TRAM) flap is a popular source for the donor tissues [11].

Appropriate counseling prior to prophylactic mastectomy should include discussion of body image issues, the time required for recovery and resumption of normal activities, costs, and the efficacy of the procedure. Breast cancer has been reported in women who had undergone bilateral prophylactic mastectomy, presumably due to residual or ectopic breast tissue that was not visible and therefore not removed at surgery [12].

Ovarian Cancer and Breast Cancer

Mutations in BRCA1, BRCA2, or mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are associated with 5–10 % of all ovarian cancer. The cumulative risk of developing ovarian cancer by age 70 ranges from 16 to 40 % in patients with hereditary breast and ovarian cancer syndrome. BRCA1 and BRCA2 mutations are also associated with primary fallopian tube carcinoma with a lifetime risk of 1.1–3.0 % [13].

Women with BRCA1 and BRCA2 mutations may be offered salpingo-oophorectomy by age 40 or when they have finished childbearing for risk reduction of both breast and ovarian cancer. The diagnosis of ovarian cancer will be established in 2–3 % of women with BRCA1 or BRCA2 mutation before the age of 40. In women with BRCA1 mutations, the risk of ovarian cancer increases during the fourth decade of life and 10–21 % of BRCA1 mutation carriers will develop ovarian cancer by age 50. Women with BRCA2 mutations have a 24–36 % chance of developing breast cancer by age 50. The maximum impact on breast cancer reduction is accomplished by removing the ovaries earlier. Risk-reducing salpingo-oophorectomy on completion of childbearing may reduce ovarian cancer risk by 80–90 % and reduce breast cancer risk by 50–60 %. Of note, salpingo-oophorectomy may not eliminate the risks of ovarian cancer entirely, because some patients may develop primary peritoneal carcinomatosis, which is clinically and histologically indistinguishable from ovarian cancer.

Another potential surgical intervention includes tubal ligation without oophorectomy, which is associated with a 50 % reduction in ovarian cancer risk in the general population [14, 15].

Fertility Issues

Estimates indicate that 15 % of breast cancer cases will occur in women younger than 40 years of age [16]. These young patients often receive chemotherapy in addition to surgery and, as such, are at increased risk of premature ovarian failure. Chemotherapy may also increase the risk of complications during pregnancy including miscarriage, premature labor, and low birth weight. Several options to preserve fertility have emerged along with an increased awareness of these options among patients.

Breast cancer diagnoses should include a discussion of fertility concerns in premenopausal women. Patients should be reassured that pregnancy does not increase the risk of recurrence of breast cancer. Consultations with fertility experts should be offered prior to the beginning of cancer therapy to determine if immediate intervention is warranted. It is therefore recommended that consultation with a fertility specialist be made at the time of initial diagnosis. The optimal time for fertility preservation is frequently after surgery but before beginning adjuvant chemotherapy.

Chemotherapy is a mainstay of treatment of many breast cancers. The ovaries are quite sensitive to a number of cytotoxic agents, which may induce irreversible damage and destroy great numbers of follicles [17]. Agents commonly used in the treatment of breast cancer include cyclophosphamide and adriamycin (considered moderate to severely gonadotoxic) and paclitaxel (mildly gonadotoxic) [18].

Fertility Options

Ovarian failure and decreased ovarian reserve are some of the issues women with breast cancer may face. Some possible treatments include pharmacological treatment, ovarian transposition, and donor oocytes and artificial gametes.

Pharmacological Treatment

Suppressing ovarian function using a gonadotropin-releasing hormone (GnRH) agonist, which inhibits pituitary gonadotropin secretion, has been reported to minimize gonadal damage [19]. It is recommended that treatment with GnRH agonists begins 10 days prior to the start of chemotherapy and continues throughout treatment. However, patients must be counseled that the efficacy of GnRH agonists is unpredictable.

