Special Issues in Breast Cancer Management

Dose-Intensive Therapy for Breast CancerEstrogen Replacement Therapy in Breast CancerMale Breast CancerBreast Cancer and PregnancyReferences

This section will examine several controversial or uncommon topics in breast cancer: use of dose-intensive therapy, estrogen replacement therapy, male breast cancer, and breast cancer in pregnancy. The section on dose-intensive therapy will trace the development and clinical rationale for the use of this therapy. For additional information, refer to the section on autologous bone marrow transplantation. Estrogen replacement therapy in patients previously treated for breast cancer is an area of active investigation and controversy. Available information is reviewed, and ongoing studies are discussed. Male breast cancer and breast cancer in pregnancy are uncommon conditions. The relevant literature is summarized and presented.

Dose-Intensive Therapy for Breast Cancer

Dose-intensive therapy for breast cancer is an area of intense clinical investigation; several major trials are underway to evaluate the effect of this therapy in various patient groups. This section summarizes the current concepts of dose intensity, outlines the areas of controversy, and discusses studies to date of the efficacy and appropriate clinical applications of this technique.

Background

Evaluation of the effect of dose intensity on the outcome of breast cancer chemotherapy began in the 1980s. There were several precipitating factors:

• the emerging success of dose-intensive therapy with autologous bone marrow transplantation for leukemias and lymphomas [1-4];
• evidence of the efficacy of dose-intensive therapy with or without bone marrow support for solid tumors, including breast cancer [5-14]; and
• the publication of retrospective reviews that suggested a reduced relapse rate in patients receiving higher doses of chemotherapeutic agents [15-17].

In laboratory animals with cancer, drug dose is proportional to cure [18]. However, tumor types and dose schedule do modify the magnitude of this effect [19]. A clinical correlation between dose and response has long been recognized as well [20-22]. The lack of complete response is often tied to drug resistance [18], which can be overcome by increasing the dose. The availability of agents that enhance hematopoietic recovery, including the cytokines and autologous hematopoietic elements from the bone marrow or the peripheral blood, has allowed the escalation of doses of chemotherapeutic agents [23]. Peters et al demonstrated the possibility of administering cyclophosphamide (Cytoxan, Neosar), cisplatin (Platinol), and carmustine (BiCNU) at escalated doses [24].

The alkylating agents exhibit a number of features that prompted their investigation of dose-intensive therapy. Most alkylating agents at conventional doses share a common dose-limiting toxic effect, myelosuppression. Marrow autografting permits dose escalation to the level at which dose-limiting nonhematologic toxic effects occur. The nonhematologic toxic effects vary with each agent (Table 1), allowing combination therapy without additive toxicity [18]. With bone marrow support, the dose of an alkylating agent can be escalated to 5 to 20 times the standard dose before nonmyelosuppressive dose-limiting toxic effects occur [23].

Schabel was the first to demonstrate that the presence of resistance to an alkylating agent did not imply cross-resistance to other alkylating agents [25]. Schabel et al also demonstrated that the toxic effects of the alkylating agents were not additive and that the therapeutic effects of these agents were synergistic [26]. Resistance to alkylating agents is of a low level, is difficult to produce by selection pressure [18], and can be overcome by increasing the dose 5 to 10 times [25].

The steep dose-response curve of alkylating agents has been previously described (Figure 1) [19]. However, the dose-response curve for solid tumors is less steep than that for the more sensitive hematologic malignancies [27].

The first evidence that chemotherapy could potentially cure breast cancer came from adjuvant chemotherapy trials, in which the death rate was 20% to 30% lower in premenopausal women who received chemotherapy than in those who did not [28]. This difference was presumably due to the eradication of micrometastatic disease by chemotherapy. Gelber and Goldhirsch reviewed the validity of this type of overview analysis and concluded that in the case of early breast cancer, the conclusions drawn were likely to be valid [29].

Data on metastatic breast cancer suggest that the achievement of complete response (CR) may be important because only patients who entered CR had prolonged survival [30-32]. The duration of CR in standard chemotherapy trials has been shown to be inversely related to the bulk of metastatic tumor [30]. It was suspected that dose-intensive therapy might increase the number of patients entering CR or prolong this CR further [33], suggesting that chemotherapy might be curative in a fraction of patients with metastatic disease.

However, this inference may not be correct. Macrometastatic disease may be less sensitive to chemotherapy than is micrometastatic disease for a number of reasons. Patients with established metastases have a large tumor burden with an increased likelihood of resistant cells. Metastatic tumors are associated with hypovascularity, poor perfusion of tumor by chemotherapy, hypoxia, low growth fraction, and increased mutation rates and, therefore, a greater propensity for drug resistance [18].

Methods of Calculating Dose Intensity

Cumulative Dose: In a retrospective analysis of the data in the first two Milan trials, Bonadonna et al calculated dose intensity as a function of cumulative total dose (total dose actually administered expressed as a percentage of optimal dose)[17]. Their results demonstrated that patients administered the highest dose of chemotherapy (85% or more of the optimal dose) had a significantly better disease-free survival rate than did control patients in the first trial or patients administered less than 65% of the optimal dose in either trial. These differences persisted after 10 years of follow-up [34]. Similar retrospective analyses have had mixed results [20].

Confounding biases in the analysis of these data may include patient age and performance status. Patients with a good performance status might be expected to tolerate higher doses of therapy. In addition, there is a highly significant correlation between performance status and response rate, response duration, and survival [35]. Furthermore, patients whose disease progressed during therapy were included in the lower dose group, worsening the outcome statistics for that group.

Dose Rate: In a second type of retrospective analysis, Hryniuk examined dose rate rather than cumulative doses of planned chemotherapy [36]. He defined dose intensity as the amount of drug given per unit of time, expressed as mg/m²/wk, regardless of schedule. Limitations of this model include the assumption that scheduling does not directly determine tumor cell kill. Additionally, the model may be applicable only after a threshold dose intensity has been reached [36-38].

Using this model, Hryniuk demonstrated an association between dose intensity and response duration in patients with metastatic breast cancer [15] and in those receiving adjuvant therapy [39,40]. In a retrospective analysis, Hryniuk and Levine assigned a dose-intensity score to chemotherapy administered in an adjuvant setting in a series of published trials [39]. The standard was the Cooper et al regimen of cyclophosphamide, methotrexate, and fluorouracil (CMF) plus vincristine (Oncovin) and prednisone (CMFVP) [41]. A high and positive correlation coefficient, statistically significant for all patient subsets, was found when 3-year disease-free survival was correlated with dose intensity in a linear regression analysis (Figure 2).

Peak Drug Dose: In the bone marrow transplant setting, peak drug dose is often the calculation used to represent dose intensity. This method emphasizes peak drug dose, as compared with the method of Hryniuk, which calculates cumulative drug dose over a defined period [20].

Early Studies of Dose Intensity

Dose intensive chemotherapy, with or without autologous bone marrow transplantation (ABMT), was initially examined in patients with treatment-refractory or recurrent cancer. Trials usually involved small numbers of heavily pretreated patients with a variety of malignancies and were rarely randomized. Of several drugs examined in the single-agent setting using autologous marrow support, active drugs included melphalan [6,10,11], cyclophosphamide [7,24], thiotepa (Thioplex)[24], fluorouracil [42], and carmustine [24].

O'Bryan et al [43] performed a dose-escalation trial of doxorubicin (Adriamycin, Rubex) for refractory malignancies using doses ranging from 25 to 75 mg/m² every 3 to 4 weeks. Only patients with breast cancer who had received multiple prior chemotherapeutic regimens showed a dose-response effect. Of 34 patients, eight (24%) with heavy prior exposure to chemotherapy responded to 50 mg/m². There were two responses to 25 mg/m².

Forastiere et al [44] treated patients who had metastatic breast cancer with 60 mg/m² or 120 mg/m² of cisplatin every 3 weeks and noted four short-lived partial responses, primarily in soft tissue and the lung, at the higher dose. There were no responders at the lower dose. One of five patients who were crossed over to the higher dose arm responded. Kolaric and Roth [45] found 13 complete responders in 35 patients with metastatic breast cancer using high-dose cisplatin given by continuous infusion. Although rapid and frequent responses were obtained in patients with treatment-resistant breast cancer, dose escalation was limited by unexpected dose-related toxic effects [46].

