Gabriel N. Hortobagyi

Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease.

PURPOSEnThe Truquant BR radioimmunoassay (RIA) (Biomira Diagnostics Inc, Rexdale, Canada) uses the monoclonal antibody B27.29 to quantitate the MUC-1 gene product (CA 27.29 antigen) in serum. We evaluated CA 27.29 antigen in a controlled, prospective clinical trial for its ability to predict relapse in stage II and stage III breast cancer patients.nnnPATIENTS AND METHODSnOver a 2-year period, 166 patients who had completed therapy for stage II (80.1%) or III (19.9%) breast cancer and were clinically free of disease were serially tested for CA 27.29 antigen levels. The study was double-masked and cancer recurrence was documented based on clinical findings. Patients with two consecutive CA 27.29 antigen test results above the upper limit of normal were considered positive.nnnRESULTSnThe Truquant BR RIA had a sensitivity of 57.7%, specificity of 97.9%, positive predictive value of 83.3%, and negative predictive value of 92.6%. The recurrence rate was 15.7%. A Cox regression analysis showed that the only variable to correlate with recurrent disease was the CA 27.29 antigen test result. Patients with a positive test result had increased odds of having a recurrence (odds ratio, 6.8; P < .00001). The test was effective in predicting recurrence in patients with both distant and locoregional disease. In a subgroup of patients with bone pain, CA 27.29 antigen level was found to identify reliably patients who would subsequently develop recurrent disease.nnnCONCLUSIONnThese data demonstrate that the Truquant BR RIA can be used as an aid to predict recurrent breast cancer in patients with stage II and III disease.

What is the prognosis of patients with operable breast cancer (BC) five years after diagnosis

585 Background: Recent publications suggested that extended adjuvant systemic therapy (AST) started 5 years after diagnosis following standard adjuvant therapy further reduced risk of recurrence. Residual risk of recurrence 5 years after state-of-the-art adjuvant therapy is not well defined.nnnMETHODSnWe identified all patients (pts) treated on prospective clinical trials of AST at our institution between 4/74 and 7/98 and who remained without recurrence 5 years after diagnosis. All received postoperative anthracycline-based AST and endocrine therapy when indicated. 5 and 10-year relapse-free survival (RFS) rates were calculated.nnnRESULTSn2246 pts were registered on 6 AST trials. 839 pts were excluded because of relapse during first 5 years, follow-up < 5years or death without recurrence. The 1407 patients relapse-free at 5 years had a median follow-up of 74 months from the 5th anniversary of diagnosis. 101 had stage I BC, 1104 stage II and 202 stage III; 823 were younger than age 50. 407 had ER/PR-negative BC; 706 had ER or PR+ tumors. RFS rates 5 and 10 years after the 5th anniversary (10 and 15 years from diagnosis) are shown on the table: [Figure: see text] Conclusions: Pts with all Stages of primary BC have substantial residual risk of relapse following completion of AST and would benefit from additional risk reduction. Additional analysis of larger databases of pts with stage Ia and Ib BC would help in calculating benefit from extended AST. No significant financial relationships to disclose.

Expression of CXCR4 predicts lymph node metastasis in early breast cancer

9525 Background: Recent experimental studies have suggested that interactions between the chemokine receptor CXCR4 and its ligand CXCL12 in host organs may play a role in breast cancer progression. There is currently no data if CXCR4 expression is associated with metastatic potential in early breast cancer. Therefore, we studied the differential expression of CXCR4 in small size lymph node positive and lymph node negative breast cancers to evaluate whether CXCR4 predicts metastasis to axillary lymph nodes.nnnMETHODSnCXCR4 expression was evaluated on paraffin-embedded tissue sections obtained from patients with T1N0 (n=98) and T1N1 (n=99) breast cancer, using immunohistochemical staining. The intensity, staining percentage, and localization pattern (nuclear, cytoplasmic) were assessed, and positivity was categorized as follows: high cytoplasmic only versus others, and predominantly nuclear versus others. The expression patterns were correlated with lymph node status, and with other prognostic markers including ER/PR, bcl-2, HER2/neu and EGFR. Chi-square or Fishers exact tests were used in categorical analyses.nnnRESULTSnHigh cytoplasmic only staining pattern was associated with increased lymph node metastasis (4% in T1N0 versus 13% in T1N1; p=0.04). In contrast, predominantly nuclear staining pattern was more frequently observed in lymph node negative patients (55% in T1N0 versus 36% in T1N1, p=0.008). Increased bcl-2 expression, previously reported as a good prognostic marker, was also more common in tumors that expressed predominantly nuclear CXCR4 compared to tumors with other staining patterns (74% vs 61%, respectively, p= 0.04). No significant correlation was identified between staining patterns of CXCR4, and ER/PR, HER2/neu or EGFR expression.nnnCONCLUSIONnThe different staining pattern of CXCR4 (nuclear versus cytoplasmic) appears to have different biological significance for metastatic potential of breast cancer. CXCR4 expression may be a useful marker to predict lymph node metastasis in early breast cancer. No significant financial relationships to disclose.

