Seminal advances in the diagnosis and treatment of premenopausal breast cancer (defined as breast cancer diagnosed in women 50 years of age or younger) have transformed the disease from a uniformly fatal condition to one with survival rates as high as 98%, with an emphasis on prevention, early detection, and patient- and disease-centered coordinated therapy. Central to these changes was the critical paradigm shift that occurred in the 1970s and 1980s, away from the traditional Halstedian view of surgery as the only curative modality, to a non-Halstedian approach of multimodality therapy that achieves adequate local control and maximizes systemic adjuvant therapy through prospectively developed patient- and tumor-specific treatment plans.
Although premenopausal women account for only a small fraction of the overall incidence and deaths from breast cancer, breast cancer is the leading cause of cancer death in women ages 20 to 59. Breast cancer is the final outcome of multiple hereditary and environmental factors, including genetic mutations, estrogen exposure, failure of immune surveillance, and alterations in angiogenesis and other examples of abnormal growth factor signaling. The relative risk of breast cancer for women receiving modern oral contraceptives (OCs) increases with duration of use, reaching approximately 1.5 for women receiving OCs for 1 year, compared with never-users and women receiving OCs for shorter durations.
Approximately 5% of breast cancers are attributable to known inherited syndromes, and another 10% to 15% of cases have a familial predisposition. Thirty-six percent of breast cancers in women ages 20 to 29 can be linked with a single dominant susceptibility gene; in contrast only 1% of women older than 80 carry such genes. The best characterized mutations, BRCA1 and 2, are tumor suppressor genes that are associated with elevated lifetime risks of breast and other cancers. For any premenopausal woman presenting with a family history of breast cancer the risk of carrying a genetic mutation can be assessed by a variety of methods, including mathematical probability tools, models that predict the likelihood of a genetic mutation, and genetic testing. The input from genetic counselors and genetic tests are critical in helping providers and patients select the elements and order of the treatment plan for a high risk patient.
It is well known that premenopausal cancers are typically biologically more aggressive than cancers in older women and possess a higher percentage of negative cellular/histological features, including high grade histology, higher Ki-67 expression, higher p53 expression, lymphovascular invasion, and estrogen-receptor and progesterone-receptor negativity. More recently, this biological difference between pre- and postmenopausal breast cancer has been better elucidated by the advent of molecular subclassification of breast cancer using gene expression assays, such as Oncotype DX and Mammoprint. The common molecular subgroups now recognized include luminal A, luminal B, basal-like, and HER-2/Neu positive.
Luminal A tumors have the best prognosis; luminal B tumors have a poorer prognosis compared with luminal A, although still better than the other molecular subtypes. Basal tumors are often termed “triple negative.” Triple negativity is a tumor feature that is linked to intrinsically poorer outcome, in part because treatment options are limited. Basal-like breast cancers have similar characteristics to breast cancers among BRCA1 mutation carriers, often biologically aggressive and resistant to chemotherapy. Similarly, tumors in the HER-2+ category are hormone receptor negative and associated with higher p53 mutation rates and poorer outcomes. It is now known that the molecular subgroups of breast cancer associated with worse outcome (eg, luminal B, basal-like, and HER-2+) are more common in premenopausal women. Further study of these subtypes may further help to explain the biologic behavior of breast cancers in young patients and suggest new treatments.
Most evidence suggests that mammography screening reduces breast cancer death among women 40 to 74 years old; National Cancer Institute (NCI) guidelines therefore recommend that all women aged 40 and older receive mammography every 1 to 2 years to achieve the best possible outcome if breast cancer is detected. NCI, American Cancer Society (ACS), and Komen guidelines recommend that women in the age group 20 to 39 should undergo a clinical breast examination (CBE) every 3 years, but not mammography. The initial presentation in younger women with breast cancer is still most often a dominant palpable mass (DPM) identified by the patient or her provider; although CBE is thus an important tool in younger women, it is an operator-dependent test, and has a high false positive rate. Because breast cancer rates are lower at younger ages and breast density limits the utility of mammography, the value of entering women younger than age 40 into breast cancer screening programs (SPs) remains unclear and state-funded mammogram-based SPs exclude women younger than 40.
Accordingly, efforts to image the breast in younger women have focused on alternate imaging tools. Ultrasound is an excellent test for younger women due to the fact that it can target and evaluate DPMs. In younger women ultrasonography has proven to be more reliable than mammography, with a reported lower false negative rate. For these reasons our group has modified the classic triple test (CBE, imaging, and needle biopsy) by substituting ultrasonography for mammography to assess breast masses in women younger than age 40. However, ultrasonography is also an operator-dependent and time-inefficient test, which does not lend itself easily to screening. Preliminary data suggest that early diagnosis of familial breast cancer is feasible by intensified surveillance with the addition of magnetic resonance imaging (MRI). However, the expense, low specificity, and requirement for special equipment and expertise are all barriers for the widespread use of screening MRI.
