Margin assessment after neoadjuvant chemotherapy in invasive lobular cancer.

BACKGROUND: Optimal surgical management of patients with invasive lobular carcinoma (ILC) who undergo neoadjuvant chemotherapy (NAC) is unknown. We evaluated optimal margin distance and local recurrence (LR) rates for these patients. METHODS: Ninety-three (30%) of 311 patients with ILC received NAC. We examined margin status, residual disease after re-excision, and clinical outcomes. RESULTS: Margin positivity rates after the final operative procedure were similar between the NAC and surgery-first group (P > .05). The proportion of patients, stratified by margin status, who were taken back for re-excision was not different between the 2 groups, and, similarly, there were no differences in frequency of residual disease (all P > .05). At a median follow-up of 3.1 years, 1 patient in the NAC group and 2 in the surgery-first group developed LR (P = 1.0). CONCLUSIONS: Patients with ILC who have undergone NAC and have margins >1 mm have a low probability of residual disease and LR.

A prospective study comparing touch imprint cytology, frozen section analysis, and rapid cytokeratin immunostain for intraoperative evaluation of axillary sentinel lymph nodes in breast cancer.

BACKGROUND: The intraoperative evaluation of axillary sentinel lymph nodes (SLNs) allows the surgeon to complete axillary dissection in 1 setting at the time of the primary breast surgery. However, to the authors' knowledge, there is no consensus regarding the optimal method for intraoperative evaluation of SLNs in breast cancer. The authors of this report prospectively compared touch imprint (TI) cytology with frozen section (FS) analysis and rapid cytokeratin immunostaining (RCI) of SLNs for the intraoperative evaluation of disease and compared the results with final pathologic examination (FP). METHODS: Patients with invasive breast carcinoma who were diagnosed with lymph node-negative disease (based on preoperative clinical and sonographic evaluation with or without fine-needle aspiration of the indeterminate lymph nodes) and who subsequently were scheduled for lymphatic mapping were eligible to participate in this prospective protocol. TI and FS analysis were performed on all SLNs, and the lymph nodes were stained by the hematoxylin and eosin (H&E) method. RCI was performed using the enhanced polymer 1-step cytokeratin method. The results of TI, FS, RCI, TI plus FS, and FS plus RCI were compared with the results from FP, including 1 H&E stain and cytokeratin immunostain of the third level. RESULTS: One hundred patients with invasive mammary carcinoma were accrued to the study. Eighty-five tumors were the ductal type, 8 tumors were lobular, 5 tumors were mixed ductal and lobular, 1 was an adenoid cystic tumor, and 1 tumor was metaplastic carcinoma. Seventy-two tumors were staged clinically as T1N0M0, 25 tumors were staged as T2N0M0, and 3 tumors were staged as T3N0M0. Metastatic carcinoma was detected in the SLNs by 1 or more methods, including TI, FS, RCI, and FP, in 20 tumors, which included 12 macrometastases and 8 micrometastases. TI detected 8 of 12 macrometastases (67%), FS detected 12 of 12 macrometastases (100%), RCI detected 12 of 12 macrometastases (100%), and FP detected 12 of 12 macrometastases (100%). TI detected 1 of 8 micrometastases (13%), FS detected 3 of 8 micrometastases (38%), RCI detected 4 of 8 micrometastases (50%), and FP detected 6 of 8 micrometastases (75%). The sensitivities of TI, FS, RCI, TI plus FS, and FS plus RCI (with FP as the gold standard) were 50%, 72%, 78%, and 83%, respectively, and the sensitivities of the same intraoperative methods were 45%, 75%, 80%, and 85%, respectively, with detection of metastatic disease by any method as the gold standard. The specificities of the different methods (with FP as the gold standard) were 100% for TI and 97.5% for FS, RCI, TI plus FS, and FS plus RCI. The specificity of each method was 100% when the detection of metastatic disease by any method was regarded as the gold standard. Although the difference in sensitivity between FS and TI was not statistically significant (P = .08), the difference between RCI and TI bordered on significance (P = .046); however, FS analysis plus RCI was significantly superior to TI (P = .03) and produced results comparable to those of FP. CONCLUSIONS: The sensitivities of FS, RCI, TI plus FS, and FS plus RCI were better than the sensitivity of TI cytology of axillary SLNs. However, only the combination of FS and RCI was statistically superior to TI and generated results comparable to those of FP in SLNs. RCI can be completed within the time constraints for intraoperative use and, in conjunction with FS, can be useful for generating results closer to those generated by FP. FS analysis plus RCI have a role in the intraoperative evaluation of SLNs.

