Early-Stage Breast Cancer and Adjuvant Therapy

April 1, 2005

Carcinoma of the breast is the most common cancer in women in the United States and is second only to lung cancer as a cause of cancer death in women. The incidence of breast cancer has risen steadily over the past decade, with the most dramatic increase seen in smaller primary breast tumors, partly because widespread use of screening mammography permits earlier detection [1].

Prognostic FactorsAdjuvant TherapyAdjuvant ChemotherapyCarcinoma of the Male BreastFuture PerspectivesReferences

Carcinoma of the breast is the most common cancer in women in the United States and is second only to lung cancer as a cause of cancer death in women. The incidence of breast cancer has risen steadily over the past decade, with the most dramatic increase seen in smaller primary breast tumors, partly because widespread use of screening mammography permits earlier detection [1].

Approximately 183,000 new cases of breast cancer will be diagnosed in 1995 [2]. Adjuvant therapy can significantly reduce the risk of recurrence and death in patients with breast cancer. However, many patients with early-stage breast cancer are cured by local therapy (surgery and radiotherapy) alone, and these patients should be spared the risks and costs of adjuvant therapy.

The challenge for the clinican is to determine which patients have the highest risk of recurrence and, thus, are most likely to benefit from adjuvant therapy. In this chapter, we will detail the prognostic factors that affect whether adjuvant therapy is indicated and then describe the various adjuvant treatments that are available.

Prognostic Factors

Breast carcinoma is characterized by a long natural history and by wide variation in its clinical course. The spread of primary cancer occurs by direct infiltration into the breast parenchyma, along the mammary ducts, and through the breast lymphatics. The most frequent site of regional involvement of breast cancer is the axillary lymph-node region. Patients with axillary node involvement have a worse prognosis than do patients with negative axillary nodes. In fact, prognosis progressively worsens as the number of disease-positive lymph nodes increases.

Nemoto et al [3] found a direct relationship between the number of involved nodes and the 5-year disease-free survival rate, with rates of 62% for one to three positive axillary lymph nodes, 58% for four to nine positive nodes, and 29% for 10 or more positive axillary nodes. The Consensus Development Council now recommends that patients with positive axillary nodes be divided into the four groups Nemoto and colleagues used [4].

Intensive efforts have been made over the last several years to identify patients who are at high risk for recurrence and would benefit from adjuvant therapy. Gasparini et al [5] recently reported that in patients with operable node-positive breast cancer, the expression of the bcl-2 protein in the primary tumor predicts for benefit of adjuvant treatment (chemotherapy or tamoxifen [Nolvadex]). Although patients with node-negative breast cancer have a relatively low risk of recurrence, it is well established that despite the best local treatment, up to 20% to 30% of these women will die of metastatic disease [6,7]. Because adjuvant therapy has been shown to reduce the risk of relapse and to improve overall survival in patients with breast cancer regardless of their lymph-node status [8], it is important to characterize the subset of node-negative patients who are at high risk for relapse and, thus, could benefit from adjuvant therapy.

The prognostic factors evaluated to identify node-negative patients at high risk for recurrence are summarized in Table 1. The standard prognostic factors commonly used today are tumor size, nuclear/histologic grade, estrogen-receptor (ER) and progesterone-receptor (PR) expression, and DNA flow cytometry-derived ploidy and S-phase fraction.

Tumor Size

There is a strong, direct correlation between tumor size and risk of recurrence, whether disease is node-positive or node-negative. Two studies have confirmed the prognostic importance of primary tumor size in axillary node-negative patients. The Surveillance, Epidemiology, and End Results (SEER) study correlated tumor diameter with survival in more than 13,000 patients and found that the relative overall 5-year survival rate was almost 99% in patients with tumors less than 1 cm in diameter, approximately 91% in patients with tumors of 1 to 3 cm, and 85% in patients with tumors of more than 3 cm [8]. The other important study revealed that node-negative patients with tumors less than or equal to 1 cm in diameter had a 20-year recurrence rate of 14%, while patients with tumors of 1.1 to 2.0 cm had a 20-year recurrence rate of 31% [9,10].

