Breast Cancer: An Overview for the Primary Care Physician, Part II
Breast Cancer: An Overview for the Primary Care Physician, Part II
Author: Mark A. Marinella, MD, FACP, CNSP, Dayton Physicians, LLC, Hematology-Oncology, Assistant Clinical Professor of Medicine, Wright State University School of Medicine, Dayton, OH.
Peer Reviewer: Sharon Lum, MD, FACS, Assistant Professor, Department of Surgery, Division of Surgical Oncology, Loma Linda University School of Medicine, Loma Linda, CA.
This issue is the second installment in a two-part series on breast cancer. The first part covered epidemiology, histologic types of breast cancer, screening, diagnosis, principles of treatment, and surgical management. This issue will cover chemotherapy, radiation therapy, endocrine therapy, metastatic breast cancer, and primary care for the breast cancer survivor.
-The Editor
Chemotherapy
Chemotherapy for breast cancer has evolved substantially in the last decade, providing the oncologist with an increasing array of drug classes for use in both the neo-adjuvant and adjuvant settings. That chemotherapy provides a significant benefit to patients with early breast cancer was demonstrated in a large meta-analysis of randomized trials that showed a decrease in the annual breast cancer death rate by 38% in women younger than 50 years and 20% in women aged 50-69 years.1 This analysis also demonstrated a significant recurrence and survival benefit of anthracycline-based regimens compared to CMF.1 Patients with DCIS or LCIS do not benefit from chemotherapy since, by definition, the tumor cells are contained within the basement membrane and do not involve breast parenchyma.2
Breast cancer is considered a systemic disease, with micrometastases already present in many patients at the time of surgery. Adjuvant chemotherapy is provided to "sterilize" occult metastasis in otherwise clinically localized disease. Based on tumor cell kinetics, chemotherapy is more effective when the tumor mass is smaller, since exponential cell growth occurs in small tumors (< 1cm) compared to larger tumors in which most cells are in the quiescent phase of the cell cycle and not sensitive to chemotherapy. An understanding of basic principles of chemotherapy is beneficial to the primary care provider. First, all known tumor should be resected for treatment to be considered adjuvant in nature. Chemotherapy should be commenced as soon as possible following surgery but allowing adequate time for wound healing - typically four to eight weeks. Chemotherapy should be administered at maximally tolerated doses and continued for a limited time period while allowing adequate treatment-free intervals to permit normal tissues to recover.3 All widely administered neo-adjuvant and adjuvant regimens for breast cancer utilize at least two drugs that possess different mechanisms of action. Furthermore, combination regimens should include agents with non-overlapping toxicities. The most common chemotherapeutic classes utilized in breast cancer treatment include anthracyclines, taxanes, anti-metabolites, and alkylating agents. (See Table 1.) Selection of an agent depends not only on applying evidence-based criteria generated by randomized phase III drug trials, but also by host characteristics that may affect response and tolerance of specific chemotherapeutic agents. For instance, patients with heart failure may not be optimal candidates to receive cardiotoxic anthracyclines, and patients with severe diabetic neuropathy may experience worsening with taxanes. Other general management principles include biopsy-proven malignancy, informed patient consent, adequate performance status and major organ function, an established and easily accessible system to monitor response and toxicity, and adequate social support.3
 |
Some of the earliest regimens, such as Bonnadona-devised classic CMF,4 were administered for 12 months; modern regimens may last from three to six months. Most combination neo-adjuvant and adjuvant regimens are administered every 21 days, although "dose-dense" regimens are administered every 14 days in conjunction with granulocyte colony stimulating factor (G-CSF) to avoid profound myelosuppression.5-9 Combination chemotherapy, or polychemotherapy, improves survival not only in LABC but also in early disease, with randomized trials demonstrating a 12% absolute mortality benefit in women younger than 50 years of age with positive lymph nodes; women older than 50 years of age derive less absolute survival benefit (2%), especially those patients with ER-positive, node negative disease.10 However, age alone should not exclude patients from receiving chemotherapy if the benefit outweighs the risk (e.g., large tumor, positive lymph nodes, ER-negative).
The most widely administered adjuvant regimen for early stage disease in recent years is doxorubicin (Adriamycin®) and cyclophosphamide (Cytoxan®) (AC) administered for four cycles, an approach that provides a 3% absolute survival benefit at five years compared to non-anthracycline regimens.1,11,12 Various other anthracycline combinations have been utilized but are beyond the scope of this review. In recent years, the microtubule-targeting agents known as the taxanes (e.g., paclitaxel [Taxol®] and docetaxel [Taxotere®]) have become vital components of breast cancer therapy. Various adjuvant taxane regimens have resulted in a 5% absolute disease-free survival and overall survival benefit at five years, with both agents appearing equally efficacious.11,12 Patients with hormone receptor-negative cancers derive the greatest absolute benefit from anthracycline- and taxane-based chemotherapy, but those with ER-positive disease benefit as well.1 Berry et al.13 analyzed data from large randomized Cancer and Leukemia Group B (CALGB) adjuvant trials and demonstrated relative risk reduction of recurrence of approximately 25% for ER-negative tumors and approximately 10% for ER-positive tumors.13
Various trials have shown that adjuvant paclitaxel or docetaxel administered every three weeks following AC improves DFS and OS in node-positive breast cancer.14-17 To improve on these outcomes, other trials have tested biweekly adjuvant taxane therapy ("dose-dense"), showing improvements in DFS and OS at 36-month follow-up.18 The most common dose-dense adjuvant regimen consists of four cycles of AC followed by four cycles of paclitaxel with G-CSF support.6,9,18 The clinical benefits of dose-density relates to the observation in experimental models that a given drug dose always kills a certain fraction of neoplastic cells rather than an absolute number.19 Dose-dense chemotherapy likely results in a more effective way of minimizing tumor cell burden between cycles than conventional 21-day regimens.20 Since dose-dense AC followed by paclitaxel does not significantly increase toxicity, it is the preferred method of many clinicians for administration of this regimen to node-positive breast cancer patients.18 Further studies of taxane administration have been performed and, recently, Sparano et al.21 studied the effects of four different regimens of docetaxel or paclitaxel therapy following AC in 4,950 women with T1-3, N1-2 or T2-3, N0 breast cancer. In this trial, women administered adjuvant weekly paclitaxel enjoyed prolonged overall survival compared to weekly docetaxel and triweekly docetaxel and paclitaxel.21
Doxorubicin-associated congestive heart failure has an incidence of 1% and 4% at cumulative doses of 300 mg/m2 and 450 mg/m2, respectively.22,23 In addition to increasing cumulative dose,24 other risk factors for anthracycline cardiotoxicity include age,25 prior or concurrent radiation therapy,26 hypertension,27 and concomitant administration of taxanes and traztuzumab.28,29 Suggested mechanisms of anthracycline cardiotoxicity include iron-dependant generation of toxic free-radicals that induce direct damage to cellular lipids, proteins, and DNA.30 Since anthracycline-cardiotoxicity can be progressive and even fatal, avoiding this complication is paramount, especially in those with expected prolonged survival. Recently, non-anthracycline adjuvant regimens have been developed for use in patients with stage I-III operable breast cancer. Currently, perhaps the most widely used non-anthracycline regimen was developed by Jones et al.,31 replacing doxorubicin with docetaxel (Taxotere®) in conjunction with cyclophosphamide (TC) administered for four cycles. At seven-year follow-up, the TC regimen was superior to the AC regimen in regard to DFS (81% TC vs 75% AC, p = 0.033) and OS (87% TC vs 82% AC, p = 0.032) in all subgroups regardless of ER status, HER2/neu status, and age above or below 65.32 The TC regimen is tolerable, with the most common adverse-effects being neutropenia, edema, arthralgia, and myalgia; febrile neutropenia occurred in 5% of patients, and death was rare.31,32 Similarly, in patients with HER2/neu-positive tumors, the non-anthracycline regimen consisting of docetaxel (Taxotere®), carboplatin, and the monoclonal antibody trastuzumab (Herceptin®) (TCH regimen) showed similar efficacy to a doxorubicin-containing regimen with a lower rate of cardiotoxicity.33 Although anthracyclines still are utilized commonly in the adjuvant setting, we may see a decline in their future use in light of the above data.
