Israel Medical Association Journal

Background: The current methods for pre‑ and post‑chemotherapy examination of the extent of disease in the breast and lymph nodes do not provide sufficiently accurate information and, not infrequently, the surgeon has to re‑operate.

Objectives: To correlate the findings between three methods of examination (physical examination, ultrasonography, mammography), all performed by the same oncologic and radiologic team, in patients with locally advanced breast cancer or a tumor/breast tissue ratio that precludes breast-conserving surgery.

Methods: Forty patients (median age 48 years, range 24–73) with locally advanced breast cancer or with a tumor/breast ratio that precluded breast‑conserving surgery were evaluated by the same medical team and received neoadjuvant chemotherapy. Surgery was performed in all, and the pathologic specimen was correlated with the results of the other examinations.

Results: In the pre‑chemotherapy evaluation, the imaging findings of the breast correlated with the physical findings in 78% of the patients and with the axilla examination in 66.7%. In the post‑chemotherapy analysis, imaging agreed with the physical findings of the breast in 62.2% and in 76.3% of the axilla. Sonography best detected occult breast disease and axillary lymph nodes but correlated with pathology in only 58% of the patients in diagnosing breast tumor and in 65.8% in diagnosing axillary lymph nodes. Mammography correlated with breast and lymph node pathology in half the patients.

Conclusions: None of the classical methods of post‑neoadjuvant chemotherapy evaluations could adequately delineate the actual extent of the disease in the breast and axillary lymph nodes. More exacting techniques of imaging combined with the classical methods are required.

Objectives: To establish the impact of breast MRI on women undergoing testing in our institution.

Methods: We analyzed 82 cases that underwent MRI between January 2001 and April 2003. Analysis appraised the clinical impact of MRI testing in cases where medical summaries were available.

Results: Studies were categorized into five indications: a) screening in high risk women (n=7), b) search for primary disease in the presence of disease (n=5), c) monitoring of chemotherapy (n=2), d) postoperative assessment of tumor bed (n=9), and e) diagnostic/characterization of primary or recurrent breast cancer (n=59). Results were defined as negative, positive or no impact on clinical management. MRI testing had a positive impact in 62 cases, affecting measurable change in 9 cases. Benefit was seen in screening, diagnosis and postoperative cases. In 15 cases, MRI stimulated investigations.

Conclusion: MRI is a valuable tool in breast imaging and affects management. Further trials are necessary to define clearly the role of MRI and to ascertain whether in cases where beneficial impact on management is noted, there is ultimate impact on outcome. 

Objectives: To examine the effect of postoperative loco-regional radiotherapy on local and regional recurrence and survival in breast cancer patients with four or more involved lymph nodes or extracapsular tumor extension.

Methods: This controlled clinical trial included 258 breast cancer patients with four or more involved nodes or ECE[1]. Eighty-nine patients in the control group had modified radical mastectomy and received adjuvant chemotherapy with melphalan and 5FU, but no radiation therapy. The 169 patients in the study group (87 with MRM[2] and 82 with lumpectomy and axillary dissection) received various adjuvant chemotherapy regimes and radiation therapy to the chest wall/breast, supraclavicular region and full axilla.

Results: With an average follow-up of more than 5 years, loco-regional radiation significantly reduced local and regional disease recurrence. The median disease-free survival was significantly longer in radiated patients (59.2 months and 63.3 months in the MRM and L+AXLND[3] groups, respectively, vs. 28.4 months in the control group; P < 0.01). There was no difference in the rate of systemic recurrence and overall survival. The median overall survival was 71.2 and 67.5 months in the study groups (MRM and L+AXLND, respectively) and 70.5 months in the control group (P = 0.856).

Conclusions: Radiotherapy to the breast/chest wall and to the draining lymphatics, in addition to surgery and adjuvant therapy, significantly reduced the risk of local and regional recurrence in high risk breast cancer patients with four or more involved lymph nodes or ECE.