Nuclear/Histologic Grade

Nuclear, or histologic, grade describes the degree of tumor differentiation and is based on the pathologist's assessment of nuclear size and shape, number of mitoses, and degree of tubule formation. Tumors of low malignancy are designated grade 1 and are associated with the best prognosis; grade 3 tumors are associated with the worst prognosis. At one center, only 10% of all patients with node-negative breast cancer had well-differentiated tumors, but this small subset of patients had a 5-year disease-free survival rate of more than 90% [11]. Since studies have demonstrated significant interobserver variability in nuclear grading, the grading should be done by experienced pathologists so that results are reliable.

Hormone-Receptor Status

Estrogen- and progesterone-receptor positivity correlate with prolonged disease-free and overall survival. However, the importance of hormone-receptor status has been documented more consistently in node-positive than in node-negative disease. McGuire found a difference of only 8% to 10% in disease-free survival between women with node-negative breast cancer who were ER positive and those who were ER negative [12]. Measurement of hormone-receptor level is valuable in both node-negative and node-positive patients for identifing patients likely to benefit from adjuvant endocrine therapy.

S-Phase Fraction and DNA Ploidy

The degree of cellular proliferation in breast cancer specimens has shown a strong correlation with outcome. Flow cytometry simultaneously measures both DNA ploidy (DNA content) and S-phase fraction (the fraction of cells actively cycling or synthesizing DNA). Aneuploid tumors with a high percentage of cells in S-phase are more likely to recur than are tumors with a low S-phase fraction. Clark et al studied S-phase fraction in node-negative patients with small (less than 3 cm), ER-positive tumors. Patients with a low S-phase fraction had a higher disease-free survival rate than did those with a high S-phase fraction, whether their tumors were diploid or aneuploid [13].

Published data suggest a relationship between tumor cell kinetics and response to chemotherapy. Remvikos et al found that patients with an S-phase fraction greater than 10% had significantly higher response rates to chemotherapy than did those with an S-phase fraction less than 5% [14]. It is important to note that the cutoff points separating low from high S-phase fractions may differ between laboratories and, therefore, may affect the validity of comparisons.

Other Factors

Other potentially important prognostic factors currently being studied include cathepsin D level, HER-2/neu oncogene expression, angiogenesis markers, histologic subtype, lymphatic invasion, epidermal growth factor receptor [15], Ki-67 [16,17], pS2(18), stress response (heat shock) proteins [19], type IV collagenases [20], nm23 [21], p53 [22,23], and plasminogen activators [24].

Cathepsin D Level: Cathepsin D is a lysosomal protein that is synthesized in normal tissues but is overexpressed and secreted in breast cancers. Cathepsin D may play a role in invasion and metastasis. Although data from a group of node-negative patients with aneuploid tumors revealed a 5-year recurrence rate of 60% in patients with high levels of cathepsin D [25], other studies were unable to confirm this finding [26]. Cathepsin D was once considered to be an important predictor of recurrence and survival in node-negative patients, but further work has failed to show its prognostic value in clinical practice [27].

HER-2/neu (c-erbB-2) Expression: Overexpression of the HER-2/neu oncogene reflects an increase in the proliferative activity of a tumor. Overexpression has been demonstrated in 15% to 30% of patients with breast cancer and has been found by most investigators to be associated with shorter survival [28,29]. However in a report from the Cancer and Leukemia Group B (CALGB) [30], HER-2/neu overexpression was associated with significantly longer disease-free and overall survival in breast cancer patients who received higher doses of anthracycline-containing adjuvant chemotherapy. Although the above data suggest a role of HER-2/neu in predicting sensitivity to chemotherapy, further studies are needed before this marker can be used in making clinical decisions.

Angiogenesis Markers: Experimental evidence has shown that angiogenesis plays a key role in tumor growth, invasiveness, and progression [31]. Tumor angiogenesis as manifested by microvessel density within the invasive primary carcinoma has been shown in preliminary studies [32,33] to be a reliable prognostic marker in node-negative breast cancer patients.

Histologic Subtypes: Rosen and colleagues found that in addition to ductal carcinoma in situ, the pure tubular, papillary, and typical medullary histologic subtypes had long-term recurrence rates of less than 10% [5]. Another study found that the recurrence rate in patients with ductal carcinoma in situ and microinvasion was only 9% at 7 years [34].

