Stage I Breast Cancer
Stage I breast cancer ranges from microinvasive tumors (≤ 0.1 cm) to tumors ≤ 2 cm without evidence of spread to the regional lymph nodes or with only limited nodal involvement (N1mi).
Pathology of Invasive Breast Cancer
Ductal carcinoma
Most cases of invasive carcinomas of the breast are ductal in origin. Of the different histologic subtypes of ductal carcinoma that have been described, tubular, medullary, mucinous (colloid), and papillary subtypes have been associated with a favorable outcome.
Lobular carcinoma
Approximately 5% to 10% of invasive breast cancers are lobular in origin. This histology has been associated with synchronous and metachronous contralateral primary tumors in as many as 30% of cases.
Radiation and Surgical Treatment
Multiple studies have demonstrated that patients with stage I breast cancer who are treated with either breast-conserving therapy (lumpectomy and radiation therapy) or modified radical mastectomy have similar disease-free and overall survival rates.
Breast-conserving therapy
Extent of local surgery. The optimal extent of local surgery has yet to be determined and, in the literature, has ranged from excisional biopsy to quadrantectomy. A consensus statement on breast-conserving therapy issued by the National Cancer Institute (NCI) recommended that the breast cancer be completely excised with negative surgical margins.
The extent of axillary surgery also continues to evolve. Patients with early-stage breast cancer who have clinically node-negative disease have the option to undergo sentinel lymph node biopsy (SLNB) rather than axillary lymph node dissection (ALND).
Contraindications to breast conservationPatient selection. Specific guidelines must be followed when selecting patients for breast conservation. Patients may be considered unacceptable candidates for conservative surgery and radiation therapy either because the risk of breast recurrence following the conservative approach is significant enough to warrant mastectomy or the likelihood of an unacceptable cosmetic result is high. Some patients who are candidates for breast conservation can undergo breast MRI to identify sites of additional disease within the breast that may preclude breast-conserving treatment, although this is not a standard for evaluation. No study has documented an improved local recurrence or IBTR rate with MRI presurgical screening. Contraindications to breast-conserving surgery are listed in Table 1.
• Risk factors for ipsilateral recurrence—For patients undergoing conservative surgery followed by radiation therapy to the intact breast, the risk of IBTR has been reported to range from 0.5% to 2% per year, with long-term failure rates varying from 7% to 20%. Risk factors for IBTR include, but are not limited to, young age (< 35 to 40 years), an extensive intraductal component, major lymphocytic stromal reaction, peritumoral invasion, presence of tumor necrosis, and positive resection margins. After a wide excision has been performed, the specimen should be oriented and inked; the pathologist may then ink each margin a different color. If a positive surgical margin is present, the color-coded system will guide the reexcision to obtain negative surgical margins with the removal of the least amount of breast tissue possible.
Earlier studies demonstrated that an extensive intraductal component was a risk factor for local relapse. In subsequent reports, however, when negative surgical margins were achieved, patients with an extensive intraductal component could be safely treated with breast conservation. Although it is desirable to achieve negative surgical margins, the available data do not preclude the use of conservative treatment, provided that adequate radiation doses (> 6,000 cGy) to the tumor bed are employed. The role of the remaining previously cited risk factors in predicting recurrence is unclear, and patients should not be denied breast conservation because of their presence.
• Cosmetic considerations—Cosmetic considerations include primary tumor size and location, overall breast size, total body weight, and a history of preexisting collagen(Drug information on collagen) vascular disease.
Tumor size and breast size are important in determining whether the patient will have an acceptable cosmetic outcome after surgical resection. Patients with large tumors with respect to breast size may consider neoadjuvant chemotherapy to reduce the size of the primary tumor and allow breast preservation. (See "Stage III and IV Breast Cancer" chapter for a discussion of neoadjuvant chemotherapy.)