Israel has a National Screening Program for early detection of breast cancer. The need to continue and even expand this program was recently stressed in light of the high risk in the population. However, the optimal modalities for breast cancer screening are controversial, especially for women at risk. Mammography, the established screening method, is critically examined, and molecular imaging techniques, such as magnetic resonance spectroscopy and spectroscopic imaging are explored, especially for primary breast cancer detection. MRS[1] and MRSI[2] are currently limited by their reliance on the conventional framework for data analysis in biomedical imaging, i.e., the fast Fourier transform. Recent mathematical advances in signal processing via the fast Pade transform can extract diagnostically important information, which until now has been unavailable with in vivo MRS. A clinical MRS signal illustrates the rapid and stable convergence provided by FPT[3], yielding accurate information about key metabolites and their concentrations at short acquisition times. We suggest that the next step would be to apply the FPT to in vivo MRS/MRSI signals from patients with breast cancer and to compare these to findings for normal breast tissue. The potential implications of such an optimized MRS/MRSI for breast cancer screening strategies are discussed, especially for younger women at high risk.

Background: Hyperthermia combined with radiation therapy was shown to be more effective in local recurrent breast cancer than radiotherapy alone, but it use is limited due to technical difficulties, stringent reimbursement policies and because it is time consuming.

Objectives: To report our experience with a simple and convenient XRT+HT[1] delivery system.

Methods: XRT was delivered through either electron or photon beams (total dose 30–40 Gy in previously irradiated fields or 50–70 Gy in non-irradiated fields). Hyperthermia was delivered by a dedicated HT device operating at 915 MHz. The heating session lasted 45 minutes. The maximal tumor surface temperature was set at 45°C and modified according to patient comfort. No intratumoral (invasive) thermometry was used. At least two HT sessions were scheduled to each HT field during the entire XRT treatment period. Tumor response was evaluated every 3 months after completion of treatment. The overall survival was measured from XRT+HT initiation until the last follow‑up.

Results: Fifteen women underwent 114 HT treatments delivered through 28 HT fields. Twenty-four HT fields (15 patients) were previously irradiated. There was complete infield response in 10 fields (6 patients), partial response in 8 fields (4 patients), no response or progressive disease in 4 fields (3 patients), and no parameters in 6 fields (5 patients). Eighteen (64%) fields had complete or partial response. Seven patients had outfield recurrence despite wide XRT+HT fields. Ulceration was the only major side effect (three patients, three fields).

Conclusions: The combined HT+XRT delivery system, with no invasive thermometry, is a simple and effective method for treating local recurrent breast cancer.

Background: Major efforts are being directed at the early diagnosis of breast cancer. The diagnosis rate of non-palpable tumors is steadily growing as a result of increased screening by mammography. In most patients with non-palpable lesions, percutaneous image-guided biopsies have replaced wire localization with surgical excision for obtaining tissue diagnosis. In recent years the Israel Ministry of Health initiated a mammograpy screening program. Percutaneous image-guided biopsies have also become widely available.

Objective: To assess the impact of these changes on breast cancer surgical treatment in our hospital.

Methods: The charts of 483 patients operated on in our department for primary breast carcinoma during the years 1997 to mid-2001 were reviewed. Data on the mode of diagnosis, tumor stage, resection margins, and number and types of operations were recorded and analyzed. The term non-palpable tumors relates to tumors necessitating wire localization for surgical excision.

Results: The percentage of patients diagnosed with non-palpable tumors rose from 16.2% in 1997 to 47.4% in 2001, with an average size of 2.6 cm for palpable and 1.7 cm for non-palpable tumors. The rate of preoperative diagnosis for non-palpable tumors rose from 6.2% in 1997 to 96.4% in 2001. The rate of involved or very close margins was reduced by 73% in the patient group diagnosed preoperatively as compared to those without a preoperative diagnosis (10.6% vs. 39.4%). Finally, the percentage of patients who had two operations fell from 56.2% in 1997 to 11.1% in 2001.