Antman has reviewed the single-agent data in patients with failed or refractory breast cancer. She found that all complete responses were obtained with alkylating agents (melphelan [Alkeran] or thiotepa) and that these alkylating agents initiated a response rate of 39% compared with 16% for nonalkylating agents [47].

Only one nonrandomized study has prospectively compared patients treated with high-dose therapy with patients treated with standard doses of chemotherapy [48]. Vincent et al compared the survival of patients treated with 140 to 200 mg/m² of melphalan with that of patients administered conventional therapy. Patients had already had responses to induction therapy. Based on performance status, partial or complete response to chemotherapy, and minimal disease burden, 15 patients were selected to receive high-dose melphalan with autologous bone marrow rescue. There were three treatment-related deaths in the high-dose group. Of the 12 assessable patients, 11 had relapses. The median survival was 7 months. The overall survival rate of the two groups was the same [48].

Dose-intensive combination chemotherapy without autologous marrow infusion has also been studied. Six trials examined the CMF regimen in a prospective randomized fashion in patients with metastatic breast cancer [49-54]. Although five trials have shown an increased response rate with higher-dose CMF [49-53], only two have demonstrated an increase in survival [49,52], and in only one did the survival advantage achieve statistical significance [49]. Tannock et al [49] demonstrated a positive dose-response effect using a relative dose intensity of 2 for the high- and low-dose CMF regimens compared. A significant difference in response rate (11% vs 30%) and survival (13 vs 16 months) was found [49]. When adjustments were made for inequalities noted between the two groups for the time from first relapse to randomization, the significance of the dose response effect was diminished.

Other important trials examining dose intensity include the Ludwig trial group study of CMF with (n = 250) or without (n = 241) prednisone. Patients who received prednisone required fewer dose reductions for hematologic toxicity, receiving an average of 83% of the full CMF doses compared with 72% of full doses in patients treated with CMF alone (P < .001). However, at a median follow-up of 48 months, there was no significant difference in disease-free or overall survival between the two groups [55].

The Cancer and Leukemia Study Group B (CALGB) randomized patients to receive one of two different dose schedules of CMFVP. The dose intensities actually delivered, as calculated by the system of Hryniuk and Levine [39], were 84% and 76%. However, this significant difference in dose intensity did not result in a significant difference in disease-free or overall survival after a median follow-up of 45 months [56].

In a follow-up study, the CALGB enrolled more than 800 patients in a three-arm comparison of cyclophosphamide, doxorubicin, and fluorouracil (CAF) at high doses for 4 months, intermediate doses for 6 months, or low doses for 4 months [57]. The high-dose regimen comprised 600 mg/m² of cyclophosphamide on day 1, 60 mg/m² of doxorubicin on day 2, and 600 mg/m² of fluorouracil on days 1 and 8. The moderate- and low-dose regimens used two thirds and one half, respectively, of the doses in the high-dose regimen. At a median follow-up of 3.4 years, results for 1,529 women were published. The women treated with high or moderate dose intensity had a significantly higher disease-free survival rate (74% and 70%, respectively, at 3 years) and overall survival rate than did women treated with the low-dose regimen (63% disease-free survival rate at 3 years).

Some of these of these large trials [49,57] suggest a positive correlation between dose intensity and disease response. However, the effect appears to be modest and is associated with a significant increase in toxicity.

High-dose epirubicin has also been studied in a randomized fashion as a single-agent [58] and as part of a combination regimen for breast cancer [59]. There was no difference in response rates between standard and high doses in the combination regimen [59]; a higher response rate was seen with high-dose single-agent epirubicin [58], but this did not affect overall survival or the progression-free interval.

Hortobagyi et al used the M.D. Anderson Cancer Center regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) in a randomized trial treating patients with a dose intensity of 1 or 3. Patients were placed in a protective environment and given supportive care and cytokines. Overall response rates were identical (78%), as were CR rates. No difference was seen in median survival (20 months for both groups) [60]. The toxicity of the high-dose regimen was considerably higher. It was concluded that the extramedullary toxicity of FAC was severe enough to preclude further dose escalation, which might have produced a therapeutic difference [61]. Hortobagyi et al have also reviewed the M.D. Anderson Cancer Center experience with dose intensity [61]. It is notable that in all trials at M.D. Anderson between July 1973 and June 1976, patients who received higher doses of chemotherapy had a higher response rate and a longer survival duration. The correlation of response rate with drug dose was highly statistically significant, whereas the correlation with survival showed a trend that did not reach statistical significance [61]. Similar correlations were also seen in the institution's adjuvant therapy trials [62].

High-Dose Chemotherapy With or Without Hematopoietic Support

Early trials of high-dose chemotherapy with hematopoietic support in patients with metastatic breast cancer were often small, were seldom randomized, and produced mixed results. Important positive observations for high-dose chemotherapy with hematopoietic support included the following: a higher overall response rate (70% to 80%) than that of standard-dose therapy (50% to 60%) and a higher complete response rate (30% to 40%) than that of standard therapy (10%). Failure to respond to prior chemotherapy appeared to reduce the rate of CR to high-dose therapy substantially. Conversely, patients who responded to standard chemotherapy had a very high rate of CR to high-dose chemotherapy (70% to 80%).

Metastatic Disease: High-dose chemotherapy for metastatic breast cancer has been used in pretreated patients, as initial therapy in patients with or without a history of adjuvant therapy, and as consolidation of an initial response to conventional-dose therapy [20].

Pretreated patients were the first to be examined. In this group, high-dose chemotherapy with ABMT has not substantially improved disease-free survival in patients with advanced treatment-refractory disease. The duration of response of 2 to 5 months without maintenance therapy approximates that achieved with a second-line regimen of standard-dose therapy [63]. Patients with advanced refractory disease, which easily justifies the use of aggressive high-dose therapy, thus appear to be the ones least likely to benefit from the treatment.

In 1988, Peters et al [64] published results of a study that examined the effect of high-dose combination alkylating agents with bone marrow support as initial treatment of metastatic breast cancer. They evaluated 22 premenopausal, estrogen-receptor (ER)-negative patients; 12 (55%) of 22 obtained a CR. The median duration of response in complete responders was 9 months. Five patients died of therapy-related complications. The median disease-free survival and overall survival were not improved (7.0 months and 10.1 months, respectively). However, 3 of the 22 patients remain in continuous unsustained remission at 3.3 to 6.4 years [65].

Spitzer et al [66] evaluated high-dose cyclophosphamide, etoposide (VePesid), and cisplatin (CVP) for hormonally unresponsive metastatic breast cancer. Following induction therapy with doxorubicin and cyclophosphamide, patients received two courses of CVP. There was a 65% CR rate and a 27% partial response rate [66].

Table 2 outlines some of the trials of high-dose chemotherapy with ABMT for metastatic disease (20 patients or more) for which survival data are available [65-77].

Important points include the lower response rate seen in patients with treatment-refractory disease compared with that in patients in whom ABMT was used as the first-line therapy for metastatic disease. Although there is no difference in overall survival when these results are compared with those for standard chemotherapy, the presence of long-term survivors (10% to 15%) in the study population is noteworthy. The ability to achieve similar results with dose-intensive therapy without hematopoietic support is controversial. Some studies appear to achieve comparable results without the use of ABMT. The Eastern Cooperative Oncology Group evaluated 80 premenopausal women who had positive or unknown ER status and who were treated with CAF plus oophorectomy and 50 women with ER-negative disease who were treated with CAF alone. The response rate was 80% in the ER-positive/unknown group (with a CR of 37%) and was 70% in the ER-negative group [78]. Bezwoda et al [79] conducted a small randomized study of high-dose cyclophosphamide, 60 mg/kg, etoposide, 2.5 g/m², and mitoxantrone (Novantrone), 12 mg/m², compared with standard doses of a similar regimen (cyclophosphamide, 600 mg/m², mitoxantrone, 12 mg/m², vincristine, 1.4 mg/m²) in 33 patients. Of the 16 patients in the high-dose arm, the response rate was 100% (50% CR) vs a response rate of 50% among the 17 patients in the standard-dose arm. No ABMT was used. Follow-up data was not given.