Embryo Cryopreservation

Cryopreservation involves storing tissues or organs at very low temperatures in order to maintain viability. Embryos may be preserved and stored for future use in patients with breast cancer. Cryopreserved embryos may be used for in vitro fertilization (IVF). The resulting survival for thawed embryos ranges from 35 to 90 %, with implantation rates from 8 to 30 %. According to the Society for Assisted Reproductive Technology, the pregnancy rate with transfer of cryopreserved embryos in the United States in 2005 was 28 %, with the pregnancy rate being 34 % for fresh embryos [20]. Limitations of embryo cryopreservation include time constraints since ovarian hyperstimulation and oocyte retrieval may take 2–3 weeks, possibly delaying the onset of chemotherapy. Another limitation can be the willingness of a patient’s partner to take part in IVF treatment and embryo cryopreservation. Further, supraphysiologic estradiol levels from ovarian hyperstimulation may be an adverse factor in patients with estrogen-dependent tumors. Finally, all patients should be encouraged to sign an advance directive for the use of the embryos (including donation, destruction, or research) if the patient chooses not to utilize them or does not survive.

Oocyte Cryopreservation

Oocyte cryopreservation of unfertilized oocytes may be considered as an option for women without a partner who choose not to use a sperm donor for IVF. The cytoskeleton, mitotic spindle, cortical granules, and zona pellucid of oocytes are sensitive to cryoinjury [21]. As with embryo preservation, 3 weeks may be required to stimulate and collect mature oocytes, thus delaying the onset of chemotherapy. The patient’s risk of ovarian hyperstimulation is likewise increased. IVF with in vitro maturation from a spontaneous menstrual cycle has been shown to yield pregnancy rates comparable to conventional IVF treatment, but is currently only performed in highly specialized fertility centers [22].

Menopause and Hormone Replacement Issues

Breast cancer treatment is often complex and may include multiple surgical options, chemotherapy, and/or radiation therapy. Menopausal symptoms and premature menopause are frequent side effects of these treatments. The specific mechanisms of this effect include estrogen receptor blockade (tamoxifen) or downregulation (aromatase inhibitors) [23].

Menopausal Symptoms

Common menopausal symptoms include hot flushes, night sweats, sleep disturbances, vaginal dryness, and loss of sexual interest. Menopausal symptoms may be more acute in premenopausal patients with breast cancer secondary to the acute onset of ovarian failure or suppression [24, 25].

Hot flushes or flashes appear to result from an exaggerated response of the thermoregulatory region of the hypothalamus, induced by decreased estrogen and progesterone levels, leading to an exaggerated response of the thermoregulatory center of the hypothalamus [26]. This stimulates central alpha-adrenergic receptors that modulate core temperature, causing vasodilation and sweating [27].

Vaginal atrophy results from low circulating estrogen levels or use of antiestrogen therapy using tamoxifen or aromatase inhibitors. This effect may lead to decreased sexual interest.

The type and intensity of menopausal side effects from tamoxifen and aromatase inhibitors were compared in the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination trial) which showed fewer vasomotor symptoms among subjects given anastrozole in comparison to those using tamoxifen [28, 29]. Vaginal dryness and dyspareunia have, however, been shown to be more common among women taking aromatase inhibitors compared to those taking tamoxifen [30].

Treatment of Menopausal Symptoms

Lifestyle changes and pharmacological and alternative therapies may be used in the management of menopausal symptoms. The U.S. FDA considers breast cancer to be a contraindication to the use of estrogen replacement therapy. However, the safety of estrogen (and progestin) hormone therapy in breast cancer survivors is not fully known. Several trials from the 1990s ended when findings showed an increased risk of breast cancer recurrence [31]. This remains a controversial area, and hormone therapy is generally not recommended in patients with breast cancer (particularly estrogen receptor-positive types).