Lymphatic Invasion: Lymphatic invasion, which refers to the presence of tumor emboli in breast lymphatics, is seen in approximately 25% of breast tumors. It is associated with a lower likelihood of survival [35].

Application

In summary, factors associated with a low risk of tumor recurrence include ductal carcinoma in situ, the pure tubular, papillary, and typical medullary histologic types, tumor size smaller than 1 cm, tumors of nuclear grade 1, diploidy low S-phase fraction, the presence of hormone receptors, and intermediate tumor size in the absence of other high-risk features. Factors associated with a high risk of recurrence include tumor size larger than 3 cm, high nuclear grade, aneuploidy, high S-phase fraction, and the absence of hormone receptors.

Estimating the risk of recurrence in an individual patient remains a difficult issue. For patients with tumors less than 1 cm in diameter, the chance of recurrence is less than 10% at 10 years. Therefore, it may be reasonable not to offer these patients systemic adjuvant therapy [1]. With larger tumors, other prognostic factors can be considered when deciding whether to use adjuvant therapy.

Adjuvant Therapy

Node-Negative Disease: There is increasing evidence that systemic adjuvant therapy can lead to improved disease-free and overall survival in node-negative breast cancer patients. The Early Breast Cancer Trialists' Collaborative Group is a worldwide collaboration to obtain information on mortality and recurrence for each patient entered in a randomized trial of systemic adjuvant therapy for early-stage breast cancer before 1985. Data are now available on 75,000 women in 133 randomized trials. The majority of women in these trials were node positive, but about 31% were node negative.

The percentage reduction in recurrence and mortality in node-negative patients is summarized in Table 2. A total of 12,910 node-negative patients were treated with tamoxifen, with a 26% ± 4% (SD) reduction in recurrence and a 17% ± 5% reduction in mortality. A total of 2,710 node-negative patients were treated with combination chemotherapy, with a 26% ± 7% reduction in the recurrence rate and an 18% ± 8% reduction in the mortality rate [8].

Number of patientsPercent reductionª in
RecurrenceMortality
Tamoxifen12,91026 ± 417 ± 5
2,71026 ± 718 ± 8

Node-Positive Disease: The benefit of systemic adjuvant therapy in node-positive breast cancer patients is established. The greatest benefit has been seen in patients with one to three positive nodes, with more modest benefit seen in patients with four or more involved nodes. Most trials have not included patients with 10 or more positive nodes, the majority of whom will have disease recurrence within 5 years if they are treated with local therapy alone.

At M.D. Anderson Cancer Center, 283 patients with 10 or more positive nodes were included in a prospective trial that examined adjuvant doxorubicin (Adriamycin, Rubex)-containing regimens. The 5-year disease-free survival rate in these patients was about 41% [36]. Patients with 10 or more positive nodes are currently being entered into randomized trials with high-dose chemotherapy and autologous bone-marrow rescue because of the high failure rate with conventional adjuvant therapies.

Tamoxifen Therapy: The Early Breast Cancer Trialists' Collaborative Group reviewed data on 30,000 women with breast cancer in 42 randomized tamoxifen trials. Results were broken down by age group, nodal status, and ER status. A meta-analysis of these trials is summarized in Table 3. Overall, there was a significant, 25% ± 2% reduction in the risk of recurrence with adjuvant tamoxifen at 10 years. Tamoxifen also significantly reduced mortality overall (by 17% ± 2%). There was a statistically significant reduction in the risk of recurrence in all age groups, but the improvement in the survival rate was statistically significant only in patients 50 years of age and older.

TreatmentNumber of patientsPercent reductionª in
TreatmentControl*RecurrenceMortality
4,12216 ± 311 ± 4
7,73627 ± 218 ± 3
3,19638 ± 424 ± 6
Total15,02215,05425 ± 217 ± 2

The duration of tamoxifen therapy in the majority of these trials was 1 to 2 years. Although data from direct randomized comparisons of different durations of tamoxifen therapy (usually 5 years vs 1 or 2 years) suggested that a longer duration was associated with longer survival, the differences were not significant (7% ± 11% reduction in mortality) [8].