The Dana-Farber Cancer Institute recently published an update of its experience with ABMT for metastatic breast cancer [80]. A progression-free rate of 19% was found in patients with metastatic disease at a median follow-up of 40 months. Other large centers have also reviewed their data, with similar findings [71,81].

Antman and Gale [63] evaluated 27 trials in 172 patients who received single or multiagent chemotherapy with ABMT, with or without radiation. The overall response rate was 58%. The response rate was highest in trials involving multiple alkylating agents (76%) or previously untreated patients (81%) [63]. Patients with chemotherapy-sensitive disease, good performance status, and few sites of metastatic disease appear to derive the most benefit from high-dose therapy with ABMT [82]. Dunphy et al [83] examined the factors that predict long-term survival of metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support. These factors include the absence of relapse in the liver or soft tissue, few metastatic sites, and a disease-free interval longer than 1 year from initial diagnosis to detection of stage IV disease.

Given the disappointing results of high-dose therapy with ABMT in its overall application to patients with metastatic breast cancer, attention has turned to the use of this treatment to intensify a substantial response to induction chemotherapy. This strategy has been evaluated by a number of authors [74-77](Table 2). Common features of these studies include use of this therapy as initial treatment of metastatic disease and selection of only patients with a favorable response to induction therapy and, consequently, a very high rate of CR. deVries et al [73] have extended this strategy; using myeloablative therapy in 30 patients who had metastatic disease, they achieved CR prior to high-dose therapy. The median disease-free survival was 27 months.

The results of high-dose chemotherapy with ABMT in patients with metastatic cancer have provided a number of lessons for further application of this technique.

• Success of bone marrow transplantation in the treatment of leukemia/lymphoma has been dependent on pretransplant reduction in tumor burden by remission-induction chemotherapy [3,4]. In breast cancer, the approach to this problem has been to induce maximum tumor regression, hopefully a CR, prior to intensification therapy.
• The most powerful predictor of long-term disease-free survival following bone marrow transplantation for non-Hodgkin's lymphoma has been response to chemotherapy before transplantation [4]. Breast cancer trials have mirrored this [63], and many trials are using ABMT only in patients who respond to induction chemotherapy.
• The rate of CR appears to be increased by the following: the use of three or more agents; the use of agents that are individually effective in the treatment of breast cancer; the use of agents with steep dose-response curves that are maintained through multiple logs of tumor stem-cell death. The optimal agent for a curative regimen should maintain fractional tumor kill through multiple logs, ie, a straight line on semilog plots [40]; the use of minimally cross-resistant or non-cross-resistant agents; the use of agents with experimentally or clinically demonstrated synergism; the use of agents whose tolerable doses in the setting are at least 5-fold the standard maximum safe doses; and the use of agents with nonmyelosuppressive dose-limiting toxic effects that are sufficiently different from the agents may be used in combination in the ABMT setting without significant compromise of the doses.

Adjuvant Therapy: The superior response to high-dose chemotherapy with ABMT in patients with a small tumor burden in the metastatic setting prompted the study of this technique in patients with locoregional disease who were at high risk for relapse. The prognosis for patients with stage II breast cancer with 10 or more involved axillary lymph nodes is extremely poor. The median time to relapse despite adjuvant chemotherapy is 1 year. The median survival is 3.4 years, and long-term disease-free survival occurs in only 20% of patients [34]. Buzdar et al [84] examined the outcome of patients with 10 or more positive nodes who had received doxorubicin-containing adjuvant chemotherapy; the estimated disease-free survival rate at 5 years was 41%.

Given these poor outcomes, trials have examined dose-intensive therapy with and without hematopoietic support in this patient group. Hudis et al [85] treated 60 patients with high-risk node-positive primary breast cancer (more than four ipsilateral axillary nodes) with doxorubicin for four courses followed by high-dose cyclophosphamide for three courses, without bone marrow support. All planned treatment was completed in 97% of patients. At 15-month follow-up, the actuarial relapse-free survival rate was 84% (standard error 5%). A Johns Hopkins pilot study [86] of 53 women with 10 or more positive nodes treated with CAF, methotrexate, and leucovorin rescue but no hematopoietic support had an actuarial disease-free survival rate of 61%.

Blumenschein et al [87] recently demonstrated response rates comparable to Peters's response rate with high-dose alkylating therapy and ABMT [88] using standard-dose chemotherapy and regional radiotherapy. They achieved a disease-free survival rate of 80% at 4 years. Cocconi et al [89] published a randomized trial of conventional vs intensive sequential chemotherapy as adjuvant treatment of stage II breast cancer with ten or more involved axillary nodes. Group 1 received six cycles of standard CMF; group 2 received intensive sequential chemotherapy including three cycles of cisplatin-etoposide, three cycles of CMF, and three cycles of fluorouracil, leucovorin, and doxorubicin. A total of 108 patients were entered in the study. No ABMT was used. Two-year actuarial disease-free survival rates were 53% and 58%, respectively, a difference that was not statistically significant.

In a study by de Graaf et al [90] of 24 patients with more than five involved axillary nodes, patients were treated with induction chemotherapy followed by myeloablative therapy with marrow support, regional radiotherapy for extranodal disease, and tamoxifen. The 5-year disease-free survival rate is predicted to be 84%. Two patients died of treatment-related toxicity. Peters et al [88] treated 102 women with high-risk disease involving 10 or more axillary lymph nodes. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil, followed by high-dose cyclophosphamide, cisplatin, and carmustine with autologous bone marrow support. Of 85 evaluable patients, at a median follow-up of 2.5 years the actuarial event-free survival rate was 72%. The therapy-related death rate was 12%, and pulmonary toxic effects occurred in 31% of patients. Table 3 lists the trials of high-dose adjuvant therapy with ABMT published to date. Ongoing trials include CALGB 8451, CALGB 9082, and MDACC DM 89-102.

Inflammatory Breast Cancer: Gisselbrecht et al [93] treated eight patients with inflammatory breast cancer using a regimen of cyclophosphamide and total-body irradiation with ABMT following induction chemotherapy. All patients responded, and none had a relapse at the time of the report, although all follow-up was shorter than 1 year.

Israel et al [94] treated 25 consecutive cases of inflammatory breast cancer with high-dose cyclophosphamide and fluorouracil given in 5-day courses every 3 weeks for 2 years. The median disease-free survival was 46 months, and expected median survival was longer than 6 years.

Extra et al [95] randomized patients with inflammatory breast cancer to receive intensive chemotherapy with or without ABMT. A total of 67 patients were treated with high-dose cyclophosphamide (122 mg/m²) and epirubicin (75 mg/m²) for six cycles. This regimen was followed by mastectomy, local irradiation, and CMF/FAC/FMV(methotrexate, vinblastine, fluorouracil) in 54 patients or ABMT intensification in 13 patients. The chemotherapy used for dose intensification was not stated. At the time of mastectomy, pathologic response of the tumor was complete in 7 patients (10%) and major in 25 (37%). The actuarial 4-year progression-free survival rate was 54%; the outcome seemed to be influenced mainly by pathologic response and not by the use of ABMT. High-dose therapy combined with surgery and local irradiation to the chest wall is also used for treatment of locally advanced unresectable disease, including stage IIIB and inflammatory breast cancer.

Ayash et al [96] treated 16 patients, rendering them all disease-free, with induction therapy with doxorubicin, local therapy, followed by high-dose cyclophosphamide, thiotepa, and carboplatin (Paraplatin) with ABMT.

Other Important Issues: The mortality rate with conventional-dose chemotherapy is 2% to 4%, whereas with high-dose chemotherapy the rate ranges from 3% to 24% [47]. Concerns have been raised about treating patients who are responding well to standard chemotherapy with potentially deadly myeloablative intensification regimens and about treating high-risk patients who are free of disease with therapy that has such high potential morbidity and mortality.

Breast Cancer Micrometastases: The presence of breast cancer stem cells in the autograft and the role, if any, of transplanted cancer cells in the relapse rate are areas of investigation. The role of either overt or occult bone marrow involvement in ABMT is unknown. More than 40% of patients with metastatic breast cancer and 55% of patients with bony metastases (documented by positive bone scan or plain radiographs) have morphologically involved bone marrow [97]. Patients also may have morphologically undetected bone marrow involvement.