Hot flushes can be triggered by stimuli such as spicy food, alcohol, and anxiety. Lifestyle adaptations include dressing in layers so that clothes may be easily removed during episodes. Obesity seems to exacerbate hot flushes, while weight loss may relieve these symptoms [32, 33]. Nonhormonal pharmacological therapies for vasomotor symptoms include serotonin reuptake inhibitors (SSRIs), serotonin noradrenalin reuptake inhibitors (SNRIs), Gabapentin (gamma-aminobutyric acid), and clonidine (alpha-adrenergic agonist). Although not generally as effective as estrogen therapy, these treatments can offer some relief from hot flushes in 40–45 % of subjects [34, 35]. An important consideration is that SSRIs are potentially irreversible CYP 2D6 inhibitors, which can prevent tamoxifen from being metabolized into an active compound [36]. Gabapentin, a drug often used to manage neuropathic pain, can improve vasomotor symptoms and sleep quality at low doses, although adverse effects such as dizziness were common [37]. Of note, none of the abovementioned nonhormonal treatments are FDA approved for treatment of vasomotor symptoms.

Other non-pharmacological treatments, such as herbal products, acupuncture, and exercise, have also been studied to determine their effects on vasomotor symptoms. Black cohosh, an herbal supplement, has shown mixed results. The efficacy of black cohosh on treatment for hot flushes remains unproven, and the safety regarding possible drug interactions with chemotherapy as well as tamoxifen has not been studied in depth [38]. Trials evaluating the efficacy of soy products and phytoestrogens in the treatment of vasomotor symptoms in breast cancer patients have shown no benefit for the treatment of these symptoms [39].

Other alternative therapies including dietary changes, exercise, acupuncture, relaxation techniques, and paced breathing have also been suggested for treatment of vasomotor symptoms. Acupuncture has recently been found to be equally effective as venlafaxine in reducing hot flushes and produces less side effects while having a longer duration [40]. Homeopathy, acupuncture, exercise, and relaxation therapy were recently evaluated in meta-analysis form for treatment of vasomotor symptoms. Relaxation therapy showed a benefit in this review [41]. In contrast, insufficient evidence was available to determine the effectiveness of exercise [42].

Treatments for vaginal atrophy include nonhormonal lubricants and moisturizers. These lubricants can be used safely during intercourse to avoid discomfort and microtrauma of the vagina. Vaginal estrogen therapy in cream or gel form has been considered for atrophy, as the systemic absorption seems to be minimal. The estradiol vaginal ring has also been used, but there are no randomized controlled trials to assess safety of either of these methods [43].

Breast Cancer Treatments

Selective Estrogen Receptor Modulators (SERMs)

This is a class of nonsteroidal compounds that competitively bind estrogen receptors (ER) at the cellular level. The effects vary, depending on the precise structure of the individual compound. SERMs can function as ER agonists, antagonists, or mixed agonists/antagonists depending on the tissue type. The mechanism of action of SERMs is not fully understood, but appears to involve recruitment of a series of co-activator and/or corepressor proteins based on the conformation of binding to ER [44]. SERMs used in the treatment of breast cancer and their gynecologic effects will be discussed here.

Tamoxifen

First manufactured in the 1950s as a possible contraceptive, tamoxifen was not identified as a treatment for breast cancer until the 1980s, when several prospective trials showed a survival advantage, particularly in women with early breast cancer, and often in combination with chemotherapy [45, 46]. Since then, further studies have shown that tamoxifen is most effective in women with ER-positive tumors, and the drug is now widely used as a standard part of breast cancer therapy [47].

The side effect profile of tamoxifen is largely determined by its function in different tissues. Due to small variations in ER structure, tamoxifen functions as an antagonist in the breast and an agonist in the uterus. So while tamoxifen effectively slows breast tissue growth, it can accelerate uterine (especially endometrial) growth. Resulting side effects of tamoxifen therefore include uterine bleeding, polyp formation, endometrial hyperplasia, and endometrial cancer [48]. Specifically, the risk of endometrial cancer appears to increase with the extended use of the drug, which has resulted in a recommended usage of no more than 5 years [49]. A beneficial side effect of tamoxifen is its preventive effect on osteoporosis. The drug acts as an agonist in the bone and therefore mimics the bone-sparing effect of estrogen [50].