Until recently, the vast majority of patients with primary tumors exceeding 1 cm were offered systemic chemotherapy, which led to overtreatment of many women, resulting in occasional long-term toxicity. Indeed, late cases of chemotherapy-induced heart failure or acute leukemia are tragic and have prompted attempts to determine which patients may have tumors that are unlikely to recur and, therefore, may not derive significant benefit from cytotoxic therapy. Paik et al.34 developed a 21-gene assay (Oncotype DX®) to retrospectively predict risk of recurrent breast cancer from ER-positive, node-negative patients enrolled in NSABP-14 treated with tamoxifen. Analysis of DNA from paraffin-embedded specimens identified 16 cancer genes of various genotypes (including proliferation, HER2, estrogen, invasion genes) that were used in a complex alogorithm to calculate a numerical score and recurrence risk at 10 years: < 18, low risk (6.8%); 18-31, intermediate risk (14.3%); and > 31, high risk (30.5%).34 Most patients (51%) had low-risk tumors with only a 6.8% risk of distant recurrence at 10 years and did not receive significant benefit from chemotherapy. Conversely, 27% of patients were in the high-risk category and would be expected to achieve the greatest benefit from cytotoxic therapy. Other authors have studied this 21-gene assay in ER-positive, N1 patients and have verified its usefulness in predicting which patients benefit most from adjuvant cytotoxic therapy and those with a low-risk of recurrence in whom treatment could be withheld.35 Use of Oncotype DX® in this situation is off-label, however. Paik et al.36 tested their assay to predict response to adjuvant chemotherapy and tamoxifen versus tamoxifen alone in ER-positive, node-negative patients from NSABP-20. Patients with a high recurrence score (> 31) derived a 27.6% absolute decrease in disease recurrence at 10 years (risk ratio 0.26) compared to a -1.1% absolute decrease in recurrence at 10 years (risk ratio 1.31) for those with a low recurrence score (< 18).36 Although data are still emerging, adjuvant therapy for an individual breast cancer patient is evolving into genomic-based therapy aimed at specific targets within the individual's tumor cells.
Trastuzumab
Trastuzumab is a recombinant monoclonal antibody directed at the HER2/neu receptor, a member of the epidermal growth factor (EGFR) receptor family that is involved in signal transduction from the cell surface to the cytoplasm and stimulates pathways involved in cellular proliferation, division, invasion, and angiogenesis.6 Overexpression of HER2/neu is associated with more aggressive tumor behavior and an increased risk of recurrence and metastatic disease. Detection of overexpressed HER2/neu involves immunohistochemical (ICH) staining or fluorescence in-situ hybridization (FISH) and is important since pharmacologic targeting of the receptor by trastuzumab has improved prognosis in the adjuvant as well as the metastatic settings.6,37 In the adjuvant setting, trastuzumab is combined with chemotherapeutic agents, most often anthracyclines, taxanes, antimetabolites, or carboplatin. Due to a high risk of cardiotoxicity, trastuzumab should not be administered concurrently with anthracyclines. Regular monitoring of left ventricular ejection fraction with echocardiography or multi-gated analysis (MUGA) scan is suggested at regular intervals to detect asymptomatic cardiac dysfunction that may require adjustment of therapy.38 Otherwise, this antibody is well tolerated, with a side-effect profile including fatigue, mild cytopenia, and, rarely, severe infusion reactions.6,33,38,39
The greater amount of data for one year of adjuvant trastuzumab was reported in the combined data analysis of the NSABP B-31 and North Central Cancer Treatment Group (NCCTG) 9831 trials as well as the Herceptin Adjuvant (HERA) trial.40,41 In aggregate, the NSABP B-31 and NCCTG 9831 trials demonstrated a significant increase in three year DFS (87.1% vs 75.4%) and OS (94.3% vs 91.7%) when trastuzumab was added to an AC and paclitaxel regimen.41 The HERA trial utilized a variety of chemotherapeutic agents combined with one- or two-year adjuvant trastuzumab and revealed an absolute increase in DFS at two years of 8.4%.40 Another notable study of adjuvant trastuzumab, the Breast Cancer International Research Group (BCIRG) 006, evaluated 3,222 patients with HER2-positive cancer randomized to AC followed by docetaxel (AC-T), AC followed by docetaxel and trastuzumab (AC-TH), and a novel non-anthracycline regimen consisting of docetaxel, carboplatin, and trastuzumab (TCH).42 The rationale of the BCIRG 006 study was to compare the efficacy of a non-anthracycline regimen in hopes of avoiding anthracycline cardiotoxicity. Both trastuzumab-containing arms were superior in regard to DFS and OS compared to the AC-T arm yet were similar to each other in regard to DFS, with a significantly lower incidence of cardiotoxicity in the TCH arm.42 As a result of this trial, many oncologists are administering adjuvant TCH to their patients with HER2-positive breast cancer to avoid potentially fatal future cardiotoxicity from anthracyclines.
Radiation Therapy
Whole-breast radiation therapy (WBRT) has been demonstrated in large, randomized controlled trials to decrease local recurrence following BCS in patients with DCIS43 and invasive breast cancer,44 a benefit that extends to all analyzed subgroups. Indeed, no patient group has been definitively identified in whom post-BCS WBRT can be withheld safely when local control and preservation of the breast are clinical end-points.45 Another study by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) analyzed data from studies involving 42,000 patients treated with various extents of surgery and radiation therapy and found that improved local control at five years resulted in a significant improvement in OS at 15 years.46 Additionally, post-operative WBRT significantly improved 15-year OS by 5.3% (p = 0.005) following BCS and by 4.4% (p = 0.001) following mastectomy in node-positive patients.46 Local control of breast cancer recurrence seems to serve as a surrogate for improved OS following BCS and mastectomy in patients with invasive breast cancer.47
Typically, adjuvant WBRT is administered in 1.8-2.0 cGy increments to a total of 45-50 Gy over a five- to six-week period, followed by a "boost" of 16 Gy directly to the tumor bed over another seven- to 10-day period.9 This boost dose has been shown to decrease the absolute risk of local recurrence by 3% (p < 0.001) following lumpectomy in patients with early breast cancer.48 Post-mastectomy chest wall radiation typically is limited for patients with positive margins, tumors exceeding 5 cm (T3), and/or tumoral involvement of four or more lymph nodes.33 Overgaard et al.49 randomized 1,708 pre-menopausal women with high-risk breast cancer who underwent mastectomy to receive CMF chemotherapy plus chest wall and axillary radiation versus CMF alone. The incidence of locoregional recurrence in the CMF group versus the CMF-radiation group was 32% versus 9% (p < 0.001), and 10-year OS 45% vs. 54% (p < 0.001), respectively.49 Generally, axillary radiation is withheld if an ALND reveals negative nodes.50 Radiation therapy is administered following adjuvant chemotherapy since studies have demonstrated statistically significantly lower rates of distant metastasis (p = 0.05) and a trend toward improved OS by 8% (p = .011) when administered in this sequence.51
Recently, a technique known as partial breast irradiation (PBI) has been developed to deliver higher local doses of radiation over an accelerated time period to the vicinity of the tumor bed to achieve a shorter therapy duration and to spare radiation to normal tissue.9 The evolution of PBI is supported by data that most local breast cancer recurrences occur in or around the tumor bed and that localized radiation may be ample to prevent local recurrence while avoiding potential toxicity to the heart and lungs.52 Additionally, PBI has the ability to shorten the treatment duration due to the higher delivered doses with each application, which may be more appealing to patients with busy lifestyles. A device known as Mammosite® (Proxima Therapeutics, Alpharetta, GA) was approved by the FDA in 2002 and is currently the most widely utilized device for delivering PBI.53 This device is an interstitial balloon-based catheter inserted into the lumpectomy cavity by the surgeon at the time of surgery or several days later. To be effective, the balloon must conform to the cavity and have an ample margin (5-10 mm) from the skin to prevent cutaneous radiotoxicity. A number of second-generation catheters with improvements in geometry and physics are becoming available for clinical use. A commonly utilized PBI regimen with the Mammosite® catheter delivers 34 Gy (typically Iridium-192) in 10 fractions over five days to the cavity and a surrounding margin of 1-2 cm.9,53 Cosmesis usually is excellent, although skin damage, seroma, infection, incision breakdown, and fat necrosis can occur in some patients.54 At very early follow-up, local control rate appears to be equal to WBRT.55,56 General criteria for the use of PBI include solitary invasive ductal cancer < 2 cm, negative lymph nodes, age younger than 45 years, and negative resection margins.55,57 Adjuvant chemotherapy, if necessary, is administered no sooner than three weeks following PBI to minimize the risk of cutaneous radiation recall and suboptimal cosmesis.58 Although initial data appear favorable for PBI compared to WBRT in regard to local recurrence, long-term data do not exist. The NSABP and the Radiation Oncology Group have been conducting a large phase III randomized trial of WBRT to PBI (via either Mammosite, interstitial brachytherapy, or 3-dimensional conformal radiotherapy) following lumpectomy for localized breast cancer. Until then, PBI can be considered in select candidates but, overall, WBRT remains the standard option for the majority of patients.