Redding et al [98] demonstrated that 31 (28%) of 110 patients with “negative” bone marrow had positive findings by immunocytochemical techniques. However, the viability of these positive cells has been called into question, prompting evaluation of more specific monoclonal techniques [99]. Cote et al [100] followed 49 stage I and II patients, 18 of whom had bone marrow micrometastases identified by monoclonal antibody staining techniques. At a median follow-up of 30 months, 12 patients had had recurrences. A 2-year projection indicated that the presence of bone marrow micrometastases was positively correlated with the risk of relapse. The fact that at least some of these micrometastases are viable has also been shown by Mann et al [101], who, using long-term marrow cultures, detected metastatic breast carcinoma in the morphologically normal marrow of a patient awaiting autotransplantation. The effect of such contamination on patient survival and the rate of relapse remains controversial.

Purging has been studied as a method of potentially reducing bone marrow contamination by breast cancer micrometastases. Monoclonal breast cancer cell antibodies conjugated to toxins [102], soybean agglutinin-bound magnetic beads that bind selectively to breast cancer cells [103], and 4-hydroxy-peroxycyclophosphamide (4-HC)[104] are some of the modalities that have been studied. Shpall et al [105] recently demonstrated that patients who have morphologically detectable tumor in bone marrow have a shorter survival than patients without morphologically detectable tumor in bone marrow, and that purging before ABMT prolongs the disease-free interval.

Peripheral Stem Cells: Rapid reengraftment has been demonstrated with peripheral stem cells, and they are now frequently used as the sole hematopoietic support following myeloablative therapy. There are data [106] showing identical engraftment patterns to unselected stem-cells with CD34-positive peripheral stem-cells derived by positive selection. This selection was thought to decrease contaminating tumor cells by approximately 3 logs. The clinical significance of this 3-log reduction in contaminating tumor cells is unknown.

The Role of Cytokines: In randomized trials, the hematopoietic growth factors granulocyte-colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]) have been found to decrease the time to reengraftment [107-109] and, in the case of the former, to decrease the duration of neutropenia and associated morbidity [110]. The availability of hematopoietic growth factors allows the use of high-dose cyclophosphamide, thus maximizing its dose-response relationship [24] while reducing the time to reengraftment [111]. G-CSF has also been shown to accelerate the time to reengraftment after a high-dose chemotherapy regimen that utilized marrow purged with 4-HC [112].

Conclusions

The role of high-dose chemotherapy in breast cancer remains under active investigation. Clearly, its role will not be as broad as was initially hoped. Rather, high-dose chemotherapy may be most appropriate for certain subgroups of patients whose characteristics are still being defined. Current reviews explore the topic further [113-115].

Estrogen Replacement Therapy in Breast Cancer

The use of estrogen replacement therapy (ERT) in postmenopausal women has increased dramatically over the past 10 years. Estrogen replacement in postmenopausal women has been demonstrated to maintain bone mineral density [116], to reduce the rate of hip fracture by 30% to 60% [116-118], and to decrease the incidence of coronary artery disease in postmenopausal women [119-121]. The long-term use of ERT has been shown to benefit women studied in a case-control fashion [122], leaving little doubt about the beneficial effect of estrogens on postmenopausal morbidities.

At the same time, the incidence of breast cancer has increased, with an estimated 182,000 cases expected to be diagnosed in 1995 [123], making it one of the most common malignancies. The proven benefit of adjuvant therapy to disease-free and overall survivals in women with resectable disease has sharply increased the proportion of patients with breast cancer who are exposed to chemotherapy and its associated morbidities [28]. Prominent among these is amenorrhea due to primary ovarian failure [124].

The incidence of postchemotherapy amenorrhea is age and drug dependent. Among those who experience amenorrhea, ovarian failure is permanent in 57% of women age 40 years or younger and in 96% of women older than age 40 [125]. The cyclophosphamide/methotrexate/fluorouracil regimen produces amenorrhea in 53% of women younger than age 35 years, in 84% of patients 35 to 44 years, and in 94% of women age 45 or older [126]. There is an inverse relation between age and the duration of treatment required to produce ovarian suppression with CMF [127]. With doxorubicin-containing regimens, which are used at M.D. Anderson Cancer Center, amenorrhea occurs in 80% of premenopausal women. In a review of the M.D. Anderson experience, the incidence of amenorrhea was 0% in patients younger than 30 years, 33% in patients 30 to 39 years, 96% in women 40 to 49 years, and 100% in patients older than 50 years. This was reversible in 50% of women younger than 40 but was permanent in the majority of patients older than 40 [128].

Atrophic vaginitis, dyspareunia, hot flashes, and sleep disturbance are the most immediate effects of estrogen deficiency. However, the long-term effects of premature coronary artery disease, osteoporosis, and increased rate of hip fracture have greater potential morbidity.

Several nonhormonal treatment alternatives are available for menopausal symptoms (Table 4). However, they are ineffective in the majority of patients, and many have unpleasant side effects. They also lack the long-term benefits of ERT.

Vassilopoulou-Sellin and Zolinski [129] evaluated the attitudes of breast cancer survivors toward ERT and found that most (78%) had concerns about the risk of cancer recurrence; however, almost half (44%) were willing to consider ERT under medical supervision.

The issue of ERT has thus become one of immense importance, with a profound ability to influence the quality of life of breast cancer survivors.

The standard of care is to discourage the use of ERT in survivors of breast cancer . The American College of Obstetricians and Gynecologists, while supporting the use of ERT in postmenopausal women, considers breast cancer a contraindication [130]. Evaluation of the role of ERT for survivors of breast cancer has focused on indirect data on the action of estrogens in breast carcinogenesis and the effect of ERT on the outcome of patients who develop breast cancer while receiving ERT.

Effects of Estrogens on Breast Cancer

Estrogens have two effects with respect to breast cancer. First, estrogen is probably a promoter in the two-step model of breast carcinogenesis. Estradiol is the most powerful promoter of breast carcinogenesis in animal models. Nonestradiol estrogens are either weak promoters or function as antipromoters and protect against carcinogenesis [131]. Second, estrogen functions as a growth factor for the tumor. Estradiol is the most potent growth factor of the estrogens. Any estrogen that binds to the estrogen receptor in ER-positive tumors and inhibits estradiol will inhibit tumor growth [132].

In vitro studies show that low-dose estrogen stimulates and high-dose estrogen inhibits breast cancer cell growth [133]. Estrogen has been successfully used to treat metastatic breast cancer, demonstrating a therapeutic antitumor effect [134,135]. The doses of estrogens used for breast cancer treatment are pharmacologic and not physiologic, and this may account for the inhibitory effect seen in the clinical setting [136]. Stoll [135] treated 105 patients with postmenopausal breast cancer with an oral contraceptive containing estrogen (17-alpha-ethinylestradiol [0.15 mg]) and a progestin (17-alpha-ethinylestrenol [5 mg]) and found that a significant proportion of patients with measurable soft-tissue disease had partial responses [135].

The association between the use of ERT and the development of primary breast cancer is controversial. Several studies have found a slight but statistically significant increased risk of breast cancer associated with the use of oral estrogens [137-140]. Bergkvist et al [141] studied the issue in postmenopausal women, focusing on 653 women who responded to a questionnaire and extrapolating these data to draw conclusions about 23,244 women who had received estrogens from 1977 to 1980. The relative risk of breast cancer reached 1.7 after 9 years of ERT. The increased risk was associated only with the use of estradiol; no increase was found with the use of conjugated estrogens. Study weaknesses included the study design (case-cohort) and reliance on the responses of 653 women to draw inferences about a much larger group.

In contrast, Hunt et al [142] found a reduction in the overall incidence of breast cancer in their long-term surveillance of 4,544 ERT users, who had a relative risk of breast cancer of .55 compared with national rates. These studies suggest that ERT using conjugated estrogens does not promote carcinogenesis in postmenopausal women with no prior history of breast cancer. Similarly, Dupont et al, [143] in a recent meta-analysis, concluded that the use of low-dose (0.625 mg/d) conjugated estrogens for several years does not appreciably increase the risk of breast cancer, and Henrich concurred [144].