Raloxifene

Raloxifene differs from tamoxifen by functioning as an estrogen antagonist in both the breast and uterus and agonist in the bone. The drug has therefore been used to prevent osteoporosis since the late 1980s. The landmark STAR trial compared the use of tamoxifen and raloxifene for prevention of breast cancer in women at high risk. This study showed that raloxifene was as effective as tamoxifen in preventing breast cancer, but was associated with fewer cases of uterine cancer, fewer cataracts, and fewer blood clots [51]. As a result, in 2007, the U.S. Food and Drug Administration approved raloxifene for postmenopausal women at high risk for breast cancer as a preventive agent.

Gynecologic Considerations Associated with SERMs

The risk of uterine pathology is the primary gynecologic concern with the use of tamoxifen. The current recommendation is that endometrial sampling be performed in women using tamoxifen who experience irregular uterine (particularly postmenopausal) bleeding. There is no clear evidence that increased levels of surveillance, including random endometrial sampling or ultrasonography (transvaginal or abdominal), will reduce the morbidity associated with tamoxifen, and they are not recommended.

Raloxifene is recommended for postmenopausal women at high risk for breast cancer, particularly those with or at risk for osteoporosis.

Aromatase Inhibitors

Aromatase is an enzyme that functions to synthesize estrogen in humans. Aromatase inhibitors (AIs) block estrogen production and have been used in the treatment of breast and other cancers in women. In postmenopausal women, the primary natural source of estrogen is peripheral fat, which converts circulating androgens (via aromatization) to estrogens. AIs can block this process and therefore lower total estrogen load. The large, international ATAC study showed improved survival in postmenopausal women with ER-positive breast cancer who used an AI [28]. AIs currently approved for use in breast cancer include anastrozole, exemestane, and letrozole.

Gynecologic Considerations of AIs

The effect of AIs in premenopausal women is paradoxical. AIs will block the production of estrogen in the ovary (the natural source in premenopausal women), but this effect will also stimulate the hypothalamic–pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to produce more androgens, which potentially counteract the effect of the AI. As a result, ovarian ablation (either surgical or chemical) may be recommended with the use of AIs in premenopausal women with ER-positive tumors.

The use of anastrozole has been associated with an increased risk of bone fractures in women with breast cancer [52]. The risk of osteoporosis should be thoroughly discussed with women using anastrozole, and the use of bisphosphonates, calcium supplements, and/or weight-bearing exercises are generally recommended.

Progestins

Progestins are synthetic progestogen hormones with progesterone-like effects. They can counteract the effect of estrogen in the breast and uterus and are primarily used in a variety of contraceptive agents.

Progestins may be used as palliative treatment in women with breast cancer, particularly those with ER-positive tumors. The use of progestins in this setting has declined in recent years with the advent of SERMs and AIs [53].

Gynecologic Considerations of Progestins

Progestins can cause amenorrhea or irregular uterine bleeding in premenopausal women. High-dose progestins may also have appetite-stimulant effects.

Cancer Screening in Breast Cancer Patients

Gynecologic Cancers

Cervical Cancer

The recognition of human papillomavirus (HPV) as the probable causative agent for most cases of cervical cancer has changed screening strategies dramatically. While the basis of the screening process remains the Papanicolaou smear, most recommendations also include concurrent HPV testing and typing. The distinction between low-risk and high-risk HPV types helps identify those women who will get the greatest benefit from additional evaluations [54].

Further, this understanding of the role of HPV has made it clear that breast cancer and cervical cancer, while not mutually exclusive, have entirely different risk factors and probable causes. There are currently no well-understood or widely accepted links between HPV infection and breast cancer, just as there is no clear data showing that the hormonal milieu (or any other factors) associated with breast cancer has an effect on the pathophysiology of cervical cancer. As a result, recommendations for cervical cancer screening can mirror those of the general population, as published in detail elsewhere [55]. What follows is a summary of the current guidelines.

The recent approval and widespread utilization of HPV vaccines as preventive measures for cervical cancer could have a dramatic effect on the incidence of cervical cancer in the future. It is predicted that comprehensive HPV vaccination of women ages 9–25 (prior to HPV infection) could prevent up to 80 % of all cervical cancers. HPV vaccination holds great promise for developing countries in particular. Many nations lack the standard infrastructure needed for Pap smear-based screening and as a result have much higher rates of cervical cancer than the developed world. Cervical cancer prevention by means of a simple vaccination could have an enormous impact on these populations [56].