Obese women with large, pendulous breasts may experience marked fibrosis and retraction of the irradiated breast, making a good to excellent cosmetic outcome less likely. Techniques of brachytherapy may prove beneficial for these women. Such women may undergo bilateral reduction mammoplasty after the wide excision of the primary tumor site. The partial mastectomy specimen should be evaluated by the pathologist to ensure adequate resection margins. Radiopaque clips can be left to mark and identify the primary tumor site for the radiation oncologist. Unfortunately, the follow-up mammograms will be more difficult to interpret, owing to scarring and effects of radiotherapy.
Patients with collagen vascular disease may develop more severe reactions following radiation therapy. Although initial anecdotal reports demonstrated higher complication rates in patients with collagen vascular disease, a case-controlled study of patients with early-stage breast cancer showed higher complication rates only in patients with scleroderma. Other case-controlled studies have also failed to demonstrate significantly higher complication rates in patients with collagen vascular disease undergoing radiation therapy. It appears that most patients without active significant collagen vascular diseases may be candidates for breast-conserving surgery and irradiation, although this approach remains controversial.
In some instances, it is necessary to excise skin to obtain a negative surgical margin. This does not necessarily preclude the patient from undergoing breast-conserving therapy and does not mean the patient should have a poor cosmetic outcome. When skin must be removed to obtain a negative surgical margin, complex skin closures, such as V-Y advancement flaps or Z-plasties, can be utilized to enhance cosmesis.
• Patients with centrally located tumors—Traditionally, patients who have centrally located tumors requiring excision of the nipple-areolar complex have not been offered the option of breast conservation. However, the cosmetic result achieved after local tumor excision that includes the nipple-areolar complex may not differ significantly from that obtained following mastectomy and reconstruction.
Furthermore, conservatively treated patients with subareolar lesions do not necessarily need to have the nipple-areolar complex sacrificed, as long as negative surgical margins can be achieved. If the complex is not removed, however, the remaining breast tissue and overlying skin may or may not remain sensate. Recent studies also indicate that the incidence of local recurrence is not increased when primary tumors in this location are treated conservatively.
Genetically predisposed breast cancer patients. For women harboring germline mutations in BRCA1 or BRCA2, there are limited data regarding long-term outcome. To date, studies have shown acceptable local control rates in the short term and increased but acceptable rates of acute, subacute, and chronic normal tissue reactions with lumpectomy followed by radiation therapy. Women with germline BRCA1 and BRCA2 mutations, however, are at high risk for second primary tumors in the contralateral breast.
A study from Yale University (by Smith et al, published in 2000 in the International Journal of Radiation Oncology, Biology, and Physics) demonstrated high rates of second primary tumors in the ipsilateral breast. This study suggested that if breast-conserving therapy is chosen, some prophylactic measures, such as selective estrogen receptor modulators or oophorectomy, might be considered to reduce the risk of second primary tumors in the ipsilateral or contralateral breast. Other studies also indicated a trend toward higher rates of late local relapses in BRCA carriers. Further studies are clearly warranted to assess the long-term risks and benefits of breast-conserving strategies in women harboring mutations in BRCA1 and BRCA2.
Role of axillary lymph node dissection. The role of routine ALND in breast cancer is primarily for the management of clinically node-positive disease and is discussed in subsequent chapters. For a patient with a clinically negative axilla, SLNB has replaced ALND. Patients whose SLNB is negative may not require a complete node dissection, as the risk of an axillary recurrence is extremely low.
ALMANAC is a multicenter randomized trial (UK National Cancer Research Network Trial ID 843) of 1,031 patients assigned to SLNB (n = 515) or standard ALND (n = 516). Mansel reported the primary outcome measures, which were arm and shoulder morbidity and quality of life. Drain usage, length of hospital stay, resumption of normal activities after surgery were all highly significantly better in the SLNB group. In addition, patient-recorded quality of life and arm functioning scores were also significantly better, with no increase in anxiety levels in the sentinel node group. The authors conclude that SNLB is the treatment of choice for patients who have early-stage breast cancer and clinically negative nodes.