The role of ultrasound in the surgical management of patients diagnosed with ductal carcinoma in situ of the breast.

The purpose of this study was to determine the usefulness of ultrasound (US) as an adjunct to mammography (MMG) in the surgical treatment planning for patients with ductal carcinoma in situ (DCIS) of the breast. A total of 119 patients diagnosed with DCIS, who were treated between 1999 and 2002, were identified from the institutional database. US and MMG size of suspicious abnormalities, pathologic tumor size, and findings of axillary US and surgical axillary evaluation were analyzed. The median size difference of US versus pathologic tumor size and MMG versus pathologic tumor size was 1.0 and 2.0 cm, respectively. Correlation coefficients for US versus pathologic tumor size and MMG versus pathologic tumor size were 0.53 and -0.09, respectively. The negative and positive predictive values of axillary US to predict nodal disease were 93% and 27%, respectively. US evaluation appears to be a useful tool in conjunction with MMG in determining the extent of disease in patients diagnosed with DCIS. However, the low positive predictive value of US for evaluating metastases to axillary lymph nodes does not justify the routine use of this modality for axillary evaluation in patients with DCIS. Therefore the use of US for patients diagnosed with DCIS needs further investigation.

Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy.

PURPOSE: The purpose of this study was to describe regional nodal failure patterns in patients who had undergone mastectomy with axillary dissection to define subgroups of patients who might benefit from supplemental regional nodal radiation to the axilla or supraclavicular fossa/axillary apex. METHODS AND MATERIALS: The cohort consisted of 1031 patients treated with mastectomy (including a level I-II axillary dissection) and doxorubicin-based systemic therapy without radiation on five clinical trials at M.D. Anderson Cancer Center. Patient records, including pathology reports, were retrospectively reviewed. All regional recurrences (with or without distant metastasis) were recorded. Median follow-up was 116 months (range, 6-262 months). RESULTS: Twenty-one patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures (no chest wall failure). The risk of failure in the low-mid axilla was not significantly higher for patients with increasing numbers of involved nodes, increasing percentage of involved nodes, larger nodal size or gross extranodal extension. Only 3 of 100 patients with <10 nodes examined recurred in the low-mid axilla. Seventy-seven patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). Forty-nine were isolated regional recurrences. Significant predictors of failures in this region included > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, p < 0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex. CONCLUSIONS: These results suggest that failure in the level I-II axilla is an uncommon occurrence after modified radical mastectomy and chemotherapy. Therefore, supplemental radiotherapy to the dissected axilla is not warranted for most patients. However, patients with > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, or gross extranodal extension are at increased risk of failure in the supraclavicular fossa/axillary apex and should receive radiation to undissected regions in addition to the chest wall.

Potential applicability of balloon catheter-based accelerated partial breast irradiation after conservative surgery for breast carcinoma.

BACKGROUND: Balloon catheter-based accelerated partial breast irradiation (APBI) is an alternative to whole-breast external-beam irradiation during breast-conserving therapy (BCT) for breast carcinoma, but it is limited by the size of the segmental mastectomy cavity. There are scant data on the average or optimal volume of resection (VR) in BCT. The objective of the current study was to evaluate the percentage of patients who would be eligible for balloon catheter-based APBI based on the selection criteria of the American Society of Breast Surgeons and the surgical VR. METHODS: The authors reviewed the medical records of 443 patients with ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCT. Patient treatment and pathologic data were analyzed to assess VR and eligibility for APBI. RESULTS: BCT was performed for 178 patients with DCIS and 267 patients with invasive breast carcinoma. The majority of invasive carcinomas (63.3%) were infiltrating ductal carcinomas. The median overall lumpectomy volume was 67.61 cm3, with no significant difference between DCIS and invasive carcinoma (P>0.05). Although the majority (62.9-82.0%) of patients met the individual selection criteria for APBI, only 27.4% of the cohort was found to be eligible for any type of APBI when the selection criteria were considered together. Based on VR, only approximately one-half of the patients initially eligible for APBI would be candidates for immediate balloon catheter-based APBI using the 70 cm3 balloon device (13.3%). However, with the new, larger 125 cm3 balloon device, approximately three-fourths of patients initially eligible for APBI would be eligible for balloon catheter-based APBI at the time of the initial surgical procedure (20.7%). Although not evaluated in the current study, shrinkage of the lumpectomy cavity with time may increase the number of patients eligible based strictly on VR criteria. Patients with a very large VR (> or =125 cm3) were more likely to have invasive carcinoma (P=0.02; hazard ratio [HR], 7.4) and tumors > or =5 cm on final pathology (P<0.01; HR, 22.0). CONCLUSIONS: Approximately one-fifth to one-fourth of patients presenting for BCT may be eligible for balloon catheter-based APBI according to accepted national guidelines and VR. VR must be considered when selecting patients for balloon catheter-based APBI, because a minority of patients will have a lumpectomy cavity that exceeds the size limit of the current balloon device.