Conclusions: The mammography screening program in Jerusalem in 1997–2001 was effective in increasing the relative percentage of non-palpable breast cancers with reduced tumor size at diagnosis. The improved availability of preoperative tissue diagnosis in these patients reduced the number of surgical procedures needed.

Background: Drains are inserted in the dissected axilla of most patients during surgery for breast cancer.

Objective: To evaluate the presence and prognostic value of MUC1 and Met-HGF/SF in the axillary drainage of these patients.

Methods: The study group included 40 consecutive patients with invasive ductal carcinoma of the breast who were suitable for breast-conserving treatment; 20 malignant melanoma patients found to have negative axillary sentinel lymph node served as the control group. The output of the drains, which had been placed in the axilla during operation, was collected, and the presence of MUC1, Met-hepatocyte growth factor/scatter factor and b-actin were assessed in the lymphatic fluid by reverse transcription-polymerase chain reaction assays. The data were compared to the pathologic features of the tumor and the axillary lymph nodes, and to the estrogen and progesterone receptors status.

Results: RT-PCR[1] assays of the axillary lymphatic drainage were positive for MUC1 and Met-HGF/SF[2] in 15 (37.5%) and 26 (65%) of the patients, respectively. Patients in whom MUC1 and Met-HGF/SF were not found in the axillary fluid had smaller tumors and less capillary and lymphatic invasion, compared to patients with positive assays (P < 0.02 for all these comparisons). The lymph nodes were negative for metastases in all patients with negative assays (P < 0.001). The presence of MUC1 and Met-HGF/SF showed negative correlations with the estrogen and progesterone receptors (P < 0.05).

Conclusion: MUC1 and Met-HGF/SF can be detected in the axillary fluids of patients with breast cancer. The expression of both tumor markers in the axillary drainage is strongly associated with unfavorable tumor features and can be used as a prognostic factor.

Background: The histologic status of axillary lymph nodes is one of the most important prognostic factors in breast cancer, influencing the management of these patients. Axillary lymph node dissection was traditionally performed in all patients to obtain this information but this procedure carries a considerable rate of complications. Recently, sentinel lymph node biopsy has emerged as an accurate and minimally invasive tool for predicting the axillary nodal status and has become the standard of care in selected patients with breast cancer.

Objective: To examine the accuracy of SLN[1] biopsies performed by surgical residents during surgical resident training.

Methods: This prospective, randomized controlled study included 100 consecutive patients with clinically early breast cancer (T1-T2, N0, M0) study. Lymphatic mapping was performed using radiotracers, blue dye, or both. Formal axillary lymph node dissection completed the operations in all patients. All operations were performed by surgical residents under the supervision of senior surgeons.

Results: The overall rate of identification of sentinel lymph nodes was 92%. The accuracy of SLN biopsy in reflecting the axillary nodal status was 96% with a false negative rate of 5.7%.

Conclusions: Sentinel lymph node biopsy is an accurate method for the evaluation and staging of regional lymph nodes in breast cancer patients. A dedicated instruction program for surgical residents may increase the standard of care and lead to highly trained surgeons in the management of early breast cancer.

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Background: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients.

Objective: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls.

Methods: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212-sporadic and 56 carriers of either a BRCA1:or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent auloradiography,

Results: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only {3/536, 0.6%).

Conclusions: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.
 

Background: Recent years have brought significant progress to the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, among which is the new non-steroidal aromatase inhibitor, anastrozole, introduced for clinical use in Israel in March 1997.

Objectives: To evaluate the response rate and survival duration of patients treated with anastrozole for metastatic breast cancer, who had previously received at least one line of hormonal therapy.

Methods: Anastrozole was administered to 37 patients with metastatic breast cancer. The median age was 64 years. Estrogen receptor was positive in 20 patients, negative in 10 and unknown in 7. All patients were previously treated with tamoxifen in the adjuvant setting or as first-line hormonal therapy for metastatic disease. Anastrozole was given orally, 1 mg/day. Response was evaluated 2 months after the initiation of treatment and reevaluated every 2 months. Therapy was given until disease progression. Ten ER[1]-negative patients were excluded from the final analysis.

