Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.

Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.

Outcome of MRI-guided breast biopsy.

OBJECTIVE: The objective of our study was to investigate the outcome of MRI-guided breast biopsy as a function of the indication for MRI and the MRI features of the lesions. MATERIALS AND METHODS: In 154 women (mean age, 51 years) with 172 MRI-detected lesions, MRI-guided vacuum-assisted breast biopsy was attempted. Using the original radiologic report, we evaluated the indication for the original MRI examination and the MRI findings that led to biopsy. We investigated the core and operative histology results and follow-up data. We analyzed the cancer rate as a function of the indication for MRI and the MRI features of the lesions using Fisher's exact test. RESULTS: In 22 of the 172 lesions (13%), MRI-guided biopsy was deferred due to decreased visualization or nonvisualization of the MRI finding that led to biopsy. Of 150 biopsies in 134 women, core histology revealed 39 malignant (39/150, 26%), 90 benign (90/150, 60%), and 21 high-risk (21/150, 14%) lesions. Through operative histology (n = 13) or follow-up (n = 30), four high-risk lesions were upgraded to malignancy and all deferred lesions except four lost to follow-up were confirmed to be benign. The final number of malignancies was 43 (29%) including 16 in situ and 27 invasive cancers. The probability of malignancy was different in the screening and diagnostic settings (14% vs 36%, respectively; p = 0.05), whereas it was not different according to lesion type (mass, 34%; nonmass, 27%; focus, 19%; p > 0.05) or kinetics (persistent, 23%; plateau, 31%; washout, 29%; p > 0.05). CONCLUSION: The cancer rate in our cohort of women who underwent MRI-guided breast biopsy was 29%. It varied according to the indication for the original MRI examination, but not according to the MRI features of the lesions.

Mammographic appearance of recurrent breast cancer after breast conservation therapy.

RATIONALE AND OBJECTIVES: To compare the mammographic appearance of recurrent breast cancer to the primary tumor in patients treated with breast conservation therapy. MATERIALS AND METHODS: The charts of women with American Joint Committee on Cancer Stage I or II breast cancer who underwent breast conservation therapy between 1977 and 2001 at our institution were reviewed. A total of 132 patients were diagnosed with local recurrence. RESULTS: The mammographic appearance of the local recurrence often varied from the appearance of the original breast cancer. This was especially true for women who had mammographically occult primary breast cancer. In these women, the recurrence was detected mammographically 76.9% of the time. CONCLUSIONS: Given the variable appearance of the local recurrence after breast conservation therapy, any suspicious finding needs to be carefully evaluated regardless of the mammographic appearance of the original tumor.

Biopsy findings after breast conservation therapy for early-stage invasive breast cancer.

PURPOSE: To determine the patterns and factors predictive of positive ipsilateral breast biopsy after conservation therapy for early-stage breast cancer. METHODS AND MATERIALS: We performed a retrospective review of Stage I-II breast cancer patients initially treated with lumpectomy and radiotherapy between 1977 and 1996, who later underwent post-treatment ipsilateral breast biopsies. RESULTS: A total of 223 biopsies were performed in 193 treated breasts: 171 single and 22 multiple biopsies. Of the 223 biopsies, 56% were positive and 44% were negative for recurrence. The positive biopsy rate (PBR) was 59% for the first and 32% for subsequent biopsies. The median time to the first post-treatment biopsy was 49 months. Of the patients with negative initial biopsy findings, 11% later developed local recurrence. The PBR was 40% among patients with physical examination findings only, 65% with mammographic abnormalities only, and 79% with both findings (p = 0.001). Analysis of the procedure type revealed a PBR of 86% for core and 58% for excisional biopsies compared with 28% for aspiration cytology alone (p = 0.025). The PBR varied inversely with age at the original diagnosis: 49% if >or=51 years, 57% if 36-50 years, and 83% if 180 months after completing postlumpectomy radiotherapy (p = 0.01). The PBR was not linked with recurrence location, initial pathologic T or N stage, estrogen receptor/progesterone receptor status, or final pathologic margins (all p >or= 0.15). CONCLUSION: After definitive radiotherapy for early-stage breast cancer, a greater PBR was associated with the presence of both mammographic and clinical abnormalities, excisional or core biopsies, younger age at the initial diagnosis, and longer intervals after radiotherapy completion.

Effect of breast magnetic resonance imaging on the clinical management of women with early-stage breast carcinoma.