Contralateral breast cancer was reported in 2% of controls vs 1.3% of tamoxifen-treated patients, a statistically significant difference [8]. Treatment with adjuvant chemotherapy had no effect on the development of a second breast cancer [8].

Ovarian Ablation: Ovarian ablation can be accomplished by surgery, irradiation, or hormone therapy. This mode of adjuvant therapy has been evaluated in 10 randomized trials involving 3,000 women, 1,746 of whom were younger than 50 years. A meta-analysis of these data performed by the Early Breast Cancer Trialists' Collaborative Group is summarized in Table 4. For women older than 50, ovarian ablation produced no significant effect on recurrence-free or overall survival. For women younger than 50, ovarian ablation produced a significant, 26% ± 6% improvement in recurrence-free survival and a 25% ± 7% improvement in overall survival. It appeared that ovarian ablation produced less improvement among patients given chemotherapy, but the difference was not statistically significant. The improvements in recurrence-free and overall survival were statistically significant only for node-positive patients, although the same trend was suggested in node-negative patients. All of these trials were done prior to the availability of ER and PR assays [8].

TreatmentNumber of patientsPercent reductionª in
TreatmentControl*RecurrenceMortality
Ovarian ablation alone45642230 ± 938 ± 9
Ovarian ablation + chemotherapy47846121 ± 919 ± 11
Total93488326 ± 625 ± 7

The luteinizing hormone-releasing hormone (LHRH) agonist allows for the suppression of ovarian function with minimum morbidity. Ongoing trials of the effect of an LHRH agonist and other means of ovarian ablation in patients with ER/PR-positive tumors are underway. More data are necessary to determine the effect of ovarian ablation on survival.

Other Endocrine Agents: Other endocrine agents that have been used in the adjuvant setting include progestins, antiadrenal drugs, and prednisone. Prednisone, which is thought to suppress adrenal estrogen synthesis, has been used in combination with other cytotoxic drugs in the adjuvant setting. In most randomized studies, however, it provided no additional benefit. There was some improvement in disease-free and overall survival in one trial in which prednisone was used together with ovarian ablation [37].

Aminoglutethimide (Cytadren), an aromatase inhibitor, resulted in improved disease-free but not overall survival in one adjuvant trial [38]. In a study by Tally and colleagues, progestin significantly improved disease-free and overall survival in post- and premenopausal patients with more than three positive nodes, when compared with matched historical controls [39]. These drugs have significant toxicity, and none offer any advantage over tamoxifen according to available data. Newer hormonal agents that may prove more useful are the aromatase inhibitors and the antiprogestins.

Adjuvant Chemotherapy

The early adjuvant chemotherapy trials compared one course of perioperative, single-agent chemotherapy (cyclophosphamide [Cytoxan, Neosar], melphalan [Alkeran], or thiotepa) with surgery alone and showed only minimal improvement in disease-free survival. These studies were important in establishing a role for adjuvant therapy and in leading to trials comparing single-agent and combination chemotherapy.

Combination Chemotherapy: Studies comparing single-agent and combination chemotherapy consistently show the superiority of combination regimens in terms of recurrence-free and overall survival (Table 5). In fact, single-agent chemotherapy is no longer used as an adjuvant treatment. In a review by the Early Breast Cancer Trialists' Collaborative Group of 11,041 patients randomized in 31 trials of long-term combination chemotherapy vs no chemotherapy, combination chemotherapy was clearly associated with significantly improved recurrence-free and overall survival. Indeed, with adjuvant combination chemotherapy, there were significant reductions in both risk of recurrence and mortality (28% ± 3% and 16% ± 3%, respectively) at 10 years. The improvements in recurrence-free and overall survival were greater in node-positive than in node-negative women but were statistically significant for both groups. Also, with regard to recurrence-free and overall survival, there was a trend toward greater effects among younger women [8].