Results: Twenty-seven patients were eligible for response and toxicity analysis. The median follow-up was 20 months. One patient (3.7%) achieved complete response and remains free of disease 28 months after start of therapy. No partial responses were seen. Twenty patients (74%) had stable disease. Two year actuarial survival was 57%. Median survival was 26.5 months after starting therapy and median progression free survival was 11 months. The toxicity was mild: one patient (3.7%) complained of weight gain and one patient (3.7%) had mild fatigue.

Conclusion: Although the response rate was low, hormonal therapy with anastrozole seems to be beneficial in terms of disease stabilization, freedom from progression, and overall survival without serious toxicity.  

Background: Fibroadema, one of the most common benign breast lesions, has a characteristic age-specific incidence and is associated with other pathological entities in 50% of cases. The clinical or imaging diagnosis of fibroadenoma may be erroneous, and in some cases is found to be invasive cancer. The clustering of such entities, their correlation with age, and the risk of synchronous breast malignancy are uncertain.

Objective: To explore the possibility of any sigficant clustering of fibroadenoma-associated benign breast disease and to assess the possible risk of concomitant breast cancer.

Method: We analyzed the pathological results of 147 women undergoing excisional biopsies for fibroadenoma diagnosed pre-operatively either by clinical examination and imaging (n=117) or by radiology alone (n=30). The inter-relationships among all entities associated with fibroadenoma were studies by hierarchial cluster analysis. The correlation of the various pathologies with the risk of invasive breast cancer in relation to the patient’s age was also evaluated.

Results: Fibroadema-associated pathologies were found in 48% of the cases: sclerosing adenosis (23%), duct ectasia (17/7%), apocrine metaplasia (15.6%), florid fibrocystic disease (12.9%), duct papillomatosis (11.6%), infiltrating duct carcinoma (5.4%), duct carcinoma in situ (3.4%), and 1 case of lobular carcinoma in situ (0.6%). An orderly internal hierarchy and three significant clusters emerged: a) epithelial apocrine metaplasia, duct ectasia and sclerosing adenosis (similarity coefficients 16.0, 11.0 and 8.0 respectively); b) papillomatosis, florid fibrocystic disease and calcifications (similarity coefficients of 6.0, 4.0 and 2.0 respectively); and c) infiltrating duct carcinoma in situ (similarity coefficients of 1.8 and 1.6 respectively). Seven of the eight patients with breast cancer were older than 40 years.

Conclusions: In about half of the cases fibroadema was associated with other pathological entities clustered in an orderly hierarchy. The rarity of synchronous breast cancer in the younger age group and its more common association with fibroadema in the older age groups dictate a different approach to each. The finding of fibroadema in women older than 40 indicates the need for surgical excision.
 

Background: Breast cancer is one of the most prevalent malignancies in women, yet one of the most treatable. Early detection is essential to obtain the desired remission and longevity. Numerous studies have shown that periodic screen­ing for breast cancer can reduce mortality by 20-30%.

Objective: To assess the rates, compliance, character­istics as well as barriers in women regarding mammography screening.

Methods: The study group comprised a random sample of 702 women aged 50 or older from 5914 eligible women in two teaching clinics in southern Israel. Phone interviews using structured questionnaires were conducted.

Results: The mean age of the study population was 61 years. The vast majority of the women were not born in Israel. Sixty-three percent of the women had undergone a mammo­graphy screening, 48% in the past 2 years. Monthly self-breast examinations were performed by 12% of the women in the last 2 years. Significant factors associated with undergoing mammography were: more than 7 years since immigration, married, a higher education level, adequate knowledge about breast cancer and mammography, presence of past or current cancer, and cancer in relatives. The main reasons for not being screened was no referral (54%) and a lack of knowledge about breast cancer and mammography (19%) - conditions easily remedied by physician counseling.

Conclusion: The study suggests that promotional efforts should be concentrated on new immigrants and on less educated and unmarried women.