PURPOSE: To determine the impact of breast magnetic resonance imaging (MRI) on the clinical management of patients with early-stage breast cancer. PATIENTS AND METHODS: A review was performed of the records of 207 women with early-stage breast cancer (including five women with bilateral disease) who underwent breast MRI during work-up for breast conservation treatment. All patients presented with clinical stage 0, I, or II disease. For each patient, a determination was made whether the breast MRI affected the clinical management, and if so, whether the patient was well served by the change in management. RESULTS: The MRI findings affected the clinical management in 43 cases (20% of 212 breast cancers). Based on the pathology findings and the overall clinical course for each case, the breast MRI was judged to have had a strongly favorable effect on management in 18 cases (8%), a somewhat favorable effect in six cases (3%), an uncertain effect in five cases (2%), a somewhat unfavorable effect in 11 cases (5%), and a strongly unfavorable effect in three cases (1%). The effect of MRI was not significantly different for invasive carcinoma compared with ductal carcinoma-in-situ (all P > or =.27). However, the effect of MRI was significantly greater when the MRI was performed before an excisional biopsy (P =.0011) or for larger tumors (P =.0089). CONCLUSIONS: Breast MRI alters the clinical management for a sizable fraction of women with early-stage breast cancer and appears to offer clinically useful information for determining optimal local treatment.

Breast cancer detection based on incremental biochemical and physiological properties of breast cancers: a six-year, two-site study.

RATIONALE AND OBJECTIVES: To demonstrate that near-infrared spectroscopy would achieve sufficient sensitivity and specificity in human breast cancer to reach ROC/AUC values in the 90s and yet to warn of the potential liabilities of introduction of a novel technology in this field. MATERIALS AND METHODS: 116 subjects from two nations (44 were cancer-verified by biopsy and histopathology) were reviewed. NIR spectroscopy of total hemoglobin and its relative oxygenation were monitored in breast cancers and compared to their contralateral breast in a 2D nomogram for diagnostic evaluation. A novel handheld NIR breast cancer detector pad with a 3-wavelength LED and 8 detectors with 4 cm separation between source and detectors was placed on the subject's breast. The method is convenient, rapid, and safe and has achieved high patient compliance with minimal patient apprehension of compression, confinement, or radioactivity. RESULTS: The absorbance increments of the cancerous region are referred to the mirror image location on the contralateral breast. The two metrics are increased hemoglobin concentration due to angiogenesis and decreased hemoglobin saturation due to hypermetabolism of the cancer. The 2D nomogram display of these two metrics shows Zone 1 contains verified cancers and Zone 2 contains noncancers. ROC evaluation of the nomogram gives 95% AUC for the two sites, Philadelphia and Leipzig. CONCLUSION: A simple, economical breast cancer detector has achieved high patient compliance and a high ROC/AUC score for a population which involved a range of tumors down to and including those of 0.8-1 cm in diameter.

Outcome after treatment of patients with mammographically occult, magnetic resonance imaging-detected breast cancer presenting with axillary lymphadenopathy.

Although magnetic resonance imaging (MRI) for patients with mammographically occult breast cancer with axillary lymphadenopathy has been accepted for staging, treatment outcome data in this patient group is lacking. In this study, 16 patients, median age of 45 years (range, 27-66 years), presented with malignant axillary lymphadenopathy, negative mammograms, negative breast physical examination, and abnormal breast MRI. All 16 patients were found to have >/= 1 suspicious lesions on breast MRI. Ten patients had a solitary enhancing lesion; 1 patient had 2 enhancing lesions; 3 patients had 3 enhancing lesions; 1 patient had a mass lesion and diffuse patchy enhancement in the breast; and 1 patient had regional enhancement but no discrete lesion on MRI. Six patients underwent breast-conservation surgery using MRI-guided wire localization and 10 patients had modified radical mastectomy. Fourteen patients received adjuvant chemotherapy and the remaining 2 patients received neoadjuvant chemotherapy. With a median follow-up of 5 years (range, 1.2-7.6 years), the 5-year actuarial local control was 100%, relapse-free survival was 74%, and overall survival was 87%. Three patients developed distant metastases. Two patients died from distant metastases, and 1 patient is alive with metastatic disease. One patient had a relapse in the contralateral axilla and was treated with paclitaxel and is disease free. Although the patient population is small, the outcome after treatment for this group of patients with a mammographically occult, MRI-detected breast cancer presenting with axillary adenopathy is similar to the expected outcome for patients with breast cancer with positive axillary lymph nodes.

Breast conservation treatment for patients presenting with axillary lymphadenopathy from presumed primary breast cancer: the role of breast magnetic resonance imaging for staging.