A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up.

BACKGROUND: The current study was performed to assess whether sequential potentially noncross-resistant chemotherapy prolongs disease-free survival (DFS) and overall survival (OS) in patients with operable breast carcinoma. METHODS: Seven hundred eighty-nine patients were registered and followed for a median of 10 years. They were treated in two groups. In Group 1, patients age < 50 years or age > 50 years but with either negative or unknown estrogen receptor (ER) status were randomized to receive 6 cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) alone or followed by 4 cycles of methotrexate and vinblastine (MV). In Group 2, patients age > or = 50 years with ER-positive disease were randomized to receive either tamoxifen or combination chemotherapy (FAC + MV) for 10 cycles. Analysis was performed according to allocated treatment (intention to treat), with all randomized patients included. RESULTS: In Group 1 there were no significant differences with regard to DFS or OS between the two treatment arms. The DFS at 5 years was 0.70 and 0.76, respectively, for FAC compared with FAC+MV (P = 0.26). The OS was similar for both groups (0.84 vs. 0.83). It is interesting to note that there was a statistically nonsignificant trend for improved DFS in the FAC + MV arm for patients who were ER-positive. In Group 2, tamoxifen alone led to more prolonged DFS compared to FAC+MV (0.78 vs. 0.66, respectively) but this did not reach statistical significance (P = 0.28). OS also was associated with a trend (P = 0.86) toward prolonged survival for the tamoxifen arm compared with the FAC+MV arm (0.85 vs. 0.74, respectively). CONCLUSIONS: The results of the current trial concerning sequential adjuvant chemotherapy for operable breast carcinoma, which to our knowledge contains the longest follow-up presented to date, failed to demonstrate any additional benefit from the addition of 4 cycles of MV to 6 cycles of FAC chemotherapy.

Histologic localization of sentinel lymph node metastases in breast cancer.

Data from a recent study support the hypothesis that axillary lymph node metastases frequently localize near the inflow junction of the afferent lymphatic vessel. Our goal was to evaluate the microscopic location of axillary sentinel lymph node metastases in a prospective study of breast cancer patients. A total of 305 axillary sentinel lymph nodes from 213 breast cancer patients undergoing surgery at our institution were evaluated. Preoperative lymphoscintigraphy using technetium-labeled sulfur colloid and intraoperative isosulfan blue dye injection were used for identifying the sentinel lymph node. Intraoperatively, the surgeon placed a suture either at the point of entry of isosulfan blue dye or at the area with the highest radioactive counts, and this area was inked at the grossing bench before processing. Metastases were identified in 55 of the 305 lymph nodes examined. Thirty-four nodes contained metastases in both the inked half and the opposite half. Metastatic tumor was identified in the inked half alone in 18 lymph nodes. Only three nodes contained metastatic tumor in the opposite half with no tumor in the inked half (p <0.001). Similar results were found when nodes tagged at the point of blue dye entry and nodes tagged at the area with the highest radioactive counts were analyzed separately. Our findings suggest that metastatic tumor has a higher probability of being present in the region of the inflow junction of the afferent lymphatic vessel. This information may be useful in determining the optimal method for evaluating axillary sentinel lymph node specimens from breast cancer patients.

Feasibility of radiofrequency ablation for primary breast cancer.