Once a pathologic diagnosis of breast cancer is made, the extent of the pretreatment metastatic valuation should depend on the clinical stage of disease and target the most likely sites of metastases: bones, liver, lungs, and brain. For early-stage disease (stages I-IIA; no skin changes or palpable axillary nodes), simple inexpensive tests (“primary metastatic workup”) including blood work and a chest radiograph are generally adequate, whereas more expensive, high yield tests (“secondary metastatic workup”; CT scan, bone scan, brain MRI) are indicated for higher stages of disease or if the primary tests are abnormal. Fluoro-deoxy-d-glucose 18F (FDG)-positron emission tomography (FDG-PET), now commonly fused with computerized tomography (PET/CT), has a limited role in the primary staging of early-stage breast cancer. Better results with PET/CT have been shown in the detection and staging of more advanced primary invasive tumors and for demonstrating response to neoadjuvant therapy.
Patients presenting with early-stage, unifocal cancers can be candidates for either breast conservation therapy (BCT) with lumpectomy and radiation or total mastectomy with or without immediate reconstruction. However, younger patients present unique additional concerns, including a potential increased risk for local recurrence (LR), timing and surgical management of LR after BCT, surgical management of BRCA carriers and high risk patients, and the more frequent consideration of contralateral mastectomy and/or reconstruction. Studies addressing the question of an increased risk for LR after BCT in younger women present conflicting results and are limited by design biases. Surgeons may wish to counsel their young patients that there is an increased risk of LR after BCT, but should also note that despite this increased risk, no definitive survival advantage has been shown with mastectomy, and therefore, BCT is an acceptable surgical option for young women. The majority of LR in young patients tends to occur within the first 5 years after initial treatment, suggesting that closer surveillance of young patients in the initial years after BCT may be of benefit in diagnosing recurrences at an early and manageable stage. The surgical management of an ipsilateral breast LR generally consists of salvage mastectomy. With the emergence of newer, more targeted methods of radiation (such as accelerated partial breast irradiation), a repeated attempt at breast preservation might be considered depending on individual circumstances; this is the subject of future research.
When discussing surgical options of BCT versus mastectomy, breast cancer patients with BRCA1/2 mutations or a very strong family history of breast cancer should be counseled that they are at increased risk of developing second primary cancers and up to a 40% risk of developing a contralateral breast cancer. Due to this increased risk of subsequent breast cancer development in both breasts, bilateral mastectomy is a reasonable surgical option to consider. Whether the risk of ipsilateral LR after BCT is increased among BRCA carriers is less clear. Many authors conclude that BCT may be offered to BRCA carriers as long as patients are counseled about the risk of second primary cancers and need for surveillance. Although contralateral prophylactic mastectomy (CPM) has been shown to reduce the risk of development of a contralateral breast cancer effectively, a survival benefit from this procedure has not been demonstrated. Increased genetic testing, more frequent use of MRI, patient preference, and physician recommendations may account for the recent increase in CPM.
Younger women tend to opt for breast reconstruction more frequently than older women. The decision process for reconstruction in younger women is particularly influenced by factors such as body image and sexuality, time for recovery balanced with the wish to return to work and care of children, and the desire to resume normal physical activity as well as by patient preference, cancer stage, and need for adjuvant therapies such as postmastectomy radiation (PMRT). Skin sparing mastectomy has been shown to offer better cosmesis while being oncologically safe. Although there may be concern about postoperative wound complications delaying adjuvant treatment, studies have shown that immediate reconstruction does not cause significant delay in starting chemotherapy. Although some authorities recommend delayed reconstruction with autologous tissue in cases of anticipated PMRT, others argue that immediate reconstruction with either prosthesis or autologous tissue is feasible and can be offered, provided that patients are made aware of potential risks. For young women who opt for BCT, optimization of cosmetic outcome with oncoplastic techniques can be utilized.
At present, adjuvant systemic chemotherapy alone is typically recommended to young patients with invasive breast cancer that is hormone receptor negative (ER–). Premenopausal patients requiring systemic therapy are often treated with an anthracycline; a number of studies have now demonstrated a significant improvement in disease-free survival when a taxane is added. In addition to side effects of nausea, vomiting, and hair loss, anthracycline-containing regimens also carry cardiotoxic risks. A recent study found docetaxel-cyclophosphamide (TC) to offer superior disease-free and overall survival, with less nausea, than an anthracycline-based regimen in young patients. Some clinicians are opting to use this regimen when cardiotoxicity due to anthracycline is of concern, or in lower risk patients requiring chemotherapy. Neoadjuvant (preoperative) chemotherapy is often recommended in cases of locally advanced breast cancer (larger tumor size and node metastasis, common in younger patients). Studies show that neoadjuvant chemotherapy can successfully downstage tumors, thereby allowing for BCT; trends of improved survival have been noted among women under age 50.