Endocrine Therapy
Adjuvant endocrine therapy to counteract the trophic influence of estrogen on neoplastic breast tissue is an important aspect of breast cancer medicine. Tamoxifen, the standard first-line agent, was approved by the FDA in 1986 for the treatment of node-positive and in 1990 for node-negative breast cancer.54 The drug acts by blocking estrogen binding to the ER, thereby preventing nuclear transcription. Tamoxifen is the only approved anti-estrogen drug for pre-menopausal patients but, until recently, has been widely administered to post-menopausal women as well.9 The EBCTCG demonstrated a significant survival advantage for ER-positive women of all ages treated with five years of adjuvant tamoxifen, which decreased the risk of death from breast cancer by 31% irrespective of age or chemotherapy regimen.1 There is no benefit of tamoxifen therapy beyond five years, which is detrimental, owing to increased thrombotic events and endometrial cancers.33 Currently, based primarily on the EBCTCG data, five years of adjuvant tamoxifen remains the agent of choice in pre-menopausal women with ER-positive breast cancers. Total ovarian blockade with the addition of leutenizing-hormone releasing hormone (LHRH) agonists has been analyzed in several trials but is beyond the scope of this review. Adverse effects of tamoxifen include cataract formation, vaginal dryness, hot flushes, endometrial polyps, venous and arterial thrombotic events, and endometrial cancer.6,33,59 Therefore, a thorough risk-assessment must be performed before commencing use of this agent.
Until recently, tamoxifen was the agent of choice for post-menopausal patients. However, the development and demonstrated efficacy of the aromatase inhibitor (AI) drugs has supplanted the use of tamoxifen in the majority of cases of post-menopausal breast cancer. Aromatase, an enzyme present in non-ovarian tissues including adipose and breast, converts endogenous androstenedione and testosterone to estrone and estradiol, respectively.54 As such, extra-ovarian tissues are the predominant source of estrogen production in post-menopausal women. These drugs are not active in pre-menopausal patients and generally should not be administered outside of a clinical trial. Inhibition of the aromatase enzyme by these agents results in an approximately 95% decrease in circulating estrogen levels.6,54,59 Currently, third-generation AIs are utilized in post-menopausal women and belong to the steroidal class (exemestane) and the non-steroidal class (letrozole and anastrozole). Although numerous randomized trials have established the AIs as the most effective endocrine agents in post-menopausal localized and metastatic breast cancer, only a few of the trials that demonstrated their superior efficacy will be discussed.
The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial was an adjuvant trial randomizing 9,366 post-menopausal patients with localized breast cancer to post-operative anastrazole (Arimidex®) or tamoxifen.60 Data analysis at 33, 47, and 68 months demonstrated that anastrazole significantly prolonged DFS, distant metastasis, time to recurrence (TTR), and reduced the incidence of contralateral breast cancer compared to tamoxifen.60-62 At the latest ATAC follow-up at 100 months, findings included fewer ipsilateral and contralateral recurrences (p = 0.003) but no difference in OS compared to tamoxifen; there was no benefit of the combination regimen.103 Fractures (p < 0.0001), arthralgias, and bone density loss were more common in the anastrazole group, but incidence of thromboembolism, hot flushes, vaginal complaints, and endometrial cancer were decreased compared to tamoxifen.62,63
The Breast International Group (BIG) 1-98 trial randomized 8,010 post-menopausal women to one of the following regimens: letrozole for five years, letrozole for two years followed by tamoxifen for three years, tamoxifen for five years, and tamoxifen for two years followed by letrozole for three years.64 Although there was no difference in survival, DFS was superior with letrozole (p = 0.003), especially in those patients experiencing distant recurrence (p = 0.001). The incidence of thromboembolism and endometrial cancer was higher in the tamoxifen arm. Another letrozole trial, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 trial, assessed the effect of an additional five years of adjuvant letrozole or placebo after the completion of tamoxifen.65 At interim analysis, the trial was halted early because letrozole was shown to improve DFS. The 30-month analysis of the MA.17 trial demonstrated that the initial 2,593 patients randomized to letrozole had an improved DFS (p < 0.001) compared to placebo; OS was the same for both arms.66 However, in the subgroup of women with positive lymph nodes, OS was superior for the letrozole arm (p = 0.04).
A similar approach of extended post-tamoxifen therapy with anastrozole was assessed in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) in which 856 ER-positive women completing five years of adjuvant tamoxifen were randomized to three additional years of anastrazole or placebo.67 Similar to MA.17, at five years women in the anastrozole arm experienced a decreased risk of recurrence (locoreginal, contralateral, or distant metastasis) compared to the placebo arm (p = 0.031). As a result of these data, post-menopausal women who have completed tamoxifen therapy should be offered a non-steroidal AI. Letrozole may be considered in patients with node-positive disease given the improvement in OS in the MA.17 trial.
The Intergroup Exemestane Study (IES) trial randomized 4,742 post-menopausal women with ER-positive or ER-unknown localized breast cancer who were disease-free after two or three years of adjuvant tamoxifen to continued tamoxifen or exemestane to complete a five-year course.68 At 55-month follow-up, the exemestane group had significant improvement with regard to DFS (p = 0.0001) and OS (p = 0.05) in those patients with ER-positive cancers. Given these and other data, exemestane also is a reasonable option for adjuvant therapy in hormone receptor-positive breast cancer in post-menopausal women.
Tamoxifen Failure and Predictors of Response to Endocrine Therapy
Despite adequate data showing the benefit of adjuvant tamoxifen, may women with hormone-positive breast cancer experience disease recurrence despite adherence to recommended regimens. Tamoxifen is a pro-drug that is biotransformed to the potent anti-estrogen endoxifen via the cytochrome P450 system by isoform 2D6. Patients with wild-type CYP2D6 normally biotransform tamoxifen into endoxifen, but patients with certain mutations of the CYP2D6 gene have impaired tamoxifen metabolism resulting in decreased plasma endoxifen levels.69 A useful clinical marker for poor tamoxifen metabolism is decreased or absent hot flushes, which are, in part, a vasomotor effect of endoxifen.70 Some authors suggest an inferior outcome for women who do not experience vasomotor symptoms, but studies are ongoing before definitive treatment recommendations can be made.70 Certain selective serotonin uptake inhibitors (SSRIs) such as paroxetine (Paxil®) and fluoxetine (Prozac®) frequently are prescribed for hot flushes but are strong inhibitors of CYP2D6, thereby decreasing endoxifen formation and, perhaps, efficacy.71 Consequently, these drugs and others known to inhibit the CYP2D6 enzyme should be avoided in patients administered tamoxifen. Whether routine testing of CYP2D6 in patients prescribed tamoxifen will become commonplace remains to be seen.