Currently, there are no recommendations regarding HPV vaccination in women with breast cancer. There is no evidence to suggest that HPV vaccination would have any impact on breast cancer outcome. Thus, women with breast cancer may be vaccinated for HPV based on standard guidelines. In general, women who are not infected with HPV should be vaccinated. It should also be stated that standard screening recommendations have not changed for HPV-vaccinated women. At present, women who have been HPV vaccinated should undergo Pap smear-based screening as per standard guidelines (as described above).

Recent controversy has arisen over the cervical cancer screening recommendations of the U.S. Preventive Services Task Force [57]. Similar to the discussion on breast cancer, these new guidelines call for somewhat less frequent testing than those described above, which are based on a collaboration between the American Cancer Society (ACS), American College of Pathology (ACP), American Congress of Obstetricians and Gynecologists (ACOG), and other professional societies. Specifically, the U.S. Preventive Services Task Force guidelines were developed using cost–benefit analyses and assumptions of widespread high compliance that may not reflect real-world utilization. In fact, the women most at risk for cervical cancer are often least likely to undergo screening. Thus, it is likely that these new guidelines will result in additional cases of cervical cancer. While the overall numbers may be statistically insignificant, there is no clear way to measure the impact of a single case of cervical cancer on an individual, a family, or a community. The authors therefore will continue to recommend the ACS/ACP/ACOG guidelines for cervical cancer screening. A summary of those guidelines is shown in Table 18.2.

Table 18.2 Summarized ACS/ACP/ACOG recommendations for cervical cancer screening
Full size table

Endometrial Cancer

There is no clear evidence that screening asymptomatic women for endometrial cancer can improve outcome. Endometrial cancer is usually diagnosed early as a result of its common association with a very specific symptom: irregular vaginal bleeding, particularly postmenopausal bleeding. Potential screening tests, including Pap smears, endometrial biopsy, or transvaginal ultrasonography, lack sufficient sensitivity and/or specificity to be effective.

The use of tamoxifen by breast cancer patients has been associated with endometrial pathology, including cancer, as described elsewhere in this chapter. However, studies of potential endometrial cancer screening techniques in this population have not demonstrated significant benefit [58]. At present, screening of asymptomatic women with breast cancer, including those using tamoxifen, for endometrial cancer is not recommended. Symptoms of irregular vaginal bleeding should be thoroughly investigated, usually with endometrial biopsies and ultrasonography.

Ovarian Cancer

Screening for ovarian cancer in families with hereditary breast–ovarian cancer syndromes is described previously. In women without a family history of either cancer, there is no clear evidence that screening for ovarian cancer is effective. While the risk of developing ovarian cancer may be slightly increased in a woman with breast cancer, current screening strategies (including serum Ca-125 and transvaginal ultrasound) lack adequate sensitivity and specificity needed to be effective [59]. They may result in further diagnostic testing that can increase patient anxiety and carry additional procedure-related risks. While women with breast cancer should be made aware of the symptoms of ovarian cancer [60], no specific screening strategies are recommended.

Other Cancers

Colorectal Cancer

There is no evidence that the risk of colorectal cancer is changed by the diagnosis of breast cancer, although obesity is a shared risk factor. There is an unusual variant of hereditary nonpolyposis colon cancer (HNPCC), the Muir–Torre syndrome, that is associated with an increased risk of breast cancer [61]. Individuals with this variant are likely to be well known due to strong family histories of colon cancer and are typically screened very thoroughly. For most women with breast cancer, however, the recommendations for colorectal cancer screening are identical to those in the general population [62]. In summary, screening with colonoscopy should be done every 10 years between ages 50 and 75. Screening above or below those ages will have higher risk/benefit ratios and are not routinely recommended.