Many institutions are using immunohistochemistry (IHC) to evaluate the sentinel node. When there is no evidence of metastatic disease by routine hematoxylin and eosin staining and the node is IHC−, the node is considered pN0 (i−). When isolated tumor cells are seen but no cluster is greater than 0.2 mm, the node is staged as pN0 (i+). If the focus of metastatic disease in the node is > 0.2 mm but < 2 mm, the node is staged as pN1mi. Traditionally, women with metastatic disease identified in the sentinel node will have undergone a completion ALND. This practice may be unnecessary for certain groups of women with early-stage breast cancer, however. Giuliano et al reported on approximately 900 patients with invasive T1-T2 breast cancer with a clinically negative axillary exam who were treated with breast-conserving surgery, adjuvant tangential WBI, and SLNB. All of the patients in the study had negative surgical margins and positive SLNBs. Patients were excluded if they had three or more sentinel nodes, matted nodes, gross extranodal disease, or neoadjuvant hormonal therapy or chemotherapy. Patients were randomized to undergo completion ALND (n = 445) or no further surgery (n = 446). The patients received appropriate systemic therapy, either chemotherapy, hormone therapy, or both. At a median follow-up of 6.3 years, the 5-year disease-free survival (82.2% vs 83.9%) and overall survival (91.8% vs 92.5%) were similar in the ALND and SLND alone groups. This study suggests that patients who are treated with breast-conserving surgery, WBI, and systemic therapy may not require a completion ALND when there is minimal metastatic disease identified in the sentinel node(s). This does not apply to patients undergoing mastectomy or for patients who have had breast-conserving surgery but will be receiving partial breast radiation.
Patients who may not be candidates for SLNB are women who are pregnant or breast-feeding or who have had prior irradiation. A prior excisional biopsy does not preclude the use of lymphatic mapping and SLNB. It has been suggested that SLNB accurately evaluates the axilla, even in patients with tumors > 5 cm and in those who have been treated with neoadjuvant chemotherapy.
Once the sentinel node(s) have been identified, they can be sent to pathology for frozen section or touch-prep analysis.
• Sensitivity and specificity—In breast cancer, lymphatic mapping has been performed using a vital blue dye and/or lymphoscintigraphy. The success rate for identifying the sentinel node may be increased when these techniques are used in combination. The ability to identify the sentinel node can reach as high as 97% when blue dye and technetium-99m sulfur(Drug information on sulfur) colloid are used together. When blue dye is used alone, the success rate is 83%, and when technetium-99m sulfur colloid is used alone, the success rate is 94%.
Results from a multi-institution practice have demonstrated that SLNB using dual-agent injection provides maximal sensitivity. In the study, reported by McMasters et al in 2000 in the Journal of Clinical Oncology, 806 patients were enrolled by 99 surgeons for SLNB by single-agent (blue dye alone or radioactive colloid alone) or dual-agent injection at the discretion of the surgeons. All patients underwent complete level I/II dissection following the sentinel procedure. There were no significant differences in the identification of a sentinel node among patients who underwent single-agent vs dual-agent injection. However, the false-negative rate was 11.8% for single-agent injections vs 5.8% for dual-agent injections (P = .05).
The sensitivity and specificity of SLNB are high, and the likelihood of a false-negative result is extremely low. False-negative rates vary among series, ranging from 0% to 11%. In one series, in 18% of the cases for which the frozen-section evaluation of the node was negative, the final pathologic evaluation revealed metastatic disease, and the patient ultimately required lymph node dissection. This potential result can be distressing to patients; however, they should be informed of this possibility at the time of the procedure.
Patients whose SLNB is normal do not require a complete node dissection, because the risk of an axillary recurrence is extremely low.
Radiation therapy after breast-conserving surgery
Based on the results of a number of retrospective single-institution experiences, as well as several prospective randomized clinical trials, breast-conserving surgery followed by radiation therapy to the intact breast is now considered a standard treatment for the majority of patients with stage I or II invasive breast cancer. A meta-analysis demonstrated a substantially reduced local relapse rate and a small but statistically significant decrease in breast cancer mortality with use of radiation following breast-conserving surgery.