Although adverse effects of adjuvant hormone therapy are common in patients receiving tamoxifen or the AI drugs, the appearance of new symptoms may serve as an easily identifiable marker for drug efficacy. Cuzeck et al.72 retrospectively analyzed data from the ATAC trial to assess for correlation between the development of common side effects of tamoxifen (hot flushes) and anastrozole (myalgias and arthalgias) to the risk of cancer recurrence. The 37.5% of women who reported new vasomotor symptoms at three-month follow-up were noted to have less subsequent recurrences than those who did not report these symptoms (p = 0.04). Similarly, fewer recurrences were noted in the 31.4% of women who reported new joint complaints at the initial three-month follow-up visit compared to those patients who did not experience joint symptoms (p < 0.0001).72 Since these adverse effects may influence a woman's decision to cease endocrine therapy, these findings may encourage women who experience arthralgias or hot flushes to continue therapy. Further studies may help clarify this issue.
Breast Cancer During Pregnancy
Breast cancer complicating pregnancy is not common but most busy oncologists and primary care physicians will encounter this situation during their career. The frequency ranges between 1 in 3,000 to 1 in 10,000 deliveries, making breast cancer the second most prevalent malignancy complicating pregnancy next to cervical carcinoma.73 Similarly, studies have noted that at least 10% of patients younger than 40 years of age will be pregnant at the time of diagnosis.74,75 Unfortunately, many cases of pregnancy-associated breast cancer are diagnosed at an advanced stage, which may be due to attributing palpable abnormalities to normal physiologic pregnancy changes. The median maternal age at diagnosis is 33-34 years, with a median gestational age of 15-25 weeks.74,75 Most patients present with a painless palpable mass or thickened area, often associated with nipple discharge.74 Some patients may present to their physician with an axillary mass.76,77 A helpful clinical finding in post-partum patients is the "milk rejection sign" in which the infant avoids nursing from the cancer-laden breast.77
Although most breast complaints during pregnancy are benign, the clinician should at least consider the diagnosis of breast cancer and have a low threshold for evaluation if the situation persists. Indeed, delays in diagnosis are common, ranging from 1-6 months, and perhaps longer in the engorged, nursing breast.74 Evaluation of suspected malignancy should include thorough examination of the breast, axilla, skin, nipple, and supraclavicular area. Mammography with abdominal shielding is safe during pregnancy, with a standard two-view examination exposing the fetus to only 0.004 Gy of radiation, well below the threshold for congenital malformations and spontaneous abortion (0.05-0.1 Gy) in the first two trimesters.74,78 However, physiologic increase in breast density during pregnancy can make interpretation difficult. Breast ultrasound has gained popularity due to safety and an ability to differentiate cystic from solid lesions in up to 97% of patients.74 Magnetic resonance imaging should be avoided in routine staging of non-metastatic disease due to potential fetal heating and cavitation and since trans-placental crossage of gadolinium has caused fetal abnormalities in rats.79 In patients with clinical low-stage disease, a chest radiograph is safe,80 but bone scans are unnecessary in asymptomatic patients. If hepatic metastasis is suspected, liver ultrasonography is the imaging study of choice. Of note, plasma levels of alkaline phosphatase increase approximately two- to four-fold due to placental production and cannot be used as a reliable indicator of hepatic metastasis.74 Indeed, if this phenomenon is not appreciated, the clinician erroneously may commence an evaluation for liver or bone metastasis, exposing the patient not only to unnecessary testing but also to undue stress.
Any suspicious breast lesion discovered during pregnancy or the puerperium should be evaluated preferably with a core-needle biopsy; a fine needle aspiration also is an option, but proliferative changes during pregnancy may render pathologic interpretation difficult.74 Biopsy-related complications during pregnancy and the post-partum period include infection, bleeding, and milk-fistula formation, which can be minimized by discontinuation of breast-feeding prior to the procedure, prophylactic antibiotics, and careful hemostasis.81 Pathologically, pregnancy-associated cancers usually are of ductal histology and frequently are large ( > T2), ER-negative (56-67%), and poorly differentiated, often with lymphovascular invasion.76 Approximately 25-58% of tumors are HER2/neu positive.82 Some authors have reported axillary nodal involvement in 56-67% of pregnant patients at diagnosis.76,83 As a result, pregnancy-related breast cancer often is aggressive and at a more advanced stage at the time of diagnosis than breast cancer in women of similar age who are not pregnant.74-77,80 Axillary staging often is performed with ultrasonography, with fine needle aspiration of suspicious nodes. The use of SLNB during pregnancy has been reported in small series;83 the NCCN does not recommend this method of axillary staging due to limited data on the safety of the radioactive tracer and dyes.84 In cases of clinically or needle aspirate-positive axillary nodes, ALND should be performed.
The most commonly performed surgery in pregnant patients with breast cancer is modified radical mastectomy due to the increased frequency of nodal involvement. Furthermore, mastectomy eliminates the need for radiation in most patients, eliminating fetal risk, which includes not only teratogenicity but also later development of solid tumors and hematologic malignancies. Breast-conserving surgery is not recommended in early pregnancy but can be considered in the second or third trimesters if adjuvant post-chemotherapy radiation can be delivered post-partum.76 Surgical risk is small and includes spontaneous abortion and preterm labor.74 For patients diagnosed in the late second or third trimester, BCS can be performed since the patient would be well beyond delivery at the time of adjuvant radiation.85
Adjuvant chemotherapy generally is recommended for patients with tumors > 1 cm, node-positive, or locally advanced disease, especially in early pregnancy since delay in systemic therapy may lead to inferior outcomes.74,80 Due to the teratogenic effects of most chemotherapy drugs (all are Category D), systemic treatment is contraindicated during the first trimester; methotrexate is contraindicated during all trimesters due to its abortifacient effects.74 However, chemotherapy administered during the second and third trimester has the same incidence of fetal malformations as those who are not exposed to chemotherapy.84 Additionally, chemotherapy should be avoided past 35 weeks gestation to avoid peri-partum hematologic issues, especially thrombocytopenia and leukopenia. Although under the purview of the oncologist, administration of chemotherapy can be challenging in later pregnancy due to increased plasma volume, changes in volume of distribution, decreased albumin, and altered gastric motility, which may increase the incidence of vomiting.74 Ondansetron, lorezepam, and dexamethasone are safe anti-emetics.74,84 The florouracil, doxorubicin, cyclophosphamide (FAC) regimen is the preferred chemotherapy regimen during pregnancy.84 The group at MD Anderson reported on 57 pregnant women with breast cancer treated with FAC. All delivered live births with no miscarriages, stillbirths, or perinatal deaths; one infant had Down's syndrome, one had club foot, and one had ureteral reflux; 97% of children during follow-up were considered normal compared to peers.86 Trastuzumab has been associated with oligohydramnios and should be avoided until after delivery.87 Likewise, tamoxifen and other endocrine therapies should be avoided due to the significant risk of fetal malformations and craniofacial deformities.88 Generally, prognosis for breast cancer during pregnancy is similar to that of age-matched controls, although older studies did reveal poor outcomes possibly related to advanced stage at diagnosis and young patient age.80,89
Metastatic Breast Cancer
Metastatic breast cancer (MBC) is a heterogenous - and essentially incurable - disease, with some patients succumbing within weeks to months of their diagnosis and others surviving for years. Most long-term survivors are those with ER-positive disease and isolated skeletal metastasis.6 An in-depth review of this topic is beyond the scope of this text; however, some points salient to primary care medicine will be presented. In general, patients with ER-positive tumors can develop metastatic disease years after primary therapy, often despite optimal adjuvant endocrine therapy.90 Although ER/PR-positive breast cancer can involve any organ system, this subtype of breast cancer is more likely to present with skeletal-only disease, which can remain relatively stable for years with sequential endocrine therapy. Compared to ER-positive cancers, patients with tumors overexpressing HER2/neu are more prone to recurrent and metastatic disease, which often involves the brain, despite adjuvant trastuzumab therapy.91 Isolated brain metastases in patients with HER2/neu-positive breast cancer may result from an inability of trastuzumab to cross the blood-brain barrier, resulting in the brain serving as a "sanctuary site" for micrometastases that can present later as macroscopic disease.92 In addition, HER2-positive tumors may possess a more brain-avid phenotype, resulting in a propensity for metastasis.6,92 Patients with triple-negative breast cancers also have an increased risk of brain metastasis compared to ER-positive cancers, with brain metastasis often developing in rapid fashion even after appropriate adjuvant therapy.93 Additionally, triple-negative MBC brain metastasis seems to be more common in women younger than 50 years, especially black women and those with BRCA1 mutations.94,95 Both HER2-positive and triple-negative tumors are associated with a higher likelihood of visceral (e.g., lung and liver) metastases that can result in life-threatening disease, known as a "visceral crisis."92-95
The diagnosis of MBC should be suspected in any patient with a history of breast cancer who develops otherwise unexplained persistent symptoms such as headache (brain metastasis); limb or back pain (bone metastasis); abdominal pain (liver metastasis); dyspnea, cough, or chest pain (lung metastasis); or leg weakness (spinal cord compression).6,84,90 Although routine screening for asymptomatic metastasis following adequate adjuvant therapy with tumor markers (e.g., CA27-29 or CA15-3) is not suggested by the NCCN,84 many clinicians obtain routine laboratory and imaging studies in this population. Metastatic disease may be found by the discovery of new-onset cytopenias, elevated liver chemistries, or abnormal radiography. Although 18-fluourodeoxyglucose positron emission tomography (PET) scans are quite useful for evaluating the extent of known or symptomatic MBC or response to chemotherapy, their use in asymptomatic patients to screen for metastasis is controversial and not generally warranted.96 In fact, no convincing data exist demonstrating that diagnosis and treatment of otherwise clinically silent and asymptomatic MBC improves OS. This observation is an example of lead-time bias, or the interval that the diagnosis of MBC has been shortened by screening studies.6 For instance, suppose a patient was diagnosed with asymptomatic MBC by screening studies and treated immediately with chemotherapy and survived a total of 18 months after diagnosis. This would seem to be a superior survival time compared to a similar patient diagnosed 12 months later when symptomatic disease developed who survived only six months after commencing chemotherapy. In reality, both patients survived 18 months, but the asymptomatic patient appears to have had a longer OS (12 months) compared to the patient treated at symptom-onset (six months). One needs to be cautious about overzealous use of screening tests for MBC since aggressive therapy in the asymptomatic patient may affect quality of life and lead to undue toxicity with little impact on OS.