A phase II trial of PS-341 in metastatic breast cancer (MBC)

3102 Background: The ubiquitin proteasome pathway plays an important role in cell cycle regulation, cancer growth and metastases representing a novel target for therapy. PS-341 (Bortezomib -Velcade) is a depeptidyl boronic acid inhibitor with high specificity for the proteasome and represents the first agent of this class approved for treatment of hematologic neoplasms. We initiated a Phase 2 single Institution trial testing PS-341 in minimally pretreated metastatic breast cancer (MBC).nnnMETHODSnTwelve patients (pts) with minimally treated (1 previous regimen) measurable disease were enrolled and treated with PS-341 at 1.5mg/m2 intravenously bi-weekly for 2 consecutive weeks in a 21-day cycle. Pts. were evaluated clinically every 3 weeks to assess toxicity. Correlative studies include: level of 20-S proteasome activity in whole blood lysate before and after 1 hour of administration of the first dose (expressed as specific chymotryptic activity, SpA). Additionally we plan for evaluation of angiogenic and inflammatory cytokines (IL-12p70, TNF-α, IL-6, IL-1B, IL-8).nnnRESULTSnTen pts are evaluable, 1 died early from disease complications and 1 is still on treatment. The median age was 54 years, (range 30-72 years). Nine pts had predominant visceral disease. 20-S proteasome inhibition compared to the pre-dose administration was documented in all cases. The median number of cycles of PS-341 was 2 cycles, (range 1-5 cycles). There were 1 stable disease (SD) and 9 progressive diseases (PD). The median time-to progression (TTP) was 47 days (range 17-110 days). The most common Grade 3-4 toxicities included: fatigue 70% (n=7) and skin rash 40% (n=4). The median time of onset of the skin rash was 11 days (range 10-27 days).nnnCONCLUSIONSnPS-341 inhibits 20S-proteasome in pts with MBC. Administered in this schedule seems to have an acceptable tolerance, but little activity. The role of this agent in the management of breast cancer should be explored using combination with cytotoxics or other biological agents. No significant financial relationships to disclose.

18. Carcinosarcoma of the Breast

The book is designed to help clinicians manage the treatment of uncommon cancers, for which, in many instances, there are few established guidelines for care. No longer does each new presentation of an uncommon cancer require extended periods of research. This unique and well-established book provides balanced, authoritative, and now, wherever possible, evidence-based guidance on how to address each malignancy.

Body mass index (BMI) is a predictor for response to neoadjuvant chemotherapy in women with localized breast cancer aged 35 years or younger

600 Objective: High BMI has been linked to poor outcome in patients with breast cancer. Evidence relating to obesity as a predictor for prognosis in premenopausal patients have been controversial. The aim of this study is to evaluate the impact of BMI on response to treatment and recurrence following neoadjuvant CT in young patients with breast cancer.> Method: In this study, we analyzed the impact of BMI on the outcome of 111 patients who received anthracycline and/or taxane-based neoadjuvant CT for localized breast cancer. Median age at diagnosis was 32 (22-35). Fifty six patients (50.5%) had stage II and 54 had stage III disease. Hormonal receptors were positive in 65 patients (58.6%) and HER-2/neu was overexpressed in 29 patients (26.1%). Pathologic evaluation revealed that 27 patients had (24.3%) had downstaging in axillary LN, while 13 (11.7%) showed complete regression both in the primary tumor and axillary LN following completion of chemotherapy. Patients were grouped in quartiles of BMI calculated prior to initiation of chemotherapy. >Results: After a median follow-up period of 26 months (3-94), 39 patients experienced recurrence (35.1%). Median overall (OS) and progression-free (PFS) survival rates at 5 years were 62.6 %±9.7 and 38.6%±8.1, respectively.Multivariate Cox regression analysis revealed pathologic response (OR:2.3, p=0.04) and recurrence (OR:108.7, p:0.047) as significant independent prognostic factors for PFS and OS, respectively. Lowest BMI quartile was significantly associated with lack of pathologic response to neoadjuvant chemotherapy compared to those with a larger body size (OR: 3.9, p=0.009).nnnCONCLUSIONnObesity did not correlate with prognosis in young, premenopausal women with early breast cancer. However, patients within the lowest BMI quartile were less likely to respond to neoadjuvant anthracycline or taxane-based chemotherapy. Unresponsiveness to CT may account for the poor outcome in young premenopausal patients compared to older patients. The role of BMI on the outcome of this subset of patients should be validated further by larger prospective studies. No significant financial relationships to disclose.