The Danish Breast Cancer Cooperative Group reported on a 20 year follow-up of the DBCG-82TM trial: A series of 793 patients with invasive breast cancer treated with lumpectomy and radiation therapy were stratified based on receptor status: patients in the luminal A group were estrogen receptor-positive or progesterone(Drug information on progesterone) receptor-positive and HER2-negative; those in the luminal B group were estrogen receptor-negative, progesterone receptor-negative, and HER2-positive; those in the HER2 group were estrogen receptor-negative and progesterone receptor-negative and HER2-positive; and the basal group was estrogen receptor-negative, progesterone receptor-negative, and HER2-negative. Over a median follow-up of 70 months, the 5-year rate of IBTR was 1.8% for the luminal A group, 1.5% for the luminal B group, 8.4% for HER2 group, and 7.5% for basal subtypes. Voduc et al investigated the rate of local and regional relapse in 2,985 patients stratified by molecular subtype. With a median follow-up of 12 years, they found that after breast-conserving surgery plus RT, patients with luminal A tumors had the most favorable prognosis, with local relapse and regional relapse rates of only 8% and 3% at 10 years, respectively. HER2-enriched and basal-like groups exhibited the highest rates of local relapse (21% and 14%, respectively) and regional relapse (16% and 14%, respectively). Recently, Kiess et al reported on a series of 197 women with early-stage breast cancer with HER2-positive disease. In this cohort, 70 women received RT alone while 102 received RT plus trastuzumab(Drug information on trastuzumab) (given in standard fashion, ie, 1 year of treatment) . They found that the 3-year locoregional recurrence free survival rate was 90% with RT alone compared with 99% in those treated with RT plus trastuzumab. Finally, Abdulkarim et al reported a higher rate of local relapse among T1/T2 node-negative mastectomy patients treated without radiation who had triple-negative disease, compared with a similar node-negative cohort treated with breast-conserving surgery and radiation; this emphasizes the point that triple-negative breast cancers do not necessarily fare better with mastectomy. These results may be useful in counseling patients about their outcomes after breast-conserving therapy.
Radiation dose and protocol. Radiation therapy after breast-conserving surgery should employ careful treatment-planning techniques that minimize treatment of the underlying heart and lungs. To achieve the optimal cosmetic result, efforts should be made to obtain a homogeneous dose distribution throughout the breast. Doses of 180 to 200 cGy/d to the intact breast, to a total dose of 4,500 to 5,000 cGy, are considered standard.
Additional irradiation to the tumor bed is often administered. Although the necessity of a boost to the tumor bed has been questioned, at least two randomized clinical trials have demonstrated a small but statistically significant reduction in ipsilateral breast tumor relapses with the use of a radiation boost to the tumor bed following whole-breast irradiation of 50 Gy. In one of these trials, involving more than 5,000 women randomized to receive either a 16-Gy boost to the tumor bed or not, a 4% absolute reduction in local relapse was seen with the use of the radiation boost (6.2% vs 10.2% at 10 years). This effect was particularly evident in patients younger than age 50. The boost is directed at the original tumor bed with either electron-beam irradiation or an interstitial implant, to bring the total dose to 50 to 66 Gy.
Regional nodal irradiation. For patients who undergo axillary dissection and are found to have negative nodes, regional nodal irradiation is no longer routinely employed. For patients with positive nodes, radiation therapy to the supraclavicular fossa and/or internal mammary chain may be considered on an individualized basis (see "Stage II Breast Cancer" chapter).