For patients with hormone receptor positive breast cancer, either endocrine therapy alone or chemotherapy followed by endocrine therapy is considered, depending on individual patient and tumor characteristics. When counseling patients on the use of tamoxifen, they should be made aware of the rare, but serious side effects of thromboembolic events and uterine cancer. Aromatase inhibitors (AIs) are not effective in premenopausal patients, as they do not suppress estrogen produced by functioning ovaries. However, their use may be considered in young women who have become menopausal either due to chemotherapy or surgical or medical ovarian ablation. This question is the subject of several ongoing trials. The magnitude of additional benefit of chemotherapy, compared with endocrine therapy alone, is under debate and still being studied. Gene expression assays may be useful for identifying which ER+ patients are at highest risk of recurrence and may obtain benefit from the addition of chemotherapy.
The suppression of estrogen by oophorectomy has long been known to be of benefit in the treatment of endocrine sensitive breast cancer. Medical ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists is accepted as a comparably effective method of ovarian ablation as oophorectomy, ovarian radiation, or chemotherapy-induced ovarian failure. The question of whether the addition of chemotherapy to tamoxifen is superior to tamoxifen plus ovarian ablation among ER+ early-stage breast cancers is under study.
Trastuzumab, a monoclonal antibody that binds to the HER-2 cell surface protein, is added when a patient's tumor overexpresses the HER-2/Neu gene; several studies have shown that in HER-2-positive tumors, 1 year of trastuzumab in addition to chemotherapy results in a 50% reduction in risk of relapse, compared with chemotherapy alone.
Radiation is almost always required for BCT after lumpectomy, and a radiation boost to the lumpectomy site is generally recommended in addition to whole breast radiation for younger patients. PMRT (which includes radiation to the chest wall and regional nodes) is increasingly being used in young patients as well, due to several recent studies demonstrating decreased LR and improved survival in patients at high risk for LR. Newer, modern techniques of radiation delivery have greatly reduced the adverse cardiopulmonary side effects. American Society for Clinical Oncology (ASCO) guidelines recommend PMRT in patients with 4 or more positive lymph nodes, tumor size greater than 5 cm with positive nodes, or operable stage III disease. PMRT in cases of 1 to 3 positive nodes, node-negative tumors with tumor size greater than 5 cm, or close (<1 mm) margins is still controversial.
Once thought to be rare, pregnancy-associated breast cancer (breast cancer during, or within a year after, a pregnancy) is expected to increase in frequency as women delay childbearing until later in life, when the general risk of breast cancer begins to rise. At present, breast cancer is the second most common malignancy in pregnancy (after cervical cancer), occurring in 1 in 5000 deliveries. At least 10% of women younger than 40 with breast cancer are pregnant at diagnosis. Although women with a genetic predisposition to breast cancer may be overrepresented among pregnant patients with cancer, the majority of cases are considered sporadic. Mammography is safe for the evaluation of the breast in pregnant women, but has a high false negative rate. Ultrasound is 93% accurate for the evaluation of masses in pregnant women, and should be used in most cases, especially when the mammogram is normal during the evaluation of a suspicious DPM. The safety of breast MRI is still being established in pregnant women. Chest radiographs, low dose bone scans, and MRI can be used for metastatic evaluations, although gadolinium crosses the placenta and is a class C drug in pregnancy.
Older notions of pregnancy-associated breast cancer being more aggressive have been replaced by data suggesting a similar stage-for-stage prognosis as breast cancer in age-matched nonpregnant women, although the stage at presentation tends to be later due to the difficulty of assessing the beast in pregnant and lactating women. Thus, it is generally felt that pregnant patients should be treated with the same principles used for nonpregnant patients; that is, aggressively for cure in most cases. Surgery is a mainstay of therapy. General anesthesia and breast operations are generally safe throughout pregnancy; the surgical team should be aware of the physiologic changes of pregnancy that can complicate sedation and surgery. Standard therapeutic radiation courses expose the fetus to risks of both teratogenicity and childhood cancers/hematologic disorders, and therefore breast radiation during pregnancy is contraindicated. BCT can be offered if the radiation can be given postpartum (ie, if the patient is in the latter stages of the pregnancy, or if radiation will be delayed by prior chemotherapy). The standard axillary evaluation for invasive cancer is being replaced in pregnant patients with sentinel node biopsy (SLNB), although this must be done with some caution, as both methylene blue and isosulfan blue dye are class C drugs and have not been tested formally in pregnant women.