Three female patients presented with malignant axillary lymphadenopathy presumed to be from primary breast cancer. No evidence of primary cancer was found in the breast on either mammography or breast magnetic resonance imaging (MRI). All 3 patients underwent axillary lymph node dissection and systemic chemotherapy followed by radiation therapy to the breast and regional lymph nodes. Two patients remain relapse free with a follow-up of 3.7 years each. The third patient achieved locoregional control in the ipsilateral breast and regional lymph nodes but relapsed in the contralateral axilla. These 3 cases illustrate the potential for breast conservation treatment for patients presenting with axillary adenopathy from a presumed primary breast cancer but without either mammographic or breast MRI findings.

Breast reconstruction with a transverse rectus abdominis myocutaneous flap: spectrum of normal and abnormal MR imaging findings.

The authors retrospectively reviewed their clinical database for cases of breast magnetic resonance (MR) imaging performed in women who had undergone breast reconstruction with a transverse rectus abdominis myocutaneous (TRAM) flap. Patient histories, MR imaging results, and, when available, biopsy results were reviewed. During a 4-year period, 24 neobreasts were imaged in 22 women who had undergone TRAM flap reconstruction after mastectomy. In most of the cases (64%), the indication for MR imaging was a palpable abnormality or pain. In four of 24 cases (17%), recurrent breast cancer was detected. These cases consisted of a local chest wall tumor (n = 2), an infiltrating chest wall tumor (n = 1), and axillary nodal recurrence (n = 1). In all four cases, MR imaging demonstrated a suspicious lesion or abnormality. In 11 of 24 cases (46%), benign findings only were demonstrated. These consisted of localized or diffuse skin thickening, fibrosis, fat necrosis, and seroma. In nine of 24 cases (38%), no pathologic abnormality was identified. MR imaging is useful in detection of locally recurrent tumor in patients who have undergone breast reconstruction with a TRAM flap. MR imaging allows differentiation between benign and malignant findings in patients with palpable abnormalities or pain after TRAM flap reconstruction.

Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ.

PURPOSE: To determine the relationship of breast magnetic resonance imaging (MRI) to outcome after breast-conservation treatment (BCT) with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. PATIENTS AND METHODS: A total of 756 women with early stage invasive breast carcinoma or ductal carcinoma in situ underwent BCT including definitive breast irradiation during 1992 to 2001. At the time of initial diagnosis and evaluation, routine breast imaging included conventional mammography. Of the 756 women, 215 women (28%) had also undergone a breast MRI study, and 541 women (72%) had not undergone a breast MRI study. The median follow-up after treatment was 4.6 years (range, 0.1 to 13.5 years). RESULTS: For the women with a breast MRI study compared with the women without a breast MRI study, there were no differences in the 8-year rates of any local failure (3% v 4%, respectively; P = .51) or local-only first failure (3% v 4%, respectively; P = .32). There were also no differences between the two groups for the 8-year rates of overall survival (86% v 87%, respectively; P = .51), cause-specific survival (94% v 95%, respectively; P = .63), freedom from distant metastases (89% v 92%, respectively; P = .16), or contralateral breast cancer (6% v 6%, respectively; P = .39). CONCLUSION: The use of a breast MRI study at the time of initial diagnosis and evaluation was not associated with an improvement in outcome after BCT with radiation.

MR imaging-guided 9-gauge vacuum-assisted core-needle breast biopsy: initial experience.

PURPOSE: To perform magnetic resonance (MR) imaging-compatible vacuum-assisted 9-gauge core-needle biopsy of suspicious enhancing breast lesions identified at MR imaging. MATERIALS AND METHODS: The institutional review board granted exempt status for this HIPAA-compliant study and waived the requirement for informed consent. The MR imaging-guided 9-gauge vacuum-assisted core-needle biopsy findings of 85 lesions in 75 patients aged 31-89 years were retrospectively reviewed. The biopsies were performed as part of the patients' clinical care with a Food and Drug Administration-approved biopsy system and not within a research protocol. All included patients had received a diagnosis of malignant, benign, or high-risk (for cancer) breast tissue at core-needle biopsy and had undergone subsequent surgery or follow-up imaging. MR imaging-guided biopsy results were compared with final histopathologic or follow-up imaging findings. RESULTS: At MR imaging-guided core-needle biopsy, malignancy was identified in 52 (61%) lesions: 35 invasive cancers and 17 ductal carcinoma in situ (DCIS) lesions. Four (24%) of the 17 DCIS lesions were upgraded to invasive cancer at excisional biopsy or mastectomy. A high-risk lesion (ie, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or radial scar) was identified in 18 (21%) cases. Two (25%) of eight atypical ductal hyperplasia lesions were upgraded to DCIS at excision. No malignancy was found in the atypical lobular hyperplasia (n = 2), lobular carcinoma in situ (n = 5), or radial scar (n = 3) lesions. Fifteen (18%) lesions were found to be benign lesions of unknown type at excision or mastectomy. For 13 of these 15 lesions, the benign results were concordant with the imaging findings. Both (two of 86, 2%) discordant cases represented false-negative lesions. The remaining 13 benign lesions were validated at excisional biopsy (n = 9) or follow-up imaging (n = 4). CONCLUSION: Initial experience revealed MR imaging-guided 9-gauge vacuum-assisted core-needle breast biopsy to be a reasonable alternative to MR imaging-guided wire localization of suspicious lesions identified at MR imaging only, on the basis of published information regarding the latter.