As the management of breast cancer evolves towards less invasive treatment, the next step is the possibility of removing the primary tumor without surgery. The most promising of the noninvasive ablation techniques is radiofrequency ablation, which uses frictional heating caused when ions in the tissue attempt to follow changing directions of a high frequency alternating current. The radiofrequency probe is typically placed into the tumor under ultrasound guidance, and the ablation is performed with real time ultrasound monitoring. Preliminary studies in which RFA was followed by standard surgical resection have indicated that this technique is effective for the surgical ablation of small (

Primary chemotherapy in the treatment of breast cancer: the University of Texas M. D. Anderson Cancer Center experience.

The use of primary systemic (neoadjuvant) therapy has become widespread in the treatment of patients with locally advanced and operable breast cancer. The utilization of this therapeutic approach provides several advantages. By monitoring changes in the dimension of the tumor, efficacy can be evaluated or assessed in vivo; unnecessary toxicity can be avoided by allowing the physician to discontinue ineffective therapy. Furthermore, downstaging of a tumor through primary therapy may allow for breast-conserving surgery in patients with large operable breast cancer and render inoperable tumors resectable. Also, the use of primary therapy can provide a pathological complete response, which correlates with prolonged periods of remission. Treatment with FAC (5-fluorouracil/doxorubicin/cyclophosphamide) has proven to be effective as neoadjuvant therapy in locally advanced breast cancer in several trials. More recently, the integration of taxanes into primary therapy regimens has been explored with promising results. Studies have suggested that the use of primary therapy, particularly the use of FAC, should perhaps become the standard in patients with locally advanced disease. The history of clinical trials focusing on primary therapy in breast cancer at the M. D. Anderson Cancer Center will be reviewed.

Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer.

Previous studies by us and others have shown a significantly higher level of aromatic DNA adducts in normal adjacent breast tissue samples obtained from breast cancer patients than in those obtained from non-cancerous controls. The increased amount of DNA damage could be related to excess environmental carcinogen exposure and/or genetic susceptibility to such exposure. In the current study, we investigated the relationship between the levels of aromatic DNA adducts in breast tissues and polymorphisms of the drug-metabolizing genes cytochrome P4501A1 (CYP1A1), N-acetyltransferase-2 (NAT2), and glutathione S-transferase M1 (GSTM1), in 166 women having breast cancer. DNA adducts were measured using (32)P-postlabeling and information on smoking status was obtained from medical records. When pooled data of smokers and non-smokers were analyzed by multiple regression analyses, no significant correlation was found between the level of total DNA adducts and age, race, or polymorphisms of CYP1A1, GSTM1, and NAT2. The only significant predictor of the level of DNA adducts in breast tissues was smoking (P = 0.008). When data were analyzed separately in smokers and non-smokers, however, a significant gene-environment interaction was observed. Smokers with CYP1A1*1/*2 or *2/*2 genotypes had a significantly higher level of DNA adducts than those with the CYP1A1*1/*1 genotype. This effect was not seen among non-smokers. There was also a gene-gene interaction, as smokers with combined CYP1A1*1/*2 or CYP1A1*2/*2 genotypes and GSTM1 null had a much higher level of adducts than those with either CYP1A1 or GSTM1 polymorphism. Genetic polymorphisms of CYP1A1 and NAT2 were also significantly correlated with the frequency of certain types of DNA adducts. For example, a bulky benzo[a]pyrene (B[a]P)-like adduct was detected in 26% of the samples, the presence of which was not related to age, race, smoking status, or GSTM1 and NAT2 genotype. However, a significantly higher frequency of the B[a[P-like adduct was found in individuals having CYP1A1*1/*2 or *2/*2 genotypes than in those having the *1/*1 genotype (P = 0.04). In addition, individuals having slow NAT2 alleles had a significantly higher frequency of the typical smoking-related DNA adduct pattern, i.e. a diagonal radioactive zone (DRZ), than others did (P = 0.008). These findings suggest that polymorphisms of CYP1A1, GSTM1, and NAT2 significantly affect either the frequency or the level of DNA adducts in normal breast tissues of women having breast cancer, especially in smokers. Further large-scale studies are required to determine the exact role of these polymorphisms and types of DNA damage in breast cancer susceptibility.