If estrogens stimulate breast cancer growth, postmenopausal women diagnosed with breast cancer should have a better prognosis than women who are diagnosed prior to menopause. In fact, however, the prognosis of postmenopausal women is worse when compared with that of premenopausal women [145].

If the tumor-promoter effect of estrogen that is demonstrable in the laboratory has clinical significance, women who develop breast cancer while receiving ERT would be expected to have a poor prognosis. However, the opposite is the case, and several studies have demonstrated a significantly better prognosis for women using hormonal therapy who develop breast cancer than their counterparts who were not receiving ERT [146,147].

Gambrell [146] evaluated the effect of ERT on breast cancer survival in 256 postmenopausal women. In this prospective trial, the mortality rate was 46% among patients not using the hormone and 22% among regular hormone users (P < .002). More of the hormone users had negative lymph nodes (57%) than did nonusers (42%); the death rate within the node-negative group was 8% for hormone users and 22% for nonusers.

In addition, Henderson et al [147] observed a 19% reduction in the breast cancer mortality rate among 4,988 ERT users compared with 3,865 nonusers who subsequently developed breast cancer. Furthermore, in a study of patients with breast cancer who had received ERT, Bergkvist et al [148] found a reduction in mortality of 40% but only in patients 50 years or older. The effect was most pronounced in women who were still receiving or had recently discontinued (within 1 year) ERT. The relative survival rate was higher by about 10% in patients who had received ERT than in patients who had never received ERT. These survival curves are shown in Figure 3.

Nevertheless, there remains a concern that select subgroups of the population will be adversely affected by the use of ERT. Some studies have suggested that long-term ERT (10 years or longer) does increase the risk of breast cancer [149].

Mammographic Changes Associated With ERT

Yearly mammograms are recommended for screening in all women who have a history of breast cancer and in women older than 50 years. A concern is that ERT may produce changes in breast density that would decrease the sensitivity of mammography. In a matched cohort study of 405 women who underwent screening mammography, Bland et al [150] demonstrated no increase in breast density among ERT users. However, patients treated with ERT had an increased frequency of a more glandular parenchymal pattern, which may increase the interpretation error rate. In a retrospective study of 50 postmenopausal women receiving ERT, Stomper et al found that 25% of the women developed increased parenchymal density [151]. They suggested that this might decrease the sensitivity of mammography for early detection of breast cancer.

Berkowitz et al compared the mammograms of individual women obtained with and without ERT [152]. Increased parenchymal density on mammograms obtained during ERT was shown in only 17% of these women.

The Role of Tamoxifen

Tamoxifen (Nolvadex) is a weak estrogen that is widely used in the treatment of metastatic disease and in the adjuvant setting. An overview of breast cancer treatments has suggested that tamoxifen might benefit all women with invasive tumors [153]. Tamoxifen reduces the incidence of cancer in the contralateral breast of women with a history of breast cancer [153]. Among eight prospective, randomized trials of tamoxifen vs no adjuvant therapy, the reduction in relative risk of contralateral breast cancer was 35% for women receiving tamoxifen [154]. Because of its estrogenic properties, tamoxifen also maintains bone mass and reduces death from heart attack by nearly 20% in postmenopausal women [155-158].

Tamoxifen's mechanism of action was initially thought to be mediated through its antiestrogenic effects on the estrogen receptor. However, its effectiveness in premenopausal women with high levels of estrogen, which should competitively inhibit the effect of tamoxifen, has raised questions about this mechanism.

Tamoxifen has also been shown to inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens [159]. This suggests a non-estrogen-dependent effect of tamoxifen on the proliferation of breast cancer. Further research has demonstrated several other effects of tamoxifen on breast cancer cells, including increasing the secretion of inhibitory growth factors and decreasing the secretion of stimulatory growth factors [160]. Other suggested mechanisms of action have been outlined. These include inhibition of protein kinase c [161], binding to calmodulin, a protein that plays a role in DNA synthesis [162], and stimulation of natural killer cell activity [163]. Dose-dependent effects on the clonogenicity of breast tumor cells have been demonstrated [164].

A concern over the concurrent administration of estrogen and tamoxifen is that estrogen might antagonize the effect of tamoxifen on tumor cells. However, the response of premenopausal women to tamoxifen, despite their high levels of circulating estradiol [165-168], suggests that this is not the case. In the National Surgical Adjuvant Breast and Bowel Project B-14 [169], women with node-negative estrogen receptor-positive breast cancer were randomly assigned to receive either tamoxifen or placebo for 5 years after surgery. Premenopausal women derived a greater disease-free survival benefit from tamoxifen than did postmenopausal women. This indicates that the effect of endogenous estrogens was not deleterious to the anticancer effect of tamoxifen. Furthermore, in the British Breast Cancer Prevention Trial [170], which uses tamoxifen as the preventive agent, postmenopausal women who experience severe hot flashes are given ERT, apparently with no ill effects. It has also been suggested that the benefits to heart and bone may be accentuated by combined tamoxifen and ERT [154].

ERT and Breast Cancer Relapse

The most important question to be answered with the use of ERT in women who have been previously treated for breast cancer is, will ERT increase the rate of relapse? No controlled randomized trials have been published to date, but several small series have been reported. Stoll [171] reported on postmenopausal women who received 0.625 mg of conjugated equine estrogens and 0.15 mg of norgestrel per day. Patients were followed for 2 years, and no relapses occurred.

Wile et al [172] conducted a case-control study of 25 breast cancer survivors who received various types of ERT. The average interval between the diagnosis of malignancy and the start of ERT was 2 years; ERT was initiated in 17 patients less than 2 years after the primary diagnosis. Each patient was matched with two non-ERT users for age, stage of disease, and duration of observation. There were one cancer-related death in the treatment group and two in the control group. At further follow-up (mean, 35 months), three women receiving ERT had had relapses, and no non-ERT users had had a relapse [132]. The three relapses all occurred in the group in which ERT was initiated less than 2 years after the initial diagnosis of malignancy. In the overall group, two patients with positive lymph nodes were disease-free at 35 and 50 months.

Eden et al [173] conducted a case-control study of 901 survivors of breast cancer, 90 of whom received combined continuous estrogen and moderate-dose progesterone for relief of menopausal symptoms. Patients were matched for age at disease-free interval prior to the start of ERT. Significantly fewer tumor recurrences were seen in the ERT group. DiSaia et al [174] reported on their experience with 77 survivors of breast cancer who received ERT and were followed for up to 15 years (median follow-up, 59 months). The majority of patients (43 of 70) had stage I disease. Ninety-two percent had no evidence of recurrent disease at the time of the report.

Future Studies

Vassilopoulou-Sellin and Theriault [175] have instituted a prospective randomized study of ERT in postmenopausal survivors of breast cancer. The aims of the study include the development of specific benefit vs risk criteria that can be used in a clinical setting. Patients are eligible if they have survived stage I or II ER-negative breast cancer with no evidence of disease for at least 2 years or if they had unknown receptor status and no evidence of disease for at least 10 years. Patients with ER-positive disease and patients with carcinoma in situ are excluded, as are patients taking tamoxifen. Daily conjugated estrogens are being administered at a dose of 0.625 mg/d on days 1 through 25. Progesterone is not administered. Parameters of benefit and risk will be measured to detect a 10% change in disease-free survival for up to 5 years. The most recent published data on the trial are shown in Table 5.

Conclusions

While the beneficial effects of ERT in postmenopausal women are definite and substantial, it must be remembered that both ERT [176-178] and tamoxifen [179] increase the risk of endometrial cancer, the former by four to eight times compared with that of the general population. This risk remains elevated even after the use of estrogens has been discontinued [178].

Several reviews have summarized the current controversy on the assessment of the risk-benefit ratio of ERT in survivors of breast cancer [154,180,181]. Opinions range from advocating the use of ERT in all patients with breast cancer who desire it to avoiding estrogens altogether in survivors of breast cancer and using nonhormonal therapies, progestogens, and tamoxifen to treat the symptoms of menopause [182]. This divergence of opinion highlights the need for scientific study in this area.