Accelerated whole breast irradiation (AWBI). In contrast to conventional assumptions, the fractionation sensitivity for breast tumors may be much lower than expected; this allows for increasing the daily dose of radiation and shortening the overall treatment time. Based on this information, the Royal Marsden Hospital and the Gloucestershire Oncology Centre collaborated in a randomized clinical trial to evaluate the relative toxicity and efficacy of different whole-breast fractionation schemes. A total of 1,410 women were randomized to one of three arms: 50 Gy in 25 fractions over 5 weeks; 39 Gy in 13 fractions (3 Gy/fx) over 5 weeks; 42.9 Gy in 13 fractions (3.3 Gy/fx) over 5 weeks. The primary and secondary endpoints were late breast changes and local control. The 39 Gy arm was less likely to develop late radiation change compared to both 42.9 Gy and 50 Gy, but also had worse local control than the 42.9 Gy arm. Interestingly, the 42.9 Gy arm was not significantly different from the 50 Gy arm for both development of any late radiation change and local control. The Canadian NCI randomized 1,234 patients (1993–1996) with T1 and T2 tumors with negative margins and pathologically negative nodes (on level 1 and 2 dissection) to 50 Gy in 25 fractions (2 Gy/fx) over a period of 35 days or 42.5 Gy in 16 fractions (2.66 Gy/fx) over 22 days. With a median follow-up of 69 months, local recurrence-free survival was equal (97.2% vs 96.8%), and there was no difference in overall and disease-free survival. Cosmesis was identical with excellent or good scores at 3 and 5 years in 77% of patients in both groups. Toxicities were also comparable. A major limitation of the Canadian study is the lack of a standardized lumpectomy boost, which has been shown to significantly improve local control. The patients eligible for the study had low risk for disease recurrence, limiting the general scope of the results. Whelan et al updated the 15-year Canadian experience with hypofractioned WBI. The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation vs 6.2% among the 622 women assigned to the hypofractioned regimen. They concluded that 10 years after treatment, accelerated hypofractionated WBI was not inferior to standard radiation treatment.
The American Society for Radiation Oncology (ASTRO) convened a task force to formulate evidence-based guidelines on WBI fractionation. The task force conducted a systematic review of the literature, supplemented by the expertise and clinical experience of the task force members, to provide the rationale for the recommendations listed below. Trials that met inclusion criteria for the review were six randomized clinical trials comparing AWBI vs WBI, two randomized clinical trials comparing AWBI vs APBI, two randomized clinical trials comparing AWBI vs no irradiation, one randomized trial of AWBI alone with or without a boost to the tumor bed, and 34 nonrandomized clinical studies. After reviewing these studies, the task force reported that there was evidence to support the equivalence of AWBI and WBI for patients who satisfy all of the following criteria:
• Age 50 years or older
• Pathologic stage T1-2 N0 treated with breast-conserving surgery
• Not treated with systemic chemotherapy
• Within the breast along the central axis, minimum dose no less than 93% and maximum dose no greater than 107% of the prescription dose (± 7%) (as calculated with 2-dimensional treatment planning without heterogeneity corrections)
• Patients should also be otherwise suitable for breast-conserving therapy in regard to standard selection rules (ie, not pregnant, no history of certain collagen-vascular diseases, no evidence of multicentric disease, no prior radiotherapy to the breast).
For patients who do not satisfy all of these criteria, the task force could not reach consensus and chose not to render a recommendation either for or against AWBI in this setting. They did note, however, that their guideline should not prohibit or oppose the use of AWBI for patients not meeting all the criteria listed above. No consensus could be given, owing to the relative lack of evidence.
Accelerated partial breast irradiation. Several reports have demonstrated promising results of partial breast irradiation, a potentially more convenient option for patients than the extended course of postoperative radiotherapy. Additional options are now available to shorten the radiotherapy treatment time to 1 to 5 days (accelerated irradiation) and to focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast irradiation). Current accelerated partial breast irradiation (APBI) approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (three-dimensional conformal) radiotherapy. Intraoperative radiotherapy time is even shorter, with the entire treatment given as a single dose delivered immediately after surgery. Each approach has benefits and limitations. Ongoing randomized trials will shape how APBI is utilized in routine clinical practice. Some of the more important outcomes from these trials will be local toxicity, local and regional recurrence, and overall survival. If APBI is ultimately demonstrated to be as safe and effective as WBI, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.