TreatmentNumber of patientsPercent reductionª in
TreatmentControl*RecurrenceMortality
Cyclophosphamide + methotrexate + fluorouracil (CMF)2,0982,07832 ± 422 ± 5
CMF with additional chemotherapeutic agents1,2981,27723 ± 610 ± 7^
Other chemotherapeutic agents2,3442,35525 ± 512 ± 6
Total5,7405,71028 ± 316 ± 3

Duration of Therapy: In most of the early adjuvant chemotherapy trials, therapy was continued for 1 to 2 years. Subsequent studies were designed to evaluate the efficacy of shorter durations of chemotherapy. Studies showed that there was no improvement in disease-free or overall survival when chemotherapy was continued beyond six cycles. Limited data suggest that to achieve the maximum effect, therapy must be continued for more than 3 months. In a retrospective study from M.D. Anderson Cancer Center, patients who received less than six cycles of combination chemotherapy had decreased disease-free survival, compared with those who received six or more cycles of the same regimen [40].

Regimens With and Without Anthracycline: Anthracycline-containing regimens have been compared to non-anthracycline-containing regimens in several studies (Table 6)[41-50]. Even though some studies had a relatively small number of patients and short follow-up, data suggest that anthracycline-containing regimens may be associated with better disease-free survival. However, only 3 of the 12 studies showed a statistically significant improvement in overall survival with the addition of an anthracycline.

TrialRegimenªNumber of patientsFollow-up (mo)Disease-free survival with anthracycline (%)Disease-free survival without anthracycline (%)P
Onco, France [41]AVCF CMF3251205443.04
Institut Curie [42]mMAC mMFC12196---
ICCG [43]FEC CMF63637--.22
SECSG [44]CAF CMF52742---
Milan [45] (1-3+ nodes)CMF ×12 CMF × 8 -> A ×4433617472.73
ECOG [46]CMFPT × 12 CMFPTH/ vATHT × 12533616370.04
CALGB [47]CMFVP CMFVP-> vATH89723--.01
Milan [48] (4 modes or more)A × 4 -> CMF × 8 CMF/A × 12359725638.0007
NSABP-11 [49]pF pAF697883846.01
NSABP-12 [49]pFT pAFT1,093875658.36
NSABP-15 [49]CMF AC1,473446464.5
SWOG [50]FACM CMFVP532385252NS

Ten-year results from a randomized prospective French trial were published in 1992: Among 249 node-positive breast cancer patients given either cyclophosphamide, methotrexate, and fluorouracil (CMF) or an anthracycline-containing regimen, the addition of doxorubicin reduced the risk of relapse by one third and the risk of death by one half in premenopausal patients [51].

Non-Cross-Resistant Therapies: Tumor cell heterogeneity and the presence of subsets of cells resistant to certain drugs provide the rationale for treatment with multiple non-cross-resistant drugs. The Milan group reported updated results from a study in which pre- and postmenopausal patients with more than three positive axillary nodes were randomized to four courses of doxorubicin followed by eight courses of CMF (sequental chemotherapy) or two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating chemotherapy). Relapse-free and overall survival rates were significantly superior in the sequential chemotherapy group and appeared superior to those obtained with CMF alone [48].

The CALGB reported a higher disease-free and overall survival across all nodal subgroups in patients treated with CMF plus vincristine (Oncovin) and prednisone (CMFVP) than in those who received vinblastine, doxorubicin, thiotepa, and fluoxymesterone (VATH)[47]. An M.D. Anderson Cancer Center study showed that the addition of methotrexate and vinblastine after FACVP (fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone) significantly prolonged disease-free survival but not overall survival in ER-positive patients [52]. These preliminary data support the use of sequential, non-cross-resistant chemotherapy, although further studies are needed to confirm these observations.

Chemohormonal Combinations: The addition of tamoxifen to adjuvant chemotherapy has been evaluated in several clinical trials. Earlier reports from these trials suggested that adding tamoxifen resulted in no definite advantage. However, more recent data suggest a potential benefit, particularly in postmenopausal patients. One study randomized postmenopausal patients to receive CFP (cyclophosphamide, fluorouracil, and prednisone) alone, CFP plus tamoxifen, or no treatment. At 7 years median follow-up, both the chemotherapy-alone and chemotherapy-plus-tamoxifen groups had a significantly better disease-free survival than the control group had. There was also a trend toward on improved overall survival rate in the chemotherapy-plus-tamoxifen group [53].