Lung Cancer

Again, there is no evidence that the risk of lung cancer is changed by a diagnosis of breast cancer. The most important risk factor for lung cancer, by far, is cigarette smoking. Further, screening for lung cancer has been proven to be effective only in individuals at high risk; specifically heavy smokers or former smokers with a minimum 30-pack/year history. In this group, the National Lung Screening Trial (NLST) showed that low-dose spiral computed tomography scanning resulted in 20 % reduction in mortality compared to chest X-ray alone [63]. Based on this, women with breast cancer should undergo screening for lung cancer based on the general population criteria as defined in the NLST.

Follow-Up Care

Women with breast cancer require continued gynecologic follow-up and care for all the reasons described in this chapter. Gynecologic evaluation should be a routine part of breast cancer care. Gynecologists, who commonly maintain an ongoing and long-term relationship with their patients, may be uniquely situated to allay patient concerns and correct misconceptions. Female cancer patients often maintain a level of trust in their gynecologists that is difficult for oncologists to achieve. Gynecologists should make specific inquiries about the breast cancer patients’ level of understanding of the disease process, comfort with the recommended treatment plan, and confidence in her cancer specialists.

The patient will often reveal problems or concerns to the primary gynecologist that she will not tell her oncologist [64]. Concerns about appearance, femininity, and sexuality are frequent among breast cancer patients. Many oncologists do not routinely discuss these issues and many patients may perceive that their “cancer doctor” is not interested in or able to address them. Gynecologists should encourage a frank discussion of these and other personal concerns of the breast cancer patient as part of routine care. Often, simple reassurance is sufficient to alleviate fear or uncertainty. Or, the gynecologist may suggest specific, commonsense interventions that oncologists are less familiar with, such as using adequate amounts of warmed lubricant as a routine part of sexual activity to alleviate chemotherapy-induced mucosal irritation. Finally, the gynecologist can communicate information that may impact therapy to the oncologist who may be unaware [65].

The authors recommend a baseline complete gynecologic evaluation for all women diagnosed with breast cancer by a clinician conversant with the concepts described in this chapter and summarized in Table 18.3. This visit will identify existing or potential problems and prepare the patient for her initial treatment, including surgery, radiation and/or chemotherapy. It is further recommended that a second visit to the gynecologist be scheduled shortly after the completion of the first-line therapy. New findings often become apparent at this visit, and/or patient concerns about the future can be addressed. After this, annual gynecologic evaluation is appropriate. Additional visits may be triggered by new symptoms, such as vaginal bleeding, hot flushes, night sweats, or mood disturbance. The diagnosis of a recurrence of the cancer should prompt strong consideration of an additional gynecologic evaluation as well. The gynecologist should therefore be an ongoing member of the patient’s cancer care team. Optimal care for this most intimate of physical concerns should not be overlooked at such a critical juncture in a woman’s life.

Table 18.3 Follow-up gynecologic care for breast cancer patients
Full size table

Conclusion and Future Perspective

Gynecologic care for women with or at risk for breast cancer is frequently underemphasized and should be considered a component of comprehensive cancer care. The emergence of Women’s Health as a unique medical specialty should facilitate the study of these issues and their inclusion in routine management strategies. Genetic risk assessment is recommended for patients with a greater than 20 % chance of having inherited predispositions to breast or ovarian cancer. While the data regarding risk-reducing treatments is rapidly evolving, it is currently recommended that women with BRCA1 or BRCA2 mutations should be offered a salpingo-oophorectomy by age 40 or when childbearing is complete.

Advances in chemotherapy and radiation have improved survival but often compromise fertility and hasten menopause. Numerous options for fertility preservation are available and should be addressed with each patient individually. High-tech procedures for ovary and embryo conservation have great promise but may be both expensive and not covered by insurance.

Menopausal symptoms can have a major impact on quality of life in breast cancer patients, even years after primary therapy has been completed. Optimal benefit will be attained by means of continued discussions over time as the various symptoms wax and wane. Development and testing of new estrogen-like molecules hold the promise of alleviating symptoms in the future.

The future of cancer screening is likely to be primarily determined at the molecular level. The concept of personalized medicine, based on an individuals’ specific genetic profile, has the potential to predict cancer risk with great accuracy. Integration of “DNA profiling” into current screening strategies will require careful analysis of the benefits in an era of increased quality/cost awareness.