ASTRO convened a task force to formulate clinically useful evidence-based guidelines on APBI. A systematic review of the literature, which, supplemented by the expertise and clinical experience of the task force members, provided the rationale for their recommendations. After conducting a literature review, the panel identified four published randomized clinical trials and 38 prospective single-arm studies involving APBI. The task force reported that there was evidence to support use of APBI outside the realm of a clinical trial for patients who satisfy all of the following criteria: age ≥ 60 years; ≤ 2 cm of invasive ductal carcinoma, pN0; ≥ 2 mm margins; unicentric disease, without lymphovascular invasion; and estrogen receptor positivity. They also formed recommendations for a "cautionary" patient group and an "unsuitable" group for treatment with APBI outside of a clinical trial.
Mastectomy options. Data accruing in the literature suggest that nipple-sparing mastectomy is oncologically safe and can be utilized in select cases of skin-sparing mastectomy. This surgical procedure can be considered in patients who will be undergoing mastectomy and immediate reconstruction. During the course of the surgery, the retroareolar tissue is removed and sent for frozen-section analysis. If the tissue sent for frozen section is negative, the nipple-areolar complex (NAC) can be spared. If the final pathology is positive, the NAC can be removed at a subsequent surgery. Factors associated with tumor extension to the NAC are subareolar tumor location, multicentricity, tumor size, and nodal positivity. The rate of complications may be higher with this technique, owing to partial loss of the NAC caused by impaired blood supply.
Medical Treatment
Medical management of local disease depends on clinical and pathologic staging. Systemic therapy is indicated only for invasive (infiltrating) breast cancers.
In the past, systemic therapy was not offered to patients with stage I disease (tumors up to 2 cm). However, adjuvant chemotherapy and hormonal therapy have been shown to improve disease-free and overall survival in selected patients with node-negative disease.
The sequence of systemic therapy and radiation therapy for patients treated with breast-conserving therapy has been the subject of considerable debate. Although concurrent CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) and radiation therapy have been used with acceptable toxicity, the concurrent use of chemoradiation therapy has fallen out of favor due to reports of enhanced toxicities. Delaying chemotherapy for 6 to 8 weeks of radiation therapy does not appear to negatively impact systemic disease or survival. Recent studies do not demonstrate a compromise in local control if radiation is delayed until chemotherapy is complete. It is important that the patient receive radiation therapy in a timely manner, however. For instance, irradiation should not be delayed for 3 to 4 months while Oncotype DX test results are awaited. Currently, the majority of patients receiving chemotherapy and radiation therapy are treated with chemotherapy prior to radiation therapy.
For patients receiving tamoxifen(Drug information on tamoxifen) or other hormonal agents, there had been considerable controversy regarding whether the hormonal agents should be administered during or after radiation therapy. Theoretically, tamoxifen may place cells in a resting state, making them less radiosensitive. Three retrospective studies, conducted independently but published together, reached a similar conclusion about the timing of therapy, namely that it had no impact on local relapse rates. Additionally, no significant difference was found in time to any event, metastasis, or death whether subsequent therapy was radiotherapy first or chemotherapy first among patients with breast conservation.
Adjuvant chemotherapy regimens for node-negative breast cancerTreatment regimens
Multiagent therapy with CMF, CMFP (CMF and prednisone(Drug information on prednisone)), MFL (sequential methotrexate and 5-FU), AC (Adriamycin [doxorubicin] and cyclophosphamide(Drug information on cyclophosphamide)), and taxanes (paclitaxel, docetaxel(Drug information on docetaxel) [Taxotere]) has been used in patients with node-negative disease (Table 2). Hormonal therapy with tamoxifen (20 mg PO every day for 5 years) has been shown to be of value in both pre- and postmenopausal women with hormone receptor-positive breast cancer. (See "Stage II Breast Cancer" chapter for further discussion about tamoxifen and the ATAC (Arimidex and Tamoxifen Alone or in Combination) trial, as well as for adjuvant chemotherapy regimens for node-positive breast cancer.)