The National Surgical Adjuvant Breast and Bowel Project B-16 study randomized node-positive, ER-positive patients to receive doxorubicin, cyclophosphamide, and tamoxifen; melphalan, fluorouracil, doxorubicin, and tamoxifen; or tamoxifen alone. This study found a superior 5-year disease-free survival rate in the chemotherapy-plus-tamoxifen groups [54]. An Eastern Cooperative Oncology Group (ECOG) study in postmenopausal, node-positive patients found a delayed time to recurrence among patient groups given chemotherapy plus tamoxifen, as compared with groups given chemotherapy alone [55].

Biological Therapies: Several different biological agents (bacillus Calmette Gurin [BCG], levamisole [Ergamisol], polyA-polyU, Corynebacterium parvum, Azimexon, Basidio.p.p., interferon) have been evaluated in a total of 24 randomized trials involving 6,300 women. There has been no consistent improvement in either disease-free or overall survival with the use of these agents as adjuvant therapy for early-stage breast cancer [8].

Dose-Intensive Chemotherapy: In general, retrospective studies support the concept that higher dose intensity correlates with a better response [56-58]. CALGB conducted a study in which breast cancer patients with stage II, node-positive disease were randomized to one of three FAC (fluorouracil, doxorubicin, and cyclophosphamide) dose-intensity arms, all within the standard dose range [59]. After a median follow-up of 3.4 years, there was a significant improvement in disease-free and overall survival in the high-dose arm as compared with the low-dose arm. This study suggests that doses that were 50% lower than the standard dose produced inferior outcomes. What remains to be determined is whether doses higher than the standard dose would further improve the efficacy of adjuvant therapy. Preliminary results of a randomized trial to assess the efficacy of high-dose adjuvant chemotherapy with doxorubicin and cyclophosphamide failed to support a benefit of dose increase for cyclophosphamide above the standard range [60].

Experience with high-dose chemotherapy has largely been focused on breast cancer patients with 10 or more positive axillary lymph nodes. Peters et al conducted a study of stage II or III breast cancer patients with 10 or more positive axillary nodes [61]. Patients were treated with four cycles of FAC postoperatively followed by high-dose cyclophosphamide, cisplatin, and carmustine (BiCNU) with autologous bone marrow rescue. For the 85 evaluable patients, the therapy-related mortality rate was 12% and the estimated event-free survival rate was 72% at a median follow-up of 2.5 years. This is a significant improvement in event-free survival compared with historical controls (38% to 52%). However, comparison to historical populations is subject to many potential biases (eg, differences in patient selection, extent of pre-study staging evaluation).

In a study by Lyding et al [62], 13 patients with high-risk, stage II or III breast cancer were treated with high-dose chemotherapy (cyclophosphamide, mitoxantrone [Novantrone], and thiotepa) and autologous bone-marrow or peripheral-stem-cell rescue. All 13 patients remained in complete remission at a median follow-up of 7 months.

Whether high-dose chemotherapy offers advantages to high-risk patients remains to be determined. Patients from several centers with 10 or more positive axillary nodes are currently being entered into randomized clinical trials involving high-dose chemotherapy with autologous stem-cell support vs standard adjuvant therapy.

Carcinoma of the Male Breast

Breast carcinoma in men accounts for 0.5% of all breast cancers in the United States, and it is estimated that 1,400 new cases will be diagnosed in 1995 [2]. The epidemiology, prognostic factors, survival by stage, pattern of metastasis, and response to treatment are similar in men and women with breast carcinoma. The data suggest, however, that breast cancer in men is more likely to respond to hormonal manipulation [63].

Future Perspectives

Randomized trials addressing the issues described above are presently underway. Future adjuvant studies will include new cytotoxic agents such as paclitaxel (Taxol), docetaxel (Taxotere), and vinorelbine (Navelbine), all of which have shown encouraging results in advanced breast cancer [64-66]. Novel therapeutic approaches include ongoing trials using monoclonal antibodies targeted against growth factors or oncoproteins [67].

Current knowledge of the adjuvant treatment of breast cancer has emerged from controlled randomized trials. Because there are still many controversies, it remains of paramount importance to continue pursuing clinical and basic research in this field.

References:

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