N3: Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary lymph node involvement, or in clinically apparent* ipsilateral internal mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; or, metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
N3a: Metastasis in ipsilateral infraclavicular lymph node(s) N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c: Metastasis in ipsilateral supraclavicular lymph node(s)
Distant metastasis (M)
MX: Presence of distant metastasis cannot be assessed
Strictly speaking, it is not known to be a premalignant lesion, but rather a marker that identifies women at an increased risk for subsequent development of invasive breast cancer. This risk remains elevated even beyond 2 decades, and most of the subsequent cancers are ductal rather than lobular.
LCIS is usually multicentric and is frequently bilateral.
After the presence of a malignancy is confirmed and histology is determined, treatment options should be discussed with the patient before a therapeutic procedure is selected.
The surgeon may proceed with a definitive procedure
Estrogen-receptor (ER) and progesterone-receptor (PR) status should be determined for the primary tumor.Additional pathologic characteristics, including grade, proliferative activity, and human epidermal growth factor receptor 2 (HER2/neu) status, may also be of value.
Options for surgical management of the primary tumor include:
breast-conserving surgery plus radiation therapy,
mastectomy plus reconstruction, and
Selection of a local therapeutic approach depends on:
the location of the lesion
size of the lesion
analysis of the mammogram
breast size, and
the patient’s attitude toward preserving the breast.
relative contraindications to breast-conserving therapy
The presence of multifocal disease in the breast
history of collagen vascular disease.
A patient’s age should not be a determining factor in the selection of breast-conserving treatment versus mastectomy
Whether young women with germ-line mutations or strong family histories are good candidates for breast-conserving therapy is not certain.
Axillary node dissection even in the presence of clinically negative nodes is a necessary staging procedure.
Controversy exists as to the extent of the procedure because of long-term morbidity
The standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., 6-10 at a minimum), while reducing morbidity from the procedure.
The SLN is defined as the first node in the lymphatic basin that receives primary lymphatic flow.
Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients
These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete axillary lymph node dissection
The results of a randomized trial of 532 patients with T1 carcinomas undergoing either SLN biopsy plus complete axillary dissection or SLN biopsy alone showed no axillary recurrences in either group and no difference in the 3-year disease-free survival
The reported false-negative rates (i.e., the number of patients with negative SLN biopsy divided by the number of patients with positive axillary nodes at the time of axillary node dissection) of SLN biopsy range from 0% to 10%.
A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years ( P = .044),[and from 7.3% to 4.3% at 5 years ( P < .0001), respectively
If a boost is used, it can be delivered either by external-beam radiation therapy,or by using an interstitial radioactive implant.
The benefit of tamoxifen was found to be restricted to women with ER-positive or ER-unknown breast tumors. In these women, the 15-year absolute reductions in recurrence and mortality associated with 5 years of use are 12% and 9%, respectively.
Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women.
In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the latter group (5.3% vs. 12.5% with 5 years of use)
The current recommendation is that adjuvant tamoxifen be discontinued after 5 years in all patients as current standard therapy.
Women on exemestane had significantly more visual disturbances, arthralgia, diarrhea, and osteoporosis, but women on tamoxifen had significantly more gynecologic symptoms, muscle cramps, vaginal bleeding, thromboembolic disease, and second malignancies other than breast cancer.
Slight advantage for the anthracycline regimens in both premenopausal and postmenopausal patients. Uncertainty remains, however, about whether there is an advantage to combining both regimens.
Evidence suggests that particular tumor characteristics may predict anthracycline-responsiveness. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit is restricted to those patients whose tumors overexpress HER2/neu. The routine use of HER2/neu to select those patients that should or should not receive anthracycline-containing regimens should await further confirmation
Three clinical trials addressing the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2 overexpressing cancers released the results of interim analyses.
Highly significant improvement in disease-free survival and overall survival
Risk Categories for Women With Node-Negative Breast Cancer Low risk (has all listed factors) Intermediate risk High risk (has at least 1 listed factor) Tumor size ≤ 1cm 1-2 cm >2 cm ER or PR Status positive positive negative Tumor grade Grade 1 grade 1-2 grade 2-3
Adjuvant systemic treatment for node negative premenopausal women Patient group Low risk Intermediate risk High risk ER-positive or PR-positive None or tamoxifen 1.T ± C 2.Ov Ab 3.GnRH analog
C & T
C & Ov Ab/ GnRH analog
C & T & Ov Ab/ GnRH analog
4.Ov ab ± T
ER-negative or PR-negative — — Chemotherapy
Adjuvant systemic treatment for node negative postmenopausal women Patient group Low risk Intermediate risk High risk ER-positive or PR-positive None or tamoxifen T ± C T ± C ER-negative or PR-negative — — Chemotherapy Older than 70 years None or tamoxifen T ± C T. Consider chemotherapy if ER-negative or PR-negative
Adjuvant systemic treatment for node positive premenopausal women Patient group Treatments ER or PR-positive
C & T
C & Ov Ab/ GnRH analog
C & T & Ov Ab/ GnRH analog
4. Ov ab ± T
5. GnRH ±T
ER-negative or PR-negative Chemotherapy
Adjuvant systemic treatment for node positive postmenopausal women Patient group Treatments ER or PR-positive T ± C ER-negative or PR-negative Chemotherapy Older than 70 years Tamoxifen alone; consider chemotherapy if receptor-negative
Candidates for whom adjuvant therapy may not be necessary
Individuals with small primary tumors (<1 cm) and negative axillary nodes who have an excellent prognosis, with nearly 90% of patients alive and free of disease at 20 years in one series.
Proposals have been made to treat elderly patients with tamoxifen alone and without surgery. This approach has unacceptably high local failure rates and, outside of a clinical trial setting, should be used only for patients who are not candidates for mastectomy or breast-conserving surgery plus radiation therapy, or for those who refuse these options.
Inoperable stage IIIB or IIIC or inflammatory breast cancer
Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease.
32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) can have prolonged disease-free survival at 10 years with combined modality therapy.This result suggests such patients should be treated with the same intent.
Initial surgery is generally limited to biopsy to permit the determination of histology, ER and PR levels, and HER2/neu overexpression.
Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard.
For patients who respond to neoadjuvant chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered in patients with a good partial or complete response to neoadjuvant chemotherapy. Subsequent systemic therapy may consist of further chemotherapy.
Hormone therapy should be administered to patients whose tumors are ER-positive or unknown.
Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab (Herceptin). Radiation therapy and/or surgery may be indicated for patients with limited symptomatic metastases. Fungating tumours
Bisphosphonates to reduce skeletal morbidity in patients with bone metastases
Hormone therapy as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient’s tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year.
Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective aromatase inhibitors, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens; and the ER down-regulator, fulvestrant.[
Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist).
Patients with lymphangitic pulmonary metastases, major liver involvement, and/or central nervous system involvement should not receive hormone therapy as a single modality. Patients with structural compromise of weight-bearing bones should be considered for surgical intervention and/or radiation in addition to systemic therapy. Patients with vertebral body involvement should be evaluated for impending cord compression even in the absence of neurologic symptoms. Increasing bone pain and increasing alkaline phosphatase within the first several weeks of hormone therapy does not necessarily imply disease
Patients whose tumors have progressed on hormone therapy are candidates for cytotoxic chemotherapy. Patients with hormone receptor-negative tumors and those with visceral metastases are also candidates for cytotoxic agents.
Evidence from randomized trials that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared to routine physical examinations.Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.
Based on these data, some investigators recommend that acceptable follow-up be limited to physical examination and annual mammography for asymptomatic patients who complete treatment for stage I to stage III breast cancer.