Male Breast Cancer

About 1% of all breast cancer cases occur in men. Age-standardized rates of breast cancer in men are 1.5 to 3.0 per million. It is estimated that 1,400 men will develop the disease in the United States in 1995 and that approximately 300 men will die of the disease this year [123]. About 1.35% to 1.5% of all cancers in men are breast cancer [183].

Epidemiology and Etiology

The highest rates of male breast cancer are reported in Brazil and the lowest in Japan and Costa Rica [183]. The male to female ratio is higher among blacks than among whites in the United States [184] and Africa [185]. A higher incidence of male breast cancer is found in Jewish men compared with non-Jewish men, both in Israel [186,187] and in the United States [186].

Exposures to electromagnetic fields [188], heat [189,190], and sex steroids [183,191] have been suggested to increase the risk of breast cancer in men. In a case-control study by Rosenbaum et al [189], 71 men with breast cancer were compared with 256 healthy male controls. The authors found an elevated risk associated with heat exposure but not with electromagnetic fields. Demers et al [188] found an elevated risk (relative risk, 1.8; 95% confidence intervals 1.0 to 3.7) associated with exposure to electromagnetic fields in a case-control study of 227 men with breast cancer. Well-described associations with male breast cancer include prior breast or testicular pathology and liver disease [186,191,192]. However, Thomas et al [193] found no association between liver disease and male breast cancer in their study. A family history of breast cancer [183,190], particularly in males [183,192], and a family history of prostate cancer [194] have also been shown to confer an increased risk of male breast cancer. The breast cancer risk of men with Klinefelter's syndrome is also increased [192,195] and is estimated to be 20 times that of the general male population [183], thus approaching an incidence of 3% [195]. Interestingly, a family history of male breast cancer appears to confer an increased risk on female relatives similar to that of female breast cancer [196]. However, familial male breast cancer has been recently demonstrated not to be linked to the BRCA1 locus on chromosome 17q [197]. BRCA2 appears to be associated with male breast cancer, and was localised to chromosome 13q [198]. Figure 4 summarizes the etiologic factors associated with male breast cancer.

Pathology

The majority of breast cancers in men are epithelial. About 80% to 90% are carcinomas, most often infiltrating ductal histology [199]. Ductal carcinoma in situ comprises 3% to 7% of cases [200]. Mucinous, medullary, tubular, and inflammatory breast carcinomas have all been seen in men [199]. Paget's disease [201], cystosarcoma phyllodes [202,203], and small cell carcinoma of the breast [204] have also all been described in men. Heller et al [205] reviewed the pathologic findings in a series of male breast cancers and compared them with female breast cancers. The distribution of histologic subtypes and the pattern of distant metastases were the same in men and women. Hultborn et al [206] had similar findings. It was once thought that lobular carcinoma could not occur in the male breast because of the absence of the terminal lobular unit; however, 16 cases of lobular carcinoma in men have now been described in the literature and have been recently reviewed [207].

Ninety-two cases of ductal carcinoma in situ in men have been described in the literature and have been recently reviewed [200]. All patients presented with a mass or nipple discharge. Of the 33 patients in whom axillary lymph-node dissection was performed, none had positive nodes. It has been suggested that axillary dissection should not be performed in this subset of men unless the primary tumor is 2.5 cm or larger [208]. A similar recommendation has been made for women [209].

Clinical Features

The most common presenting feature in men with breast cancer is a painless lump in the subareolar region or upper outer quadrant, occurring in 60% to 90% of cases [194,210-218]. Nipple discharge (bloody or nonbloody) is the second most frequent presenting feature. Mastalgia, nipple pruritus and eczematoid changes (as seen in Paget's disease), and symptoms from distant metastases are sometimes presenting symptoms. Several series have described a delay of several months in presentation to a physician.

Median age at diagnosis is 68 years [183], though older series have quoted a younger median age [210]. Breast cancer associated with Klinefelter's syndrome is seen in a younger age group [183]. Cases have been described in a 5-year-old boy and a 92-year-old man [183].

A slight preponderance of left-sided tumors, similar to that observed in women, has been noted [183]. Bilateral tumors are present in 1% to 1.5% of male patients [210,215,217]. In a series of 444 men with breast cancer, 54% were node-positive. Several retrospective analyses of the clinical features and outcomes of series of patients have been published [194,210-224].

Diagnosis

The differential diagnosis for a man with a breast lump includes gynecomastia [210], mastitis [215], and fibroadenoma [203]. In contrast to the unilateral, painless, indurated lump commonly seen with breast cancer, gynecomastia is often bilateral, freely mobile, subareolar, and moderately tender. Mammography can be useful in differentiating gynecomastia from male breast cancer [225]. The incidence of preceding gynecomastia in men with breast cancer is influenced by recall bias but has been quoted as 1% to 12% [183]. The radiographic features of malignancy and other breast diseases in men have been reviewed [225-227]. Jackson and Gilmor [227] reviewed sonograms and mammograms obtained over a 3-year period for 41 men who had breast enlargement. The appearances of benign and malignant disease overlapped with both modalities, and the authors recommended that both be used in the evaluation of breast pathology in males. On the other hand, Dershaw [228] reviewed 94 mammograms done for the evaluation of male breast disease and found that gynecomastia was easily differentiated from malignancy in all but one case. However, there were only three carcinomas in his series. Borgen et al [215] found an 8% false-negative rate in the 50 patients in their series who had a mammogram; 58% had a mass, and 35% had other mammographic findings.

Men with dominant masses or inflammatory changes in the breast, or both, should undergo aspiration or surgical biopsy [229]. Fine-needle aspiration is the appropriate initial step to obtain a pathologic diagnosis [230-231]. If this is inconclusive, it is mandatory to proceed to a surgical biopsy.

Staging

Breast tumors in men are staged using the standard T (tumor size), N (nodal status), M (distant metastases) system. Male patients with breast cancer have a high incidence of T4 tumors, 69% in the series by Lartigau et al [213]. There is also high incidence of regional nodal metastases, 54% in the series of Cutuli et al [194]; in the same series, 40 of 444 patients presented with distant metastases. Heller et al [205] noted fewer men with T2N0 disease and more with T1N1 disease than in a similar group of women. T1N1 disease has a poorer prognosis than T2N0 disease, and this may contribute to the relatively poorer prognosis in men with stage II disease compared to women with a similar stage of disease.

Prognosis

Hormonal Status: Men with breast cancer have a high frequency of hormone receptor positivity: 75% to 85% [215,231-234]. Estrogen receptor (ER) positivity ranges from 80% to 83% and is slightly more frequent than progesterone receptor positivity which ranges from 70% to 76% [210,215,232]. It is not clear whether progesterone receptor positivity increases response to hormonal therapy [235]. A 76% incidence of epidermal growth factor positivity has also been described [236]. The clinical significance of this is unknown.

The high incidence of hormone receptor positivity led to the use of hormonal therapy in male patients with metastatic breast cancer, with a response rate of 80% in receptor-positive patients [232].

Prognostic Factors: Axillary nodal involvement at the time of diagnosis remains the strongest predictor of prognosis [197,216,237,238]. In a recent series by Lartigau et al [213], the 10-year survival rate was 55% for node-negative men vs 22% for node-positive men. Digenis et al [232] studied a series of 41 men with breast cancer and observed the following 5- and 10-year survival rates after all treatments: stage I, 100% and 100%; II, 65% and 52%; III, 55% and 22%; and IV, 0% and 0%. These data are similar to historical survival data for women with breast cancer [237] and conflict with earlier studies that suggested a poorer prognosis in men [238,239]. Table 6 shows the 5 and 10 year survival rates with a breakdown by nodal status, of all series with more than 100 patients [194,214,215,218,219,222-224]. Tumor size [213,240], pathologic stage [214], hormonal status [241], duration of symptoms [215], and tumor grade [214,242] are also important prognostic factors. Well-differentiated tubular carcinoma has a less favorable prognosis than do mucinous, cystic, papillary, or medullary types [242]. A recent report demonstrated a prognostic significance of the degree of proliferative activity in the tumor but no prognostic value of receptor status [243].