Several general treatment principles for MBC exist: The urgency of therapy is dependent upon organ dysfunction and not merely the presence of measurable disease; treatment should be given with palliative intent to improve quality of life without causing undue toxicity and patient inconvenience; endocrine therapy is preferred initial therapy in patients with ER-positive disease, especially older patients with skeletal-only disease; single-agent chemotherapy is better tolerated and typically not inferior to multi-agent regimens; there is no single pharmacologic standard of care for MBC; and, other non-chemotherapy modalities may be useful, including radiation therapy, analgesics, bisphosphonates, physical therapy, and treatment of depression.6,90
Endocrine agents effective in MBC include tamoxifen, AIs, and the injectable estrogen-antagonist, fulvestrant.97 Which agent the oncologist utilizes depends upon which drug was administered most recently during adjuvant therapy, the patient's ability to tolerate the adverse effect profile, and compliance. For instance, a post-menopausal patient who recently completed five years of tamoxifen before the diagnosis of MBC most likely would benefit from an AI such as letrozole or anastrozole.90 Patients progressing on an AI or tamoxifen may respond to monthly intramuscular injections of fulvestrant-a regimen that also may prove more convenient and aid compliance.97,98 Patients with bone metastases generally should receive a bisphosphonate such as zolendronic acid (Zometa®), which has been demonstrated to decrease the risk of fracture by interfering with osteoclast-mediated bone resorption.99 Patients with painful bone metastasis, impending pathologic fracture, or symptomatic brain metastasis should be evaluated by a radiation oncologist since palliative radiotherapy generally is effective at relieving skeletal pain, preventing pathologic fracture, and improving headache and/or neurologic symptoms, respectively.6 Patients with widespread, treatment-refractory bone metastases may experience pain relief with injections of the radiotracers samarium or strontium. Corticosteroids may help with cancer- or treatment-related anorexia, fatigue, vomiting, or bone pain, with dexamethasone being the most widely utilized agent. Narcotic analgesia should be provided in a generous manner for patients with ongoing pain, and the patient should be reassured that the risk of addiction is nil in this setting and should not influence aggressive pain control with these agents. Importantly, attention to bowel habits should be routine to avoid constipation that is common with narcotics, pain-associated immobility, malignant hypercalcemia, and autonomic neuropathy associated with certain chemotherapy agents such as vinorelbine. Stool softeners such as docusate sodium, irritant laxatives such as senna, and bulk agents such as psyllium are reasonable options. Adequate hydration, mobilization, and administration of stool softeners or irritants should be commonplace in these patients. Appropriate psychosocial support is an integral part of the management of advanced MBC, especially when treatment options are exhausted. Referral for end-of-life and hospice care should be anticipated and discussed with the patient and family relatively early in therapy so plans are made in a thoughtful manner to avoid unnecessary testing and prolonged hospitalization.100
No single standard chemotherapeutic agent exists for the treatment of symptomatic MBC, although many agents currently are available. Most patients should be treated with a single agent to avoid toxicity, which is more common in heavily pre-treated patients. Most patients with MBC will have received adjuvant doxorubicin and cyclophosphamide, thereby limiting these agents in the metastatic setting due to concerns for cardiomyopathy and hematologic malignancy, respectively.6 A discussion of chemotherapy regimens is beyond the scope of this review, but many oncologists initiate therapy for HER2/neu-negative MBC with weekly paclitaxel, often in conjunction with the anti-VEGF antibody bevacizumab, since recent data showed a doubling of PFS with this combination.101 Patients with HER2/neu-positive MBC often are treated with trastuzumab in combination with paclitaxel, docetaxel, capecitabine, or vinorelbine.102,103 The oral anti-HER2 agent lapatanib recently has been released and is indicated for patients who have progressive disease on trastuzumab.104 In general, continuation of endocrine therapy in some form is indicated in ER/PR-positive disease.
Special mention will be made of patients with otherwise controlled MBC who develop isolated metastatic lesions within the brain or lungs. Surgical resection or intensely focused radiation therapy (such as gamma knife or stereotactic radiosurgery) may be beneficial in select patients with an otherwise favorable prognosis and can prolong survival with improved quality of life.6,84,90 After either of these focal procedures, whole brain radiotherapy (WBRT) often is delivered to sterilize microscopic disease and has been shown to improve survival. Similarly, resection of a single or few lung metastases ("metastatectomy") also may be considered if the patient is otherwise fit, has minimal disease elsewhere, and is an acceptable surgical risk. Hepatic metastatic resection has not been as widely adopted since most patients even with single liver lesions harbor micrometastic disease elsewhere, although some studies have shown benefit in certain patients.65 Table 2 provides an overview of the various treatment modalities employed in patients with MBC at various points across the disease spectrum.