Textbook of Uncommon Cancer

The book is designed to help clinicians manage the treatment of uncommon cancers, for which, in many instances, there are few established guidelines for care. No longer does each new presentation of an uncommon cancer require extended periods of research. This unique and well-established book provides balanced, authoritative, and now, wherever possible, evidence-based guidance on how to address each malignancy.

Clinical significance of metastatic-tumor HER2 status in patients with HER2-positive primary breast cancer.

545 Background: Studies have suggested that trastuzumab may convert HER2-positive (HER+) primary breast tumors to HER2-negative (HER2-). Whether this conversion happens between primary and metastatic lesions is unknown. We tested the hypothesis that trastuzumab increases the number of patients with HER2+ primary tumors and HER2- metastases (HER2 discordance). We assessed the same effect of chemotherapy. We also compared overall survival (OS) durations of patients with HER2 discordance and patients with HER2 concordance (ie, HER2+ primary and metastatic tumors).nnnMETHODSnWe retrospectively identified 182 patients who had been diagnosed with HER2+ (IHC 3+ and/or FISH+) primary breast cancer in 1997-2008 at MD Anderson Cancer Center and had known HER2 status of the metastasis. Median follow-up was 18 (1-90) months. OS rates were determined using the log-rank test and Cox proportional regression models.nnnRESULTSnOf 182 patients with HER2+ primary tumors, 43 (24%) had HER2- metastases (discordance). Of 76 patients who received trastuzumab before their metastasis biopsies, 15 (20%) had HER2 discordance. Similarly, of 106 patients who did not receive trastuzumab before their metastasis biopsies, 28 (26%) had discordance. There was no significant difference in discordance rates based on trastuzumab (P = .296). However, discordance rates differed significantly based on chemotherapy (P = .022); 39 (27%) of 142 patients who received chemotherapy (with or without trastuzumab) before their metastasis biopsies had discordance, compared with 4 (10%) of 40 patients who did not receive chemotherapy. Patients with HER2 discordance had shorter OS than patients with HER2 concordance (hazard ratio = .43; P= .003). A survival difference remained among the 67 patients who received trastuzumab before their metastasis biopsies (hazard ratio = .56; P = .083).nnnCONCLUSIONSnOne-fourth of primary HER2+ breast cancers converted to HER2-. Our hypothesis was rejected; trastuzumab did not affect discordance rate, although chemotherapy did. Patients with HER2 discordance had poorer prognoses than those with concordance. A prospective study is warranted to determine whether HER2 discordance affects prognosis and treatment.

Neoadjuvant Systemic Therapy for Breast Cancer

Neoadjuvant systemic therapy is defined as the first systemic treatment a patient receives after cancer is diagnosed, and the term indicates that subsequent therapies are intended. Other terms used in clinical practice that involve this concept are preoperative, induction, or primary systemic therapy. This chapter provides an overview of the general benefits of and common regimens used as neoadjuvant therapy in breast cancer

Effects of ethnicity on genotype-phenotype correlations in individuals with a BRCA1 or BRCA2 mutation.

6060 Background: Genotype-phenotype correlations have yet to be established of know BRCA1/2 mutations. A recent study found that mutations in BRCA1 were most frequently located in exons 2, 11, 13, 20, and mutations in exon 2 had lower penetrance comparatively. However, no study has examined the influence of ethnicity. The study aim was to evaluate the influences of ethnicity on mutation location. Methods: Women who were evaluated in the Clinical Cancer Genetics Program and were found to have a deleterious BRCA1 or BRCA2 mutation were included in the study. BRCA1 and BRCA2 mutation location and self-reported ethnicity were obtained through a retrospective review of a prospectively maintained research database. Results: Of 443 women identified, 250 (56.4%) had a BRCA1 mutation and 193 (43.6%) had a BRCA2 mutation. The most common ethnicities identified in this population were as follows: 297 (67%) were non-Ashkenazi Jewish European including women of Caucasian ancestry, 58 (13.1%) were Ashkenazi Jewish, 32 ...