The prognostic importance of other features such as flow cytometry, S phase, thymidine labeling index, and ploidy remain under active investigation [244].

Treatment of Local-Regional Disease

Control of local disease is the first principle of breast cancer therapy, regardless of gender. Modified radical mastectomy or simple mastectomy with irradiation are the treatments of choice in men. There is no survival advantage from radical mastectomy [232]. Radical mastectomy is done only if the tumor involves the pectoral muscles. Men whose general condition precludes major surgery can be treated with lumpectomy or tumor excision followed by irradiation of the chest wall and regional nodes [211]. Adjuvant radiotherapy decreases local recurrence but does not change survival [199].

Adjuvant Chemotherapy: Adjuvant chemotherapy in men with breast cancer was first investigated using combination regimens. Bagley et al [245] treated 24 stage II node-positive men with cyclophosphamide, methotrexate, and fluorouracil (CMF) within 4 weeks of mastectomy. Median follow-up was 46 months. Median overall survival was 98 months, and the projected 5-year survival rate exceeded 80%.

Ben-Baruch et al [246] presented a cohort of 31 men treated with 12 cycles of CMF following local therapy. Cancer survival was significantly improved in the treated group compared with historical controls taken from the Surveillance, Epidemiology, and End Results data. Historical controls had stage II node-positive male breast cancer and were individually matched to the treatment group within 5 years of age and 5 years of diagnosis. Patel et al [247] treated 11 node-positive men with stage II or III disease with fluorouracil, doxorubicin, and cyclophosphamide (FAC). With a median follow-up of 52 months, four patients had recurrent disease. The 5-year survival rate was greater than 85%. This compares very favorably with the 30% 5-year survival rate demonstrated in a retrospective series of male patients treated with local therapy only [240].

Adjuvant Hormonal Therapy: The success of hormonal therapy in treating metastatic disease [248] plus data suggesting an increase in disease-free survival when tamoxifen was used as an adjuvant agent in women [249] prompted Ribeiro and Swindell [250] to study the use of adjuvant tamoxifen for male breast cancer. Thirty-nine stage II (all axillary node-positive) or operable stage III patients treated with adjuvant tamoxifen had a 5-year survival rate of 61%, compared with 44% for historical controls. The disease-free survival rates for tamoxifen-treated and control patients were 56% and 28%, respectively.

Treatment of Metastatic Disease

Men who present with distant metastases from breast cancer have a median survival of 26.5 months [232]. The high incidence of receptor positivity resulted in early interest in hormonal manipulation for metastatic breast cancer in men.

Hormonal Manipulation: An overall response rate of 55% to 80% has been seen in men with metastatic breast disease who were treated with hormonal ablation [229]. Response to orchiectomy, the earliest form of hormonal ablation, is not age related. However, orchiectomy is poorly tolerated psychologically [251]. Adrenalectomy and hypophysectomy are virtually never used because of irreversible side effects and the availability of less morbid alternatives [240].

A number of publications have described the clinical response of male breast cancer to total androgen blockade [252-256]. Doberauer et al [256] observed a partial response in one of five men treated with the luteinizing hormone-releasing hormone analog buserelin; this 12-month remission was reinduced at relapse for an additional 24 months by the addition of the antiandrogen flutamide. Lopez et al [253] treated 11 men with recurrent or progressive cancer of the breast with buserelin and cyproterone acetate. Objective responses were observed in seven patients and lasted 9 to 24 months; three additional patients had stable disease for 5 months. Cyproterone acetate used as a single agent has been compared with a combination of buserelin and cyproterone acetate. Though there was a trend favoring the combination, no statistically significant difference was demonstrated [255]. Clinical worsening of disease during the first week of treatment with cyproterone acetate and luteinizing hormone releasing hormone analogs was not seen. Side effects of androgen blockade include decrease or loss of libido, impotence, and hot flashes [252,253,256].

While it is clear that these regimens utilizing total androgen blockade are effective, they have not been compared with standard hormonal therapy to determine which therapy has the greater efficacy.

The overall response rate with tamoxifen is between 32% and 75% and rises to between 44% and 81% if the tumors are ER positive [241,257]. The high rate of hormone receptor positivity in men has resulted in a large body of literature on the use of tamoxifen [241,257-60]. It is the drug of choice in hormone receptor-positive men with recurrent or metastatic breast cancer. However, the rate of discontinuing tamoxifen because of side effects is much higher in men (20%) than in women (4.1%). Prominent side effects in men include a decrease in libido (29%), hot flashes (20%), and weight gain (25%)[261]. Responses to tamoxifen have been seen after both response and failure-to-respond to orchiectomy, suggesting that tamoxifen and orchiectomy may be non-cross-resistant [262].

Other hormonal agents that have been used include progestins such as megestrol acetate [263], medroxyprogesterone acetate [264], aminoglutethimide [241], and estrogens [265]. Pannuti et al [264] reported a partial response in five of six patients, with a median response duration of 7 months, with high-dose medroxyprogesterone acetate. Patients with ER-positive tumors that fail to respond to initial endocrine manipulation may still respond to other forms of hormonal therapy [229].

Hormone-induced tumor flares have been seen in men started on new hormonal therapy as treatment for metastatic disease [266]. It has been suggested that these flares may be a sign of hormonal dependency. Therapy should not be abandoned; rather, the patient should be treated for pain until the episode has resolved.

Kinne and Hakes [251] recently summarized the literature on hormone manipulation in male breast cancer. They found an overall response rate of 51%, reaching 71% if the tumor is ER positive.

Chemotherapy: Chemotherapy can improve the prognosis of men with advanced breast cancer [251]. Overall chemotherapy response rates are around 35% to 45% [267,268]. Yap et al [268] reviewed the M.D. Anderson chemotherapy experience for metastatic disease in 1980. Of 18 men, 11 demonstrated a response (complete or partial) to chemotherapy. Median survival for this group was 23 months, compared with 14.5 months for men who failed to demonstrate any chemotherapeutic response (P < .05). They found a similar response rate of male breast cancer to chemotherapy as seen in female breast cancer. Lopez et al [267] also found a response rate comparable to that seen in female breast cancer. They also found that doxorubicin-containing regimens seemed superior to regimens without doxorubicin, such as CMF. Single-agent chemotherapy (vinblastine or triethylenethiophosphoramide) has proved to be less effective than combination therapy [267]. Responses to chemotherapy tend to be faster but less durable than those with hormonal manipulation [224,267]. For these reasons, chemotherapy is often reserved for men who have clearly failed to respond to hormonal manipulation. Responses to both chemotherapy and hormonal manipulation have been observed in all organs, including lung, liver, and bone.

Breast Cancer and Pregnancy

The simultaneous occurrence of breast cancer and pregnancy is rare. The reported incidence of pregnancy is 1 in 3,000 to 5,000 breast cancer cases [269], though some authors quote a rate as high as 1% to 3% of all breast cancers [270-273]. The incidence in Japan is quoted as 0.76% [274]. Pregnant patients represent 10% to 15% of breast cancer patients younger than 40 years [275]. There is evidence that the incidence of breast cancer in premenopausal women is rising, and as more women delay childbearing, the simultaneous presentation of breast cancer and pregnancy may increase. The incidence of breast cancer during pregnancy is no higher than the incidence in any premenopausal woman [277].

Diagnosis

Women with pregnancy-associated breast cancer have clearly been shown to present at a later stage than do nonpregnant women. Zemlickis et al [273] demonstrated a relative risk of 2.5 (confidence interval, 1.1 to 5.3) of presenting with stage IV disease and a decreased chance of diagnosis during stage I , for pregnant patients compared with age-matched nonpregnant controls. A number of series have demonstrated a diagnostic delay in pregnant women with a breast abnormality ranging from 2 to 15 months longer than in nonpregnant women [271,276,277]. The reasons for this include physiologic hypertrophy of the breast and engorgement, which may mask a lump, and the fact that most gestational abnormalities of the breast are benign [276]. Lumps are often followed clinically for many months in pregnant women. Coincident pathology, such as mastitis, has been reported in up to 30% of breast cancers diagnosed during pregnancy [278]. Other issues apart from delayed diagnosis may play a role in the more advanced stage at presentation. For example, the effect of the high levels of circulating prolactin found during pregnancy on the growth of breast cancer is unknown [279]. The impact of the altered immunocompetence and decreased activity of mitogens found during pregnancy is also unknown [280,281].