 |
Fertility Preservation and Young Breast Cancer Patients
Although the risk of breast cancer clearly increases with age,5,37 this disease accounts for approximately one-third of all cancers occurring in women of reproductive age.106 Approximately 25% of cases of breast cancer occur before onset of menopause, and 15% occur in women younger than 45 years.5,37,107 Additionally, with the increase of women delaying first pregnancy until after age 35, more women of reproductive age will face adjuvant chemotherapy following breast cancer surgery.107,108 At about 37.5 years of age, accelerated atresia of oocytes commences with an increase in circulating serum follicle stimulating hormone (FSH).109 This age-related increase in oocyte loss and quality in conjunction with chemotherapy-induced oocyte loss results in impaired pregnancy rates following adjuvant chemotherapy, especially in patients older than 40 years of age. Indeed, chemotherapy-induced amenorrhea and menopause occur in the majority of women older than 40 years, with only 11% of women resuming menses following chemotherapy.110 In addition to age, the predominant risk factors for chemotherapy-associated infertility include type of chemotherapy and cumulative dose.106 Aklyating agents such as cyclophosphamide are the most gonadotoxic agents (odds ratio of 3.98 for causing ovarian failure), causing significant follicle loss via apoptotic cell death.110-112 Classic CMF causes amenorrhea in 68% of premenopausal women.110 Among other commonly utilized adjuvant agents, doxorubicin, flouropyrimidines, and possibly paclitaxel also increase the risk of follicle loss and infertility, although to a lesser degree.113
Although a detailed review of fertility issues in the young cancer patient are beyond the scope of this review, a few guidelines will be offered. Young women desiring fertility preservation should be referred to a reproductive endocrinologist to discuss options prior to adjuvant chemotherapy, if possible. If timely evaluation occurs, oocyte retrieval and cryopreservation can be performed after ovarian stimulation with gonadotropins if a cycle of ovarian stimulation will not prolong the time to chemotherapy administration.113 Some authors have utilized tamoxifen and letrozole to induce oocyte development.114 Cryo-preservation of immature oocytes (without pharmacologic stimulation) is an option, but retrieval numbers often are suboptimal.113 Ovarian cortex cryopreservation consists of laparoscopic harvesting of a strip of cortical ovarian tissue and delayed orthotopic implantation on or near the ovary and may result in natural conception; heterotopic implantation in the forearm may result in resumption of native ovulation in some cases.115,116 These methods, however, are not yet standard of care and remain largely investigational. Although still controversial, many oncologists administer gonadotropin receptor hormone (GnRH) receptor agonists (e.g., goserolin, leuprolide) to down-regulate the hypothalamic-ovarian axis and suppress follicular development and ovulation during chemotherapy.106,113 In essence, GnRH analogues induce quiescence of ovarian follicles to a pre-pubertal state, making them less susceptible to cytotoxic cellular damage and apoptosis. Although some studies with GnRH-analogues administered 7-10 days before and during chemotherapy have demonstrated preservation of ovarian function in more than 90% of patients,117 this method continues to be evaluated in clinical trials and is not yet accepted as standard of care by many authorities.113
Male Breast Cancer
Male breast cancer is rare, accounting for 0.8-1% of all cases of breast cancer, with approximately 1,500 cases diagnosed annually in the United States resulting in 400 deaths.118,119 The median age at diagnosis is 68 years, compared to 63 years for women, making this a disease of elderly males.119 Reported risk factors for male breast cancer include Jewish ancestry, black race, infertility, Klinefelter syndrome (XXY genotype), presence of the BRCA2 mutation, a family history of breast cancer, prior chest wall radiation, and physiologic conditions associated with hyperestrogenemia such as obesity and cirrhosis.118-121 Testicular disease such as undescended testes, orchitis, and testicular trauma also increase risk.119 The presence of gynecomastia is a marker of increased risk due to underlying hyperestrogenic states but is likely not a premalignant lesion in itself.122 Approximately 90% of male breast cancers are infiltrating ductal carcinomas, and 80% are ER-positive.119-122 Invasive lobular carcinoma is more common in patients with Klinefelter syndrome.120 Overexpression of HER2/neu is present in some cases and imparts similar tumor and prognostic characteristics. Most patients present with a painless, firm, subareolar mass, which often is fixed to surrounding tissue. The subareolar area is the typical area of involvement, since this is the location of rudimentary breast ducts. As a result, nipple retraction, ulceration, and bloody discharge are not uncommon.119-122 Due to the rarity, many cases of male breast cancer are associated with diagnostic delay and advanced disease at presentation, often involving the axillary and/or internal mammary lymph nodes.118,119 Mammography is a useful imaging procedure in cases of unilateral breast lesions and reveals an eccentric, spiculated, and irregular mass; gynecomastia is characterized by a "flame-shaped" density blending into surrounding fat.122 Ultrasonography is not as accurate as in females and adds little diagnostic information above mammography. Fine-needle aspiration is a simple but very accurate method for the diagnosis of male breast cancer, with some authors reporting sensitivity and specificity approaching 100%.123 Core-needle biopsy is a reasonable diagnostic modality as well. In addition to standard histologic analysis, immuno-staining for ER, PR, and HER2/neu should be performed. Clinical and surgical axillary staging are similar as for women, although modified radical mastectomy is the operative procedure of choice.119 Adjuvant radiation has not shown a survival benefit for male breast cancer but may prevent local recurrence if the tumor is large or fixed to underlying tissues.120-124 Cytotoxic chemotherapy principles are similar to female breast cancer. Due to the very high rate of ER-positivity, hormone therapy with tamoxifen is suggested for five years and increases five-year survival in patients with stage II and III disease.119,125 Trastuzumab should be considered in patients with HER2/neu-positive tumors. As with females, tamoxifen should be considered as first-line therapy for patients with metastatic disease unless symptomatic visceral disease is present, in which case chemotherapy would be indicated.119-122 The most important prognostic factors in male breast cancer include tumor size, lymphatic invasion, and axillary nodal involvement.122,125 The five-year survival is 85% for patients with negative lymph nodes and 57% for patients with lymph node involvement.125
Primary Care for the Breast Cancer Survivor
The population of breast cancer survivors, a number currently estimated to approximate two million, is increasing, and primary care physicians will continue to play a pivotal role in the long-term follow-up of these patients.37,126 The NCCN84 and other professional organizations such as the American Society of Clinical Oncology (ASCO)127 offer rational evidence-based guidelines to prevent overuse of laboratory and imaging studies in asymptomatic patients. Patients with DCIS require only a thorough medical history and physical examination biannually for five years and annual mammography.50 Similar follow-up is suggested in patients with stage I disease; there is no role for routine use of tumor markers, blood tests, or body imaging in patients with DCIS or stage I disease. Patients with stage II or III breast cancer require history and physical examination every three months for the first one to two years after completing treatment and every six months for years three to five, with careful attention for locoregional recurrence in the form of skin nodules, chest wall masses, or nodal enlargement.6,126-128 Mammography is the only recommended diagnostic test to assess for a new primary tumor or local recurrence.127 Most cases of recurrence occur within the first three years of primary therapy,50 although ER-positive tumors can recur more than a decade later. Routine plain radiographs, bone scans, computed tomographic scans, blood counts, serum chemistries, tumor markers, and PET scans to detect asymptomatic metastases have not been demonstrated in randomized trials to impart survival benefit or improve quality of life and, therefore, are not indicated in the absence of symptoms.129-131 In addition, an intensive surveillance approach increases annual costs compared to a more conservative approach including history, physical examination, mammography, and laboratory or imaging studies only when clinically indicated.132,133 Routine MRI is not indicated except in very high-risk patients such as those with known mutations of the BRCA1 or BRCA2 genes.126 A simplified approach to the follow-up of the breast cancer survivor is found in Table 3.
 |
Medical oncologists generally obtain more diagnostic tests in the absence of symptoms compared to primary care physicians.134 Studies comparing outcomes between primary care versus subspecialty oncology follow-up found no differences in patient anxiety, quality of life, or time to diagnose cancer recurrence.135,136 Women also may prefer that their primary care physician be involved in follow-up care; one study revealed that patients feel more "unrushed" during appointments, giving them the opportunity to share concerns.137
Patients taking tamoxifen should undergo annual pelvic examination and, if unexplained vaginal bleeding develops, transvaginal ultrasound and endometrial biopsy should be obtained to exclude endometrial carcinoma. Although tamoxifen does not decrease bone density, patients treated with AIs experience increased bone loss as shown in major trials and should be counseled regarding osteoporosis prevention.64,67,68 Weight-bearing exercise, smoking cessation, and ingestion of calcium and vitamin D supplements are recommended in women taking AIs.126 Bone densiometry (DEXA) scans should be obtained every one or two years to assess not only for baseline bone density but for subtle or overt declines that may mandate aggressive anti-resorptive therapy with bisphosphonates. Vasomotor symptoms such as hot flushes related to estrogen depletion may be treated with SSRI agents, although drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) should be avoided since they interfere with tamoxifen metabolism into the potent anti-estrogen endoxifen.69 Vaginal dryness and/or dyspareunia can be treated with various lubricants, although those containing estrogen may increase serum estrogen levels and should be avoided.126 Finally, the primary care physician also should counsel patients on other cancer prevention practices such as colonoscopy, frequent whole-body skin examination, and annual Pap smears.