Although all chemotherapy drugs are category D (teratogenic), these risks have generally been seen only in the first trimester; later in pregnancy chemotherapy is surprisingly safe. Physiologic changes during pregnancy, including increased plasma volume, decreased albumin concentration, increased liver and kidney function, and decreased gastric motility, may affect chemotherapy dosing. Many drugs typically used to treat chemotherapy side effects are safe in pregnancy. Tamoxifen has been associated with fetal abnormalities and is not recommended during pregnancy. There is no evidence that therapeutic abortion improves the outcome in pregnancy-associated breast cancer. Similarly, future pregnancies do not appear to increase the likelihood of progressive or recurrent disease, as long as the first cancer is in remission. In fact, some data suggest that breast cancer survivors who subsequently become pregnant have a better 5-year survival than controls matched for age and stage.
Despite appropriate multimodality therapy using the team approach, a certain percentage of women will develop recurrent or metastatic disease after adjuvant therapy. Patients who develop LR have a significantly increased risk for developing subsequent systemic disease recurrence, and patients with LR following mastectomy have a worse prognosis than patients who had prior BCT. A shorter interval to disease recurrence and positive axillary lymph node involvement at the time of initial diagnosis portend a worse prognosis with LR, whereas patients with new primaries have a significantly better prognosis than patients with true recurrence, defined as recurrent cancer within 3 cm of the previous cancer and of the same histology.
Treatment of the primary tumor in patients who present with metastatic disease at the time of initial diagnosis remains an unsettled issue. Because the systemic therapy the patient will receive will treat the in-breast disease, surgical resection of the primary breast tumor in this setting is often deemed unnecessary, and the primary breast tumor may serve as a clinically useful indicator for the assessment of treatment response. However, some recent retrospective studies report that resection of primary tumors may be associated with improved survival. The patients that appear to benefit from resection in these studies are typically young, have good performance status, achieve negative margins, have an excellent response to systemic therapy, and have bone-only metastatic disease.
Patients who develop metastatic disease are considered virtually—but not always—incurable; the average survival for patients with metastatic disease is 3.5 years. Endocrine blockade is an effective intervention for patients with hormone receptor positive disease. Such intervention can be particularly valuable for patients with minimal symptoms, limited extent of disease involvement, and/or involvement of predominantly bone and skin. Time to disease response tends to be slower with endocrine therapy, and such treatment is most appropriate and successful in patients who have had long disease-free intervals and had a good quality response to prior endocrine therapy. For patients with HER-2/Neu positive disease, trastuzumab can be given as monotherapy or in combination with chemotherapy or hormonal therapy. Trastuzumab may synergize with other agents, particularly taxotere, taxol, or navelbine. Combination chemotherapy with lapatinib is effective for patients whose disease progress on trastuzumab-based treatment.
For patients whose tumors are neither hormone receptor nor HER-2/Neu positive, cytotoxic chemotherapy represents the only treatment option for unresectable metastatic disease. Commonly used agents include capecitabine, doxorubricin liposomal (Doxil), taxotere, taxol, navelbine, gemcitabine, nanoparticle albumin-bound paclitaxel (Abraxane), adriamycin, and cytoxan. Monotherapy with bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a low response rate for metastatic breast cancer; the addition of bevacizumab to paclitaxel significantly improves the disease-free survival for breast cancer patients compared with treatment with paclitaxel alone. Major advances in the supportive care for patients with metastatic breast cancer include colony-stimulating factors, antiemetic agents targeting various pathways, and bisphosphonate therapy.
The follow-up of premenopausal women with breast cancer is arguably more important than for older patients because of the higher likelihood of recurrence and the existence of “lead time bias”; history and physical examination, including CBE, is recommended every 3 months for the first 2 years, then every 6 months for the next 2 years, and then yearly. ASCO guidelines do not recommend routine chest radiographs, blood tests, more intense imaging, or tumor markers—these tests are not associated with any survival benefit and are best reserved for evaluation of symptomatic patients. The decreasing mortality rate for younger women with breast cancer has led to an increasing number of younger long-term survivors with special quality-of-life issues, including early menopause symptoms and other physical alterations, fear of recurrence, work and family issues, and infertility. Several options have been proposed for maintaining fertility; discussion of risks and benefits of fertility preservation can be complex, and patients can greatly benefit from interaction with a multidisciplinary team, which includes a fertility specialist and psychological support and counseling.
FULL TEXT