Mammography is rarely performed in pregnant women because of the perceived risk of harm to the fetus [276,282]. In addition, it has been stated that increased breast density during pregnancy makes mammography interpretation difficult [276]. However, in a retrospective review of 23 women diagnosed with breast cancer during or within 1 year following pregnancy, who had a mammogram performed prior to biopsy, mammographic evidence of breast cancer was present in 18 (78%) of 23 cases [282]. Breast sonography has less risk, and in the six patients examined by Liberman et al [282] with this technique, all had a solid mass detected. Similarly, the accuracy of sonography was 93% (39 of 42) in a series by Ishada et al [274]. Sonography appears to be safe and sensitive in the evaluation of a breast abnormality.

Pathology

There is no difference in tumor type between pregnant and nonpregnant women [274], and the incidence of inflammatory carcinoma in pregnant women is 1.5% to 4%, identical to that of nonpregnant women [283]. However, the number of pregnant patients with vascular and lymphatic invasion is higher [274], as are the mean tumor size and number of lymph-node metastases. The presence of estrogen receptors (ERs) and progesterone receptors (PRs) has shown a trend toward a lower incidence in pregnant patients, perhaps because of patient age [271,283,284]. The exception has been a single case-control study [274] which suggested an independent trend toward higher levels of ER-positivity in pregnant patients. ER-negative tumors, regardless of pregnancy status, have a biologically aggressive course and carry a poor prognosis [285], and it is thought that this may contribute to a worse outcome in pregnant patients. Assay of ER status during pregnancy may result in excessive false-negatives because of high levels of circulating estrogens saturating all available ER sites [276]. Though the diagnosis of malignancy may be made by fine-needle aspiration, a surgical biopsy is required to document the presence or absence of tumor invasion [286].

Staging

The most accurate means of assessing the pregnant patient are a detailed history and physical examination with particular attention to tumor size, nodal involvement, and assessment for metastatic disease including the musculoskeletal and central nervous systems. Mammography and extensive nuclear scanning should be done only if the information is vital to treatment planning [286]. Any such procedure should be done with appropriate precautions to protect the fetus. A chest radiograph can be safely obtained with proper shielding [286]. Aggressive hydration to aid in excretion of the isotope should precede all bone scans [276]. Laboratory studies should include a complete blood count, biochemical profile, and analysis for tumor markers.

Prognosis

It has been shown that outcome in patients with concurrent breast cancer and pregnancy is the same as for their nonpregnant counterparts when adjustment is made for age and stage of disease [287,288]. Pregnant patients do present with more advanced disease. Various studies show that 56% to 89% of patients who present with breast cancer during pregnancy are lymph-node positive [289]. Most series report identical actuarial and disease-free survival rates in gestational and nongestational breast cancer once patients are matched for age and stage [273,283,287,289,290]. Von Schoultz et al [290] recently published a study on 173 women who were diagnosed with pregnancy in the 5 years preceding or following the diagnosis of breast cancer. These women were compared with 1,740 women with breast cancer who were not pregnant during that period. Though women with a pregnancy before diagnosis of breast cancer had slightly larger tumors than did the control group, they did not differ with respect to nodal status or ER status. Their prognosis was the same when compared with that of the control group. However, some studies suggest that pregnant patients do have a worse prognosis [291,292]. Guinee et al [292] recently completed a large multicenter review of 407 women aged 20 to 29 years. For women whose breast cancers were diagnosed during pregnancy, the risk of dying from breast cancer was significantly greater than that of women with breast cancer who had never been pregnant (relative risk, 3.26; 95% confidence interval, 1.81 to 5.87; P = .0004). The risk remained significant (P = .023) when adjustment was made for the number of axillary nodes and tumor size. Age at the time of pregnancy is an inconsistent prognostic factor. Clark and Reid found that survival was worse in those older than age 40 [283], while Ribeiro et al found no association with age [287].

Treatment

There is no justification for delaying in treatment in pregnant women with breast cancer. Termination of the pregnancy is not routinely indicated [270,287,293].

Local treatment remains a modified radical mastectomy. Maternal morbidity from surgery and general anesthesia is low [294]. Fetal risk is low unless complications (shock, hypotension) occur [294]. Milk production should be suppressed by bromocriptine to reduce the size and vascularity of the breasts preoperatively and to lessen the risk of infection and milk fistulae [276].

Chemotherapy and Hormonal Therapy: Chemotherapy has the highest likelihood of affecting the baby during embryogenesis [295]. Nevertheless, adjuvant chemotherapy in appropriate patients should not be withheld because of fear of potential fetal morbidity. Doll et al reviewed the reported adverse effects of in utero chemotherapy exposure and found a rate of fetal malformation of 19% in the first trimester [296]. Chemotherapy should therefore be delayed until the first trimester is past. The risk of fetal malformation secondary to chemotherapy administered during the second and third trimesters has been estimated at 2% [296]. Alkylating agents, aminopterin and methotrexate have all shown evidence of associated fetal malformations (Table 7). Turchi and Villaris [297] reported on 28 pregnancies following treatment with anthracyclines; 24 normal infants were born, 4 infants were reported to have reversible defects.

The effect of cytotoxic therapy on the maintenance of the integrity of the placental barrier is largely unstudied. It has been suggested that the anthracyclines and other agents may be prevented from entering the fetal circulation by the high levels of MDR1 protein localized in the placental membrane [298].

Ovarian ablation, by surgery or radiation, has no place in the treatment of pregnant women [283]. Postpartum breast feeding should be avoided because cyclophosphamide is secreted in breast milk.

Radiation Exposure: The effects of radiation on the fetus depend on the gestational age at the time of exposure [276]. It is estimated that a 12-week shielded fetus will receive a dose secondary to internal scatter radiation of up to 30 cGy with a standard 5,000 cGy course of radiotherapy [299]. Radiation should be avoided if at all possible during the first trimester, as the period of organogenesis is the most sensitive to radiation. In the second and third trimesters, the risk is primarily that of microcephaly and of childhood cancer developing in later years. Lower nonmorbid doses from scatter radiation have been quoted in other studies [300].

Subsequent Pregnancy

Posttreatment fertility in breast cancer patients has been looked at in several studies. Richards et al's study [301] of cyclophosphamide, methotrexate, and fluorouracil showed a 37% incidence of premature menopause in women 40 years or younger. Doxorubicin-containing regimens at M.D. Anderson produce amenorrhea in 96% of women 40 to 49 years old, but no woman younger than 30 years has developed amenorrhea. Half of women younger than 40 who become amenorrheic resume menstruating following cessation of chemotherapy [128].

Following treatment of breast cancer, there is a concern about the safety of subsequent pregnancy. The fear is that sustained increases in the levels of estrogen and progesterone during pregnancy will stimulate the growth of occult metastatic disease. In the past, patients were advised to avoid pregnancy for at least 2 years after breast cancer treatment so that the endocrine stimulus would not activate occult systemic disease. However, Mignot et al [302] have reported that survival rates were no different in women who conceived within 6 months after breast cancer treatments were completed compared with a control group.

Peters and Meakin [303] have demonstrated that stage for stage, patients who become pregnant after breast cancer do better than their nonpregnant counterparts. The selection bias that patients who are able to become pregnant after chemotherapy were probably the group with a superior performance status and less disease is evident. Despite this, it is clear that these women do not do any worse than their nonpregnant counterparts, suggesting no role of pregnancy in disease recurrence. In Sutton et al's series [304], there were 33 pregnancies in 25 (11%) of 227 breast cancer patients younger than 35. Of these pregnancies, 10 were terminated, 2 ended with spontaneous abortion, and 19 had resulted in live births, with no fetal malformations. Two patients were still pregnant at the time of the report. Donegan found a comparable rate of 7% [305].

Conclusions

In conclusion, breast cancer associated with pregnancy poses several treatment challenges. Local therapy should never be delayed. Careful management and avoidance of chemotherapy and radiation exposure during the first trimester should help to produce a positive outcome for both mother and fetus.

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