Conclusion
Breast cancer is the most common non-cutaneous malignancy in women, and primary care physicians undoubtedly will be impacted by this disease in their daily practice. The primary care physician plays a key role in counseling women regarding their risk of developing breast cancer as well as providing guidance with regard to appropriate screening. Timely referral for percutaneous needle biopsy of a suspicious mammographic finding is important to prevent delay in diagnosis and therapy. Although a large proportion of medical care is provided by the oncologist once surgery is complete, the primary care physician should be aware of basic therapeutic principles and adverse effects of chemotherapy, endocrine therapy, and radiation. Since the number of breast cancer survivors is increasing, many non-oncologist physicians will be providing post-cancer-treatment care, which includes ongoing observation for recurrence, maintenance of bone health, and monitoring for long-term adverse effects of chemotherapy, endocrine therapy, and radiation.
References
1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;365:1687.
2. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of the breast. N Engl J Med 2004;350:1430.
3. Perry MC, Anderson CM, Donehower RC. Chemotherapy. In: Clinical Oncology, 3rd ed. Philadelphia: Elsevier Churchill Livingstone, 2003, 483.
4. Bonadonna G, Brusamolino E, Valagussa P, et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405.
5. Pruthi S, Brandt KR, Degnim AC, et al. A multidisciplinary approach to the management of breast cancer, part 1: Prevention and diagnosis. Mayo Clin Proc 2007;82:999.
6. Abeloff MD, Wolff AC, Wood WC, et al. Cancer of the breast. In: Clinical Oncology, 3rd ed. Philadelphia: Elsevier Churchill Livingstone, 2004, 2369.
7. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. J Natl Cancer Inst 1998;90:1205.
8. Fisher B, Anderson S, DeCillis A, et al. Further evaluation of intensified and increased total dose of cylcophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 1999;17:3374.
9. Pruthi S, Boughey JC, Brandt KR, et al. A multidisciplinary approach to the management of breast cancer, part 2: Therapeutic considerations. Mayo Clin Proc 2007;82:1131.
10. Bergh J, Jonsson PE, Glimelius B, et al. A systematic overview of chemotherapy effects in breast cancer. Acta Oncologica 2001;40:253.
11. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: A pooled analysis of randomized trials. J Natl Cancer Inst 2008 ;100:14.
12. DeLaurentis M, Cancello G, D'Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: A meta-analysis of randomized trials. J Clin Oncol 2008;26:44.
13. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 2006;295:1658.
14. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976.
15. Mamounas EP,Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 2005;23:3686.
16. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302.
17. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Protocol B-27. J Clin Oncol 2006;24:2019.
18. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 2003;21:1431.
19. Skipper HE. Laboratory models: Some historical perspectives. Cancer Treat Rep 1986;70:3.
20. Norton L. Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 2001;3:30.
21. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008;358:1663.
22. Hershman DL, Shao T. Anthracycline cardiotoxicity after breast cancer treatment. Oncology 2009;23:227.
23. Buzdar AU, Marcus C, Smith TL, et al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer 1985;55:2761.
24. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710.
25. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003;97:2869.
26. Shapiro CL, Hardenbergh PH, Gelman P, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 1998;16:3493.
270. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900.
28. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer. NSABP B-31. J Clin Oncol 2005;23:7811.
29. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215.
30. Rajagopalan S, Politi PM, Sinha BE, et al. Adriamycin-induced free radical formation in the perfused rat heart: Implications for cardiotoxicity. Cancer Res 1988;48:4766.
31. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24:5381.
32. Jones SE, Holmes FA, O'Shaughnessy J, et al. Docetaxal with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 2009;27:1177.
33. Jardines L, Haffty BG, Royce M. Stage II breast cancer. In: Cancer Management: A multidisciplinary approach. Medical, Surgical, and Radiation Oncology. 11th ed. Lawrence: KS, CMPMedica, 2008, 219.
34. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817.
35. Jeffrey SS, Lonning PE, Hillner BE. Genomics-based prognosis and therapeutic prediction in breast cancer. JNCCN 2005;3:291.
36. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24:3726.
37. Jardines L, Haffty BG, Fisher P, et al. Breast cancer overview: Risk factors, screening, genetic testing, and prevention. In: Cancer Management: A Multidisciplinary Approach Medical, Surgical, and Radiation Oncology, 11th ed. Lawrence, KS: CMPMedica, 2008, 169.
38. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B31. J Clin Oncol 2005;23:7811.
39. Pritchard KI, Shepherd LE, O'Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006;354:2103.
40. Romond EH, Perez EA, Bryant J, et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673.
41. Piccart-Gebhart MJ, Procter M, Leyland-Jones, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659.
42. Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2Neu positive early breast cancer patients [abstract]. Presented at: 29th Annual San Antonio Breast Cancer Symposium; San Antonio, TX; December 14, 2006, Abstract 52.
43. Fisher B, Dignam, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B17. J Clin Oncol 1998;16:441.
44. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233.
45. Veronesi U, Marubini e, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of randomized trial. Ann Oncol 2001;12:997.
46. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;366:2087.
47. Punglia RS, Morrow M, Winer EP, et al. Local therapy and survival in breast cancer. N Engl J Med 2007;356:2399.
48. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378.
49. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949.
50. Jardines L, Haffty BF, Royce M. Stages 0 and I breast cancer. In: Cancer Management: A Multidisciplinary Approach Medical, Surgical, and Radiation Oncology, 11th ed. Lawrence, KS: CMPMedica, 2008, 201.
51. Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 1996;334:1356.
52. Clark RM, Whelan T, Levine M, et al. Ontario Clinical Oncology Group. Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. J Natl Cancer Inst 1996;88:1659.
53. Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite breast brachytherapy applicator in early stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003;55:289.
54. Barry M, Kell MR. Enhancing the adjuvant treatment of hormone receptor positive breast cancer. Breast J 2009;15:194.
55. Benitez PR, Keisch ME, Vicini F, et al. Five-year results: The initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer. Am J Surg 2007;194:456.
56. Kuerer HM, Julian TB, Strom EA, et al. Accelerated partial breast irradiation after conservative surgery for breast cancer. Ann Surg 2004;239:338.
57. Arthur DW, Vicini FA, Kuske RR et al. Accelerated partial breast irradiation: An updated report from the American Brachytherapy Society [corrected and republished in Brachytherapy. 2003;2:124-130]. Brachytherapy 2002;1:184.
58. Haffty BG, Vicini FA, Beitsch P, et al. Timing of chemotherapy after MammoSite radiation therapy system breast brachytherapy: Analysis of the American Society of Breast Surgeons MammoSite breast brachytherapy registry trial. Int J Radiat Oncol Biol Phys 2008;72:1441.
59. Geisler J, King N, Dowsett M, et al. Influence of anastrazole (Arimidex), a selective, non-steroidal aromatase inhibitor on in vivo aromatization and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer 1996;74:1286.
60. The ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early stage breast cancer: First results of the ATAC randomized trial. Lancet 2002;359:2131.
61. The ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003;98:1802.
62. ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60.
63. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45.
64. The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005;353:2747.
65. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after 5 years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793.
66. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262.
67. Jakesz, R, Greil R, Gnant M, et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: Results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancr Inst 2007;99:1845.
68. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' treatment (Intergroup Exemestane Study): A randomized controlled trial. Lancet 2007;369:559.
69. Higgins MJ, Rae JM, Flockhart DA, et al. Pharmacogenetics of tamoxifen: Who should undergo CYP2D6 genetic testing? JNCCN 2009;7:203.
70. Jin Y, Hayes DF, Li L, et al. Association between CYP2D6 genotype and tamoxifen-induced hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol 2008;26:5849.
71. Alfaro CL, Lam YW, Simpson J, et al. CYP2D6 inhibition inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: Intraindividual variability and plasma concentration correlations. J Clin Pharmacol 2000;40:58.
72. Cuzick J, Sestak I, Cella D, et al. Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: A retrospective analysis of the ATAC trial. Lancet Oncol 2008;9:1143.
73. Antonelli NM, Dotters DJ, Katz VL, et al. Cancer in pregnancy: A review of the literature: Part I. Obstet Gynecol Surv 1996;51:125.