Node-negative tumors < 1 cm. Patients who have the lowest risk of recurrence are least likely to benefit from systemic treatment when the risks of treatment are considered. None of the reported trials in node-negative breast cancer included women with tumors < 1 cm, and, because of the low risk of recurrence (≤ 10%) in this group, systemic adjuvant therapy is not used routinely. Recent results from the NSABP in this group of patients are provocative in suggesting a potential benefit from systemic therapy.
In the Oncotype DX validation study, the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen receptor-positive breast cancer was tested using a RT-PCR assay of 21 prospectively selected genes (16 cancer-related genes and 5 reference genes) in paraffin(Drug information on paraffin)-embedded tumor tissue. The levels of expression of the 21 genes were used in a prospectively defined algorithm to calculate a recurrence score and determine a risk group for each patient.
The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51%, 22%, and 27%, respectively. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-, intermediate-, and high-risk groups were 6.8%, 14.3%, and 30.5%, respectively. The rate in the low-risk group was significantly lower than that in the high-risk group (P < .001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P < .001). The recurrence score was also predictive of overall survival (P < .001) and could be used as a continuous function to predict distant recurrence in individual patients.
The Oncotype DX test has changed the treatment of breast cancer. It has shown that patients with low recurrence scores do not derive benefit from chemotherapy in addition to hormonal therapy, and therefore chemotherapy is omitted from their systemic therapy. Likewise, it showed patients with high risk-recurrence scores derive the most benefit from chemotherapy in addition to hormonal therapy, and therefore these patients are treated with chemotherapy followed by endocrine therapy. At this time, it is unclear whether patients with intermediate risk-recurrence scores benefit from chemotherapy in addition to endocrine therapy, but the recently completed TailoRx/PACTT-1 study is anticipated to provide an answer to this question.
Node-negative tumors ≥ 1 cm. The selection of a specific treatment program and the characteristics that predict risk of recurrence and death in women with node-negative breast cancer require further delineation and clarification in clinical trials. At present, women with tumors ≥ 1 cm who have poor histologic or nuclear differentiation, negative estrogen receptors, a high-risk Oncotype DX recurrence score, a high S-phase percentage, or a high Ki-67 level can be considered appropriate candidates for adjuvant systemic therapy.
An update of the NSABP B-20 trial indicated a significant advantage in the estrogen receptor-positive, node-negative population when chemotherapy with CMF or sequential MF is added to tamoxifen in the adjuvant setting. Patients receiving CMF plus tamoxifen appeared to derive the greatest benefit. Benefits with respect to both disease-free and overall survival have been reported for patients given chemotherapy and tamoxifen.
Chemotherapy and ovarian function suppression are both effective adjuvant therapies for patients with early-stage breast cancer. The efficacy of their sequential combination was investigated by the International Breast Cancer Study Group (IBCSG) trial VIII. This study randomized more than 1,000 pre- and perimenopausal women with lymph node-negative breast cancer to receive either goserelin(Drug information on goserelin) (Zoladex) for 24 months (n = 346), 6 courses of "classic" CMF chemotherapy (n = 360), or 6 courses of classic CMF followed by 18 months of goserelin (CMF then goserelin; n = 357). The primary outcome was disease-free survival.
In this study, patients with estrogen receptor-negative tumors achieved better 5-year disease-free survival rates if they received CMF (84% and 88% for CMF and CMF then goserelin, respectively) than if they received goserelin alone (73%). For patients with estrogen receptor-positive disease, however, chemotherapy alone and goserelin alone provided similar outcomes (5-year disease-free survival rates of 81% for both treatment groups), whereas sequential therapy provided a statistically nonsignificant improvement compared with either modality alone.
