Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes.

BACKGROUND: Epidermal growth factor receptor (EGFR) expression is associated with aggressive phenotypes in preclinical breast cancer models, but in clinical studies, EGFR has been inconsistently linked to poor outcome. We hypothesized that EGFR expression in human breast tumors, when centrally and uniformly assessed, is associated with an aggressive phenotype and resistance to systemic therapy. METHODS: In a database of 47,286 patients with breast cancer, EGFR status was known on 2567 tumors. EGFR levels were measured centrally by ligand binding assay, and tumors with > or =10 fmol/mg were prospectively deemed positive. Clinical and biological features of EGFR-positive and EGFR-negative tumors were compared. Clinical outcomes were assessed by systemic therapy status. RESULTS: Of 2567 tumors, 475 (18%) were EGFR positive. EGFR-positive tumors were more common in younger and in black women, were larger, had a higher S-phase fraction, and were more likely to be aneuploid. EGFR-positive tumors were more likely to be HER2-positive (26% vs 16%, P < .0001), but less likely to be estrogen receptor-positive (60% vs 88%, P < .0001) or progesterone receptor-positive (26% vs 65%, P < .0001). In multivariate analyses, EGFR expression independently correlated with worse disease-free survival (hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.4-2.41, P = .007) and overall survival (HR = 1.98, 95% CI, 1.36-2.88, P = .0004) in treated patients, but not in untreated patients. CONCLUSIONS: EGFR expression is more common in breast tumors in younger and black women. It is associated with lower hormone receptor levels, higher proliferation, genomic instability, and HER2 overexpression. It is correlated with higher risk of relapse in patients receiving adjuvant treatment. Blocking EGFR may improve outcome in selected patients.

Association of surgery with improved survival in stage IV breast cancer patients.

OBJECTIVE: This study aims to examine the role of surgery in patients with stage IV breast cancer. BACKGROUND: Historically, women who present with metastatic breast cancer are not offered surgical treatment. However, recent reports indicate that surgery may improve outcome. Using a large database of women whom presented with stage IV breast cancer, we compared outcome of patients who had resection of their primary cancer to those who did not. METHODS: Of 16,401 patients, 807 had stage IV disease at presentation, and 395 survived >90 days and were included in this analysis. Clinical and tumor characteristics, surgical treatment, and survival were compared for the surgically versus nonsurgically treated patients. RESULTS: Two hundred and forty-two patients (61.3%) had definitive surgery for their primary tumor and 153 (38.7%) did not. Patients who underwent surgery were significantly older, were more likely to be white, more often had hormone receptor positive disease, had small primary tumors, and had fewer metastatic sites and less visceral involvement. The median survival of surgically treated patients was 27.1 months versus 16.8 months for patients without surgical resection (P < 0.0001). In multivariate analysis, which included surgical treatment, age, race, estrogen and progesterone receptor status, number of metastatic sites, and presence of visceral metastases, surgery remained an independent factor associated with improved survival (P = 0.006). CONCLUSION: Patients with stage IV breast cancer who had definitive surgical treatment of their primary tumors had more favorable disease characteristics. However, after adjustment for these characteristics, surgical treatment remained an independent factor associated with improved survival.

Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype.

PURPOSE: Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays. EXPERIMENTAL DESIGN: For gene expression analysis, IBC (n=14) was clinically defined as rapid-onset cancer associated with erythema and skin changes, whereas non-IBC patients (n=20) had stage III breast cancers, and cDNA analysis was carried out using the Affymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from>2,000 non-IBC. RESULTS: Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93% versus 11%; P<0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P<0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P=0.002; progesterone receptor, 68% versus 42%; P=0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different. CONCLUSION: This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.

The adherence to practice guidelines in the assessment of bone health in women with chemotherapy-induced menopause.

Premenopausal women are diagnosed with 25% of all invasive breast cancers;adjuvant chemotherapy given to many of this population may induce menopause and increase the risk of osteoporosis development. Guidelines issued by the American Society of Clinical Oncology recommend regular assessment of bone health in such women. To assess appropriate attention to bone health, we performed a retrospective, cross-sectional survey of young women at high risk of osteoporosis secondary to chemotherapy-induced premature menopause. In all, 102 women with chemotherapy-induced menopause, 75% of whom were 40 years of age or younger, were asked whether they underwent screening and preventive measures for osteoporosis. Only 56% had discussed bone health with their healthcare providers; age at diagnosis, race, and use of tamoxifen were not linked to the likelihood of such discussions. Regular exercise was recommended to 73% of the women, calcium supplementation to 56%, and bone mineral density (BMD) testing to 40%. Approximately one half of the women regularly exercised and took a calcium supplement; however, over 37% of those using a supplement took less calcium than that recommended to prevent osteoporosis. Further, 32% reported having had BMD testing;women 40 years of age or younger were less likely to have had such tests (27%) than were older women (48%;P = 0.05). More emphasis must be given to educating breast cancer survivors with chemotherapy-induced menopause about bone health and its maintenance. Approved therapies to prevent osteoporosis probably are underused in this population.

Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancers.

PURPOSE: In the adjuvant setting, taxanes modestly improve clinical outcome and survival. The goal of the present study was to define the efficacy of neoadjuvant docetaxel in treatment-naïve large, locally advanced breast cancers and to better understand docetaxel's mechanism of action by evaluating biomarker modulation in response to treatment. PATIENTS AND METHODS: Fifty-one patients were enrolled. Patients received four cycles of docetaxel (100 mg/m2 q3weeks) followed by surgery and four cycles of doxorubicin and cyclophosphamide (60/600 mg/m2 q3weeks). Radiation and hormonal therapy were given if clinically indicated. Clinical responses were assessed at completion of neoadjuvant docetaxel. Pathological responses were considered complete (pCR) if no tumor cells were identified in the surgical specimen or near complete (npCR) if only occasional scattered tumor cells were seen. Proliferation (Ki-67) and apoptosis (cleaved caspase-3) were measured by IHC in tissue obtained at baseline and at surgery. RESULTS: The median tumor size was 9 cm (range 4-30 cm). Objective response rate was 75% with clinical complete response in 27%, partial response in 48%, and stable disease in 25% of the patients. pCR/npCR was reported in 20% of patients. With a median follow up of 28 months, 98 and 78% of the patients were alive at 12 and 24 months, respectively. Overall survival at 24 months was significantly better in patients who achieved a clinical response, 85 versus 51%, p = 0.008, but pCR/npCR was not a significant predictor of outcome. Apoptosis was induced in clinical responders (p = 0.002), while the proliferation index did not change significantly. In patients who had no clinical response to docetaxel, neither apoptosis nor proliferation changed significantly. CONCLUSION: Neoadjuvant single agent docetaxel is effective in treating patients with large locally advanced breast cancer and clinical response is associated with improved survival. Docetaxel acts therapeutically by inducing apoptosis and this can be used as a marker of response.

Morphologic and immunophenotypic markers as surrogate endpoints of tamoxifen effect for prevention of breast cancer.

Prevention trials using incidence or mortality as endpoints require a large number of participants and long follow-up. Trials using biomarkers as endpoints would potentially require fewer participants, less time, and significantly less resources to test promising new agents for breast cancer prevention. To test this idea, a randomized trial of tamoxifen for 1 year versus observation for 1 year was conducted to determine whether tamoxifen can cause regression of hyperplastic breast tissue, whether it changes the biomarker phenotype of premalignant disease or normal breast epithelium, and if biomarkers can be used as early surrogate indicators of response to tamoxifen. Women were identified by having an abnormal mammogram and ductal hyperplasia diagnosed by core needle biopsy. Image-directed needle biopsy was repeated in the same site of the breast after 1 year. Approximately 3000 women were screened, and 265 were eligible. Sixty-three women were randomized and paired biopsies from 45 subjects were available for analysis. There was no evidence of substantial regression of hyperplasia--fewer samples showed hyperplasia at 1 year follow-up, but this was seen in both untreated and tamoxifen-treated women. There were trends for reductions in ER and PgR and trends for increases in bcl-2 in normal and hyperplastic tissue in the tamoxifen-treated arm, though these changes did not reach statistical significance. Proliferation, determined by Ki67 staining, was not significantly changed. Clinical trials of this type are difficult to carry out and modifications in trial design are needed to make this process more efficient.

Premalignant and in situ breast disease: biology and clinical implications.

Most types of invasive breast cancer are thought to evolve over long periods from specific preexisting benign lesions. Of the many types of benign entities found in the human breast, only a few have clinically significant premalignant potential. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ. Ductal carcinoma in situ is considered to be a preinvasive malignant lesion. Two additional lesions, unfolded lobules and usual ductal hyperplasia, are sometimes considered to be very early premalignant epithelial abnormalities. Premalignant lesions are currently defined by their histologic features, and not all necessarily progress to invasive cancer. This suggests that although lesions within specific categories look alike, they must possess underlying genetic differences that cause some to remain stable and others to advance. The development of modern molecular genetic techniques has allowed breast cancer researchers to clarify the multistep model of breast carcinogenesis. Recent studies indicate that cancer evolves by highly diverse genetic mechanisms, and research into these altered pathways may identify specific early defects that might be targeted to prevent progression of premalignant lesions to invasive cancer. Current clinical management is heterogeneous and depends on histologic examination and individual patient factors. Options for breast cancer risk reduction and prevention are available.

Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.

BACKGROUND: Clinical data indicate that estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR- breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy