Whole-genome analysis informs breast cancer response to aromatase inhibition.

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Selective lymphoscintigraphy: a necessary adjunct to dye-directed sentinel node biopsy for breast cancer?

BACKGROUND: Dye-directed sentinel node biopsy (SNB) for breast cancer provides accurate staging with low morbidity, but for tumors distant from the axilla, its use has been questioned. HYPOTHESIS: Can preoperative breast lymphoscintigraphy (BL) applied selectively to medial hemisphere tumors predict a subset of patients who may not require surgical staging of the axilla? DESIGN: Prospective cohort study. SETTING: Tertiary, multidisciplinary breast center. PATIENTS: Thirty-two women with breast tumors located in the medial hemisphere (30) or inframammary crease (2). INTERVENTION: Peritumoral injection of 500 microCi of technetium Tc 99m sulfur colloid and biplanar imaging. Nonpalpable lesions were localized with ultrasound or mammography. At the time of definitive breast surgery, isosulfan blue dye-directed SNB was performed. Axillary dissection was performed when the SN contained a tumor or could not be identified. MAIN OUTCOME MEASURES: Regional nodal basins identified by BL; success rate of SNB. RESULTS: Preoperative BL demonstrated axillary drainage in 28 patients (88%); 2 patients (6%) had isolated internal mammary radionuclide uptake, and 2 patients had no nodal uptake. Dye-directed axillary SNB succeeded in 27 (87%) of 31 patients, including both patients with failed BL. Breast lymphoscintigraphy had predicted isolated internal mammary drainage in 2 of 4 patients whose SNs could not be identified. Metastases were found in 5 patients (16%). CONCLUSIONS: Axillary radionuclide uptake predicts but does not augment dye-directed SN identification. In those few patients with isolated internal mammary drainage, BL may obviate the need for surgical staging of the axilla.

Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences?

BACKGROUND: Although more than 90% of the morbidity and mortality from localized cutaneous melanoma occurs in the first decade after initial surgical treatment, melanoma can recur after a 10-year disease-free interval (DFI) with fatal consequences. We reviewed our melanoma data base of more than 8,500 prospectively acquired patients to identify clinicopathological factors that affect the type, rate of occurrence, and outcome of disease recurring 10 years or more after surgical treatment of primary cutaneous melanoma. METHODS: From 1971 to 1997, 1907 melanoma patients treated at our cancer center reached or presented with a DFI of 10 years or more after surgical treatment of clinically localized melanoma. Of these, 217 (11%) patients had recurrences (mean DFI, 182 months). The sites of recurrence were local/in-transit in 26 (12%) patients, regional lymph nodes in 101 (47%) patients, and distant sites in 90 (41%) patients. RESULTS: Univariate and multivariate analysis, using patient age and sex, type of initial treatment, and the site, Breslow thickness, and Clark level of the initial tumor, showed that the type of treatment for the primary tumor was a significant (P = .0005) prognostic factor in the development of late nodal recurrence. Of the 217 patients who had recurrences, 172 (79%) had undergone wide local excision for their primary melanoma, and 45 (21%) had undergone wide local excision plus elective lymph node dissection (ELND). The rates of nodal recurrence were 53% (92 of 172) and 20% (9 of 45), respectively, a significant (P = .0001) difference. When all patients with a DFI of 10 years or more were stratified by type of initial treatment, the ELND group demonstrated a significant improvement in disease-free survival and overall survival. CONCLUSIONS: The risk of late-recurring nodal disease increases and the chance of long-term survival decreases when wide local excision is performed without ELND. With the advent of sentinel lymphadenectomy, ELND can be selectively performed only for those nodal basins with occult tumor cells, thereby decreasing operative morbidity but allowing identification and early removal of nodal micrometastases.

Axillary dissection after unsuccessful sentinel lymphadenectomy for breast cancer.

Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) has been demonstrated to provide sensitive axillary staging for breast cancer. LM/SL has a steep learning curve, and factors associated with unsuccessful LM/SL are not well known. Two hundred sixty patients with breast carcinoma and clinically negative axillae underwent injection of about 5 cm3 of isosulfan blue dye (Lymphazurin, US Surgical Corp, Norwalk, CT) into breast tissue surrounding a cancer or biopsy site. After 5 minutes of breast compression, blue-stained lymph nodes were sought. In 47 patients, no blue nodes were detected; a standard axillary dissection was performed. All 47 patients were women with a mean age of 56 years (range, 34-80). Ductal carcinoma was most common (91.5%). Mean tumor size was 1.99 cm. Axillary dissection yielded a mean of 15.8 lymph nodes (range, 6-35). Sixteen patients (34%) had positive lymph nodes (mean, 7.6; median, 6; range, 1-24). Factors associated with LM/SL difficulty include surgeon inexperience, medial hemisphere primary location, extensive axillary metastases, and extranodal invasion. Inability to identify a sentinel node in a clinically negative axilla is a risk factor for extensive axillary tumor burden. Axillary dissection should be performed for patients with unsuccessful LM/SL, particularly those with lateral hemisphere primaries.

Sentinel lymphadenectomy for breast cancer in a community managed care setting.

PURPOSE: To evaluate the feasibility, accuracy, and reproducibility of intraoperative lymphatic mapping and sentinel lymphadenectomy (IOLM/SL) in the staging of breast cancer patients in a community managed care setting. PATIENTS AND METHODS: One hundred forty-five patients with primary breast cancer were prospectively studied over a 26-month period. They underwent vital dye injection at their primary breast cancer site. Lymphatic channels were traced to the sentinel lymph node, which was excised, serially sectioned, and examined. A level I and II axillary lymph node dissection and definitive breast surgery were then performed. RESULTS: Sentinel nodes were identified in 103 of 145 procedures (71.0%). Sentinel and nonsentinel lymph nodes were concordant in 100 of 103 cases (97.1%). Three patients (9.7%) had falsely negative sentinel nodes; there were none in the last 80 patients. Of 28 positive sentinel nodes, 12 (42.9%) represented the only tumor-containing node within the axilla. Sentinel nodes were significantly more likely to contain tumor than nonsentinel nodes (33/50, 66.0% vs 54/467, 11.6%, P < 0.0001). IOLM/SL identified more micrometastases (< 2 mm) than standard axillary lymph node dissection (13/33, 39.6% vs 4/177, 2.2%, P < 0.001). Nine of 42 patients (21.4%) whose sentinel node could not be identified had five or more nodal metastases. Two of six patients with presumed Tis primaries had nodal metastases. DISCUSSION: IOLM/SL accurately identifies the sentinel lymph node(s) most likely to contain metastatic disease. A procedural learning curve was present. An unsuccessful IOLM/SL was a risk factor for considerable nodal metastases. IOLM/SL with a tumor-free sentinel node may obviate a formal axillary lymph node dissection. The technique was feasible, economical, and reproducible within the context of a community managed care facility, while not placing exacting demands on operating room, pathology, or nuclear medicine personnel.

Outpatient definitive breast cancer surgery.

We attempted to show that surgical treatment of breast cancer, including axillary lymph node dissection with or without concomitant partial mastectomy (ALND), simple mastectomy (SM), and modified radical mastectomy (MRM) can be performed safely in an outpatient setting. The records of 100 consecutive women undergoing definitive breast cancer surgery by the authors between August 1994 and July 1996 were retrospectively reviewed. Average age was 54 +/- 10 years. Fifty patients were discharged the day of surgery, 44 were hospitalized, and 6 remained 2 or more days postoperatively. Outpatients were more likely to have undergone ALND or SM (42 versus 23 procedures) and more often completed surgery in the morning (36 versus 12); P < 0.05. Eight patients of 35 with MRM were discharged the same day. One patient was readmitted with a wound infection. There were no major complications or deaths. Ninety-four per cent of patients were discharged within 23 hours of surgery; half were discharged the same day. No complications occurred in outpatients, and there were no readmissions. For patients admitted overnight, no complications were detected during the overnight hospital stay. In conclusion, breast cancer surgery, from ALND to SM or MRM, can be safely and comfortably performed on an outpatient basis.

Feasibility of breast-conserving therapy for younger women with breast cancer.

OBJECTIVE: To determine if breast-conserving therapy (BCT) consisting of segmentectomy, axillary lymph node dissection, and postoperative irradiation is a feasible approach to breast cancer in younger women, whose breast tissue is dense and whose tumors can be difficult to detect and successfully excise. DESIGN AND PATIENTS: We studied BCT in 59 women 35 years old or younger (mean age, 31.7 years) treated for breast cancer since 1982. Ninety percent of their cancers were palpable; 44% were not visible by mammography. Most (93%) had T1 or T2 lesions (< or = 5 cm). Invasive ductal carcinoma was the predominant histologic diagnosis (68%). RESULTS: Segmentectomy with axillary dissection was the initial operative procedure for 39 (66%) of the 59 patients; of these, 21 (54%) had microscopically positive segmentectomy margins. Nine patients (23%) with diffusely positive segmentectomy margins and four patients (13%) with local recurrences after BCT required conversion to mastectomy. Three patients (8%) underwent reexcision to achieve negative margins. The 39 patients required a total of 22 additional surgical procedures for local control. Thirty-three (56%) of the 59 patients underwent mastectomy during the mean 68-month follow-up period; 20 (34%) underwent mastectomy as the initial definitive treatment. Reasons for primary mastectomy included multifocality or multicentricity (35%), large tumor size (30%), patient preference (15%), and occult primary tumor (10%). During the same time period, 474 (64%) of 745 women older than 35 years underwent BCT as treatment of breast cancer. Two percent required conversion to mastectomy and 1% required repeated excision. Twenty-four patients (5%) required mastectomy for local recurrence after BCT. After excluding mastectomies performed because of patient preference, significantly fewer older women required mastectomy to achieve local control (21% vs 50%, P < .001). CONCLUSIONS: Breast-conserving therapy is significantly more difficult in younger women despite surgeon and patient commitment. Patients and physicians should be encouraged to consider BCT but should be aware of the potential difficulty in obtaining adequate local control and the possible need for additional operative procedures.

Lymphatic mapping and sentinel lymphadenectomy for breast cancer.

OBJECTIVE: The authors report the feasibility and accuracy of intraoperative lymphatic mapping with sentinel lymphadenectomy in patients with breast cancer. SUMMARY BACKGROUND DATA: Axillary lymph node dissection (ALND) for breast cancer generally is accepted for its staging and prognostic value, but the extent of dissection remains controversial. Blind lymph node sampling or level I dissection may miss some nodal metastases, but ALND may result in lymphedema. In melanoma, intraoperative lymph node mapping with sentinel lymphadenectomy is an effective and minimally invasive alternative to ALND for identifying nodes containing metastases. METHODS: One hundred seventy-four mapping procedures were performed using a vital dye injected at the primary breast cancer site. Axillary lymphatics were identified and followed to the first ("sentinel") node, which was selectively excised before ALND. RESULTS: Sentinel nodes were identified in 114 of 174 (65.5%) procedures and accurately predicted axillary nodal status in 109 of 114 (95.6%) cases. There was a definite learning curve, and all false-negative sentinel nodes occurred in the first part of the study; sentinel nodes identified in the last 87 procedures were 100% predictive. In 16 of 42 (38.0%) clinically negative/pathologically positive axillae, the sentinel node was the only tumor-involved lymph node identified. The anatomic location of the sentinel node was examined in the 54 most recent procedures; ten cases had only level II nodal metastases that could have been missed by sampling or low (level I) axillary dissection. CONCLUSIONS: This experience indicates that intraoperative lymphatic mapping can accurately identify the sentinel node--i.e., the axillary lymph node most likely to contain breast cancer metastases--in some patients. The technique could enhance staging accuracy and, with further refinements and experience, might alter the role of ALND.

Breast-conserving surgery and radiation after augmentation mammoplasty.

BACKGROUND: Although breast-conserving therapy (tumor excision, axillary node dissection, and postoperative radiation) for women with breast cancer yields survival and local recurrence rates comparable with those of modified radical mastectomy, studies suggest that postoperative radiation leads to capsular contractures and poor cosmesis in patients with breast implants. METHODS: The authors followed 20 women in whom breast cancer developed after augmentation mammoplasty (14 subcutaneous implants and 6 retromuscular implants). Average age at diagnosis was 52 years (range, 34-72 years). Most (55%) of the patients had tumors in the upper outer quadrant. Fifteen lesions were palpable and five were nonpalpable. All tumors were excised using wide margins that attempted to include a rim of normal breast tissue. Three patients had microscopically positive margins. The predominant histology was ductal adenocarcinoma (85%). The mean greatest tumor dimension was 1.43 cm; 75% were T1 lesions. Levels I and II axillary lymph node dissection revealed metastases in five patients. After surgery, six patients received systemic chemotherapy, and all patients received 4500-5000 cGy of tangential photon radiation delivered to the whole breast, plus a 1400-2100 cGy boost delivered to the tumor site using photon radiation, electron radiation, or iridium 192 implantation. RESULTS: At a median follow-up of 3.8 years (range, 6 months to 9.3 years), there were no local recurrences; however, in two patients distant metastases developed. Seventeen (85%) of the twenty patients had good or excellent cosmetic results as determined by the degree of capsular contracture, breast shape and appearance, and the presence of skin changes. CONCLUSIONS: The authors conclude that breast-conserving therapy is a cosmetically acceptable therapeutic option for women in whom breast cancer develops after augmentation mammoplasty.

Planned segmentectomy. A necessity for breast carcinoma.

OBJECTIVE AND DESIGN: Some surgeons consider excisional biopsy with gross negative margins to be adequate surgical therapy for breast carcinomas, if followed by axillary dissection and radiation. To test our hypothesis that breast carcinoma necessitates planned operation, we reviewed the incidence of residual cancer tissue (RCT) and the significance of positive margins following excisional breast biopsy and segmentectomy. SETTING, PATIENTS, AND INTERVENTION/OUTCOME MEASURES: Using the clinical database of our multidisciplinary cancer center, we examined the tumor status of segmentectomy specimens from 375 patients treated for breast carcinoma during the past 10 years. All patients underwent excisional biopsy of the tumor mass before definitive treatment with segmentectomy and axillary dissection. Median follow-up was 32 months. RESULTS: The 284 patients (76%) whose segmentectomy specimens contained residual tumor (RCT-positive patients) had a larger median tumor diameter than RCT-negative patients (2 vs 1 cm, P < .01). Patients with tumor-positive axillary lymph nodes were more likely to be RCT positive (P < .001). Tumors of RCT-positive patients were more frequently identified by physical examination, whereas those of RCT-negative patients were more frequently identified by mammography (P < .001). Overall recurrence rate was 7% (26/384). Recurrence-free survival rates were statistically related to tumor status of the segmentectomy margins (P < .025) but not to RCT in the segmentectomy specimen. CONCLUSION: Diagnostic breast biopsy is not a substitute for planned excision to remove all malignant tissue. Anything less than a preconceived surgical procedure may leave a significant amount of malignant tissue.