74. Woo JC, Yu T, Hurd TC. Breast cancer in pregnancy. A literature review. Arch Surg 2003;138:91.
75. Merkel D. Pregnancy and breast cancer. Semin Surg Oncol 1996;12:370.
76. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999;17:855.
77. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy: A French national survey. Cancer 1999;86:2266.
78. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol 2000;27:623.
79. Garel C, Brisse H, Sebag G, et al. Magnetic resonance imaging of the fetus. Pediatr Radiol 1998;28:201.
80. Ring AE, Smith IE, Ellis PA. Breast cancer and pregnancy. Ann Oncol 2005;16:1855.
81. Petrek JA. Breast cancer during pregnancy. Cancer 1994;74(1 Suppl):518.
155. Elledge RM, ciocca DR, Langone G, et al. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer 1993;71:2499.
83. Middleton LP, Amin M, Gwyn K, et al. Breast carcinoma in pregnant women: Assessment of clinicopathologic and immunohistochemical features. Cancer 2003;98:1055.
84. National Comprehensive Cancer Network. Practice Guidelines in Oncology: Breast Cancer. 2009.
85. Gwyn K, Theriault R. Breast cancer during pregnancy. Oncology (Huntington) 2001;15:39.
86. Hahn KME, Johnson PH, Gordon N, et al. Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero. Cancer 2006;107:1219.
87. Waterson AM, Graham J. Effect of adjuvant trastuzumab on pregnancy. J Clin Oncol 2006;24:321.
88. Saunders CM. Breast cancer in pregnancy. In: Hormones and Cancer. London: Royal College of Obstetricians and Gynaecologists Press, 1999, 312.
89. Ring AE, Smith IE, Jones A, et al. Chemotherapy for breast cancer during pregnancy: An 18-year experience from five London teaching hospitals. J Clin Oncol 2005;23:4192.
90. Jardines L, Haffty BG, Royce M, et al. Stage III and IV breast cancer. In: Cancer Management: A Multidisciplinary Approach. Medical, Surgical, and Radiation Oncology. Lawrence, KS: CMPMedica, 2008, 243.
91. Altundag K, Bondy ML, Mirza NQ, et al. Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer 2007;110:2640.
92. Lin NU, Winer EP. Brain metastases: The HER2 paradigm. Clin Cancer Res 2007;13:1648.
93. Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer. High incidence of central nervous system metastases. Cancer 2008;113:2638.
94. Nanda R, Hu Z, He X, et al. Characterization of aggressive breast cancer in African American and Caucasian women: Patterns of gene expression in primary breast tumors. J Clin Oncol 2004;22:838s. Abstract 9513.
95. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: Implications for clinical practice and trial design. Clin Breast Cancer 2009;9:29.
96. Almubarak M, Osman S, Marano G, et al. Role of positron-emission tomography scan in the diagnosis and management of breast cancer. Oncology 2009;23:255.
97. Vergote I, Robertson JFR. Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: Results from clinical trials. Br J Cancer 2004;90(Suppl 1):11.
98. Mlineritsch B, Psenak O, Mayer P, et al. Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: Single centre clinical experience from the compassionate use programme. Breast Cancer Res Treat 2007;106:105.
99. Rosen LS, Gordon DH, Dugan W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36.
100. Marinella MA. On the Hippocratic facies. J Clin Oncol 2008;26:3638.
101. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666.
102. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 Study Group. J Clin Oncol 2005;23:4265-4274.
103. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 200l;344:783.
104. Geyer CE, Forster J, Lindquist D, et al. Lapatanib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733.
105. Caralt M, Bilbao I, Cortes J, et al. Hepatic resection for liver metastases as part of the "oncosurgical" treatment of metastatic breast cancer. Ann Surg Oncol 2008;15:2804.
106. Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy. Oncologist 2006;11:422.
107. Hankey BF, Miller B, Curtis R, et al. Trends in breast cancer in younger women in contrast to older women. J Natl Cancer Inst Monogr 1994;16:7.
108. Thewes B, Meiser B, Taylor A, et al. Fertility- and menopause-related information needs of younger women with a diagnosis of early breast cancer. J Clin Oncol 2005;23:5155.
109. Scott RT, Toner JP, Muasher SJ, et al. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651.
110. Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996;14:1718.
111. Meirow D, Lewis H, Nugent D, et al. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: Clinical importance and proposed accurate investigative tool. Human Reprod 1999;14:1903.
112. Meirow D. Ovarian injury and modern options to preserve fertility in female cancer patients treated with high dose radio-chemotherapy for hemato-oncological neoplasias and other cancers. Leuk Lymphoma 1999;33:65.
113. Maltaris T, Beckmann MW, Dittrich R. Fertility preservation for young female cancer patients. In vivo 2009;23:123.
114. Oktay K, Buyuk E, Davis O, et al. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003;18:90.
115. Oktay K, Buyuk E, Veeck L, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;363:837.
116. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405.
117. Blumenfeld Z. Preservation of fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: The role of inhibin-A and -B as markers. Mol Cell Endocrinol 2002;187:93.
118. Weiss JR, Moysich KB, Swede H. Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:20.
119. Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002;137:678.
120. Meguerditchian AN, Falardeau M, Martin G. Male breast carcinoma. Can J Surg 2002;45:296.
121. Ottini L, Palli D, Rizzo S, et al. Male breast cancer. Crit Rev Oncol Hematol 2009;May 6 [Epub ahead of print].
122. Krause W. Male breast cancer-and andrological disease: Risk factors and diagnosis. Andrologica 2004;36:346.
123. Vetto J, Schmidt W, Pommier R, et al. Accurate and cost-effective evaluation of breast masses in males. Am J Surg 1998;175:383.
124. Schuchardt U, Seegenschmiedt MH, Kirschner MJ, et al. Adjuvant radiotherapy for breast carcinoma in men: A 20-year clinical experience. Am J Clin Oncol 1996;19:330.
125. Memon MA, Donhue JH. Male breast cancer. Br J Surg 1997;84:433.
126. Hayes DF. Follow-up of patients with early breast cancer. N Engl J Med 2007;356:2505.
127. Khatcheressian JL, Wolff AC, Smith TJ, et al. American Society of Clinical Oncology 2006 update of breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 2006;24:5091.
128. Brennan M. Survivorship care after breast cancer. Austr Fam Physician 2008;37:826.
129. The GIVIO Investigators: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients: A multicenter randomized controlled trial. JAMA 1994;271:1587.
130. Rosselli Del Turco M, Palli D, Cariddi A, et al. Intensive diagnostic follow-up after treatment of primary breast cancer: A randomized trial-National Research Council Project on Breast Cancer follow-up. JAMA 1994;271:1593.
131. Rojas M, Telaro E, Russo A, et al. Follow-up strategies for women treated for early breast cancer. Oxford, United Kingdom, Cochrane Library, CD001768, 2, 2005.
134. Keating NL, Landrum MB, Guadagnoli E, et al. Surveillance testing among survivors of early-stage breast cancer. J Clin Oncol 2007;25:1074.
132. Schapira DV. Breast cancer surveillance: A cost-effective strategy. Breast Cancer Res Treat 1993;25:107.
133. Schapira DV, Urban N. A minimalist policy for breast cancer surveillance. JAMA 1991;265:380.
135. Gunfeld E, Mant D, Vessey MP, et al. Specialist and general practice views on routine follow-up of breast cancer patients in general practice. Fam Pract 1995;12:60.
136. Worster A, Bass MJ, Wood ML. Willingness to follow breast cancer: Survey of family physicians. Can Fam Physician 1996;42:263.
137. Adelwuyi-Dalton R, Ziebland S, Brunfeld E, et al. Patients' views of routine hospital follow-up: A qualitative study of women with breast cancer in remission. Psychooncology 1998;7:436.
This issue is the second installment in a two-part series on breast cancer. The first part covered epidemiology, histologic types of breast cancer, screening, diagnosis, principles of treatment, and surgical management. This issue will cover chemotherapy, radiation therapy, endocrine therapy, metastatic breast cancer, and primary care for the breast cancer survivor.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.