MRI before reexcision surgery in patients with breast cancer.

OBJECTIVE: The aims of this study were to assess the diagnostic accuracy of MRI in evaluating patients for residual cancer, identify the prevalence of multicentric or multifocal disease, and evaluate the impact of MRI on surgical treatment planning. SUBJECTS AND METHODS. Of 101 potentially eligible patients, 80 candidates for breast conservation therapy who had primary breast cancer in 82 breasts diagnosed by excisional biopsy with close or positive margins were included in the study group. All patients underwent contrast-enhanced MRI before further surgery and subsequently underwent either reexcision lumpectomy or mastectomy with histopathologic correlation. RESULTS: Residual carcinoma, either invasive or in situ, was present in 59.8% of the breasts. The sensitivity and specificity of MRI for detecting residual disease were 61.2% and 69.7%, respectively. Twenty-three additional lesions distant from the biopsy site were identified in 19 breasts, and 18 suspicious lesions underwent biopsy. Histology results indicated that six lesions were malignant, so the overall prevalence was 7.3%. The positive predictive value of identifying an additional suspicious lesion was 33.3%. In 24 breasts, MRI changed which procedure would be performed next from reexcision lumpectomy to mastectomy (n = 9), biopsy of an additional lesion in the ipsilateral (n = 12) or contralateral (n = 2) breast, or neoadjuvant chemotherapy (n = 1). Approximately 25% of the breasts underwent mastectomy as definitive surgical treatment. CONCLUSION: Overlap in the appearances of benign and malignant lesions limits MRI evaluation for residual disease. MRI can show additional suspicious lesions that are likely to be multicentric or multifocal disease. These findings changed the original treatment plan for approximately 30% of breasts.

Relation between the method of detection of initial breast carcinoma and the method of detection of subsequent ipsilateral local recurrence and contralateral breast carcinoma.

BACKGROUND: Mammography and physical examination are routine methods for the detection of ipsilateral local recurrence and contralateral breast carcinoma in patients initially undergoing breast conservation treatment. The current study reports the relation between the method of detection of the initial breast carcinoma and the method of detection of subsequent ipsilateral local recurrence and contralateral breast carcinoma. METHODS: A retrospective review was performed of the records of female patients with initial American Joint Committee on Cancer (AJCC) Stage I and II invasive breast carcinoma who developed ipsilateral local recurrence or contralateral breast carcinoma after breast conservation treatment. The method of detection of local recurrence in the ipsilateral breast and the method of detection of contralateral breast carcinoma were compared with the method of detection of the primary tumor. RESULTS: There were 125 ipsilateral breast local recurrences and 71 contralateral breast carcinoma cases detected. Of the 125 recurrences in the ipsilateral breast, 38% (48 recurrences) were detected by mammography only, 37% (46 recurrences) were detected by physical examination only, and 25% (31 recurrences) were detected by both methods. Of the 71 contralateral breast carcinoma cases, 53% (38 cases) were detected by mammography only, 23% (16 cases) were detected by physical examination only, and 24% (17 cases) were detected by both methods. When the primary tumors were detected by mammography only, 21% of the local recurrences (3 of 14 local recurrences) and 19% of the contralateral breast carcinoma cases (4 of 21 cases) were detected by physical examination only. When the primary tumors were detected by physical examination only, 24% of the local recurrences (14 of 58 local recurrences) and 42% of the contralateral breast carcinoma cases (8 of 19 cases) were detected by mammography only. When stratified by the interval between diagnosis of the primary tumor and ipsilateral local recurrence or contralateral breast carcinoma (< or = 5 years vs. > 5 years) or age of the patient at the time of ipsilateral breast recurrence or contralateral breast carcinoma (age < or = 49 years vs. age > or = 50 years), both breast examination and mammography were found to be important in the detection of locally recurrent tumor and contralateral breast carcinoma in each subgroup of the patients, regardless of the method of presentation of the primary tumor. CONCLUSIONS: Both mammography and physical examination were found to be significant in the detection of locally recurrent tumor in the ipsilateral breast and in the detection of contralateral breast carcinoma, regardless of the method of detection of the primary tumor.

Magnetic resonance imaging-guided biopsy of mammographically and clinically occult breast lesions.

BACKGROUND: Breast magnetic resonance imaging (MRI) is a very sensitive technique for detection of breast cancer. We report on MRI-guided needle localization for biopsy of abnormalities seen only on MRI. METHODS: A retrospective review was performed of 231 patients with invasive breast cancer or ductal carcinoma-in-situ who had MRI as part of their evaluation and treatment at the University of Pennsylvania between 1992 and 1998. Clinical, radiological, and pathologic data were examined. RESULTS: MRI needle localization was performed in 41 (18%) patients. MRI needle localization was required for a finding of a mammographically or clinically occult lesion in 31 patients, better MRI definition of tumor in 5 patients, and surgeon's choice in 5 patients. In all cases, MRI localization and excisional biopsy were successfully completed. Nineteen of 31 patients were found to have additional mammographically and clinically occult tumors. There were 12 (29%) false-positive MRI scans. CONCLUSIONS: MRI has a high sensitivity for detection of breast cancer; additional mammographically and clinically occult sites of tumor are detected in approximately 1 (15%) of 7 breast cancer patients. These otherwise occult sites of disease can be appropriately biopsied with MRI needle-localization techniques.

MR imaging screening of the contralateral breast in patients with newly diagnosed breast cancer: preliminary results.

PURPOSE: To investigate the role of screening magnetic resonance (MR) imaging in the detection of synchronous contralateral breast cancer in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: Between January 1999 and July 2001, 182 patients with newly diagnosed breast cancer (after either core or excisional biopsy with positive or close margins of resection) underwent bilateral contrast material-enhanced MR imaging at 1.5 T with a dedicated bilateral breast multicoil array. The contralateral breast was imaged for cancer screening. Family history of breast cancer, index cancer histology, breast density, and age at diagnosis of first breast cancer were assessed as potential risk factors for synchronous contralateral breast cancer. RESULTS: Fifteen patients (8.2%) had a suspicious enhancing lesion depicted in the contralateral breast. Seven patients (3.8%) had malignant results: ductal carcinoma in situ (DCIS) in four, invasive ductal carcinoma with DCIS in two, and invasive ductal carcinoma in one. Eight patients (4.4%) had benign results: fibrocystic changes in four, atypical ductal hyperplasia in two, atypical lobular hyperplasia and focal lobular carcinoma in situ in one, and ductal hyperplasia in one. Six patients with negative MR findings underwent prophylactic mastectomy; no malignancy was found. No significant differences were noted among patients with true-positive (n = 7), false-positive (n = 8), or negative (n = 167) MR findings with regard to family history of breast cancer (P <.27), index cancer histology (P <.19), breast density (P <.34), or age at diagnosis of first breast cancer (P <.10). CONCLUSION: The preliminary results demonstrate the feasibility of using MR imaging of the breast in a screening role, specifically to evaluate the contralateral breast in patients with newly diagnosed breast cancer to detect mammographically and clinically occult synchronous breast cancer.

Changes in the surgical management of patients with breast carcinoma based on preoperative magnetic resonance imaging.

BACKGROUND: Breast magnetic resonance imaging (MRI) is a developing technique for the evaluation of patients with primary breast carcinoma. The authors assessed the impact of preoperative breast MRI on surgical management. METHODS: The current study was a retrospective review of 267 patients with primary breast tumors who had MRI studies prior to undergoing definitive surgery. RESULTS: Two hundred sixty-seven patients with invasive breast carcinoma who had preoperative breast MRI studies and had complete clinical, radiologic, and pathologic data available were identified and formed the basis of this analysis. The overall sensitivity of MRI for detecting primary, intact breast tumors was 95%. Planned surgical management was altered in 69 of 267 patients (26%); and, in 49 of those patients (71%), there was pathologic verification of malignancy in the surgical specimen that confirmed the need for wider or separate excision or mastectomy. Forty-four of 267 patients (16.5%) had conversion of planned breast conservation to mastectomy. In a univariate analysis, change in management was associated significantly with histology; management was altered in 11 of 24 lobular tumors (46%) compared with 58 of 243 ductal tumors (24%; P = 0.02). CONCLUSIONS: Breast MRI was very sensitive for the detection of primary, intact, invasive breast carcinoma and improved local staging in almost 20% of patients. Preoperative breast MRI studies may be particularly useful in surgical planning for and management of patients with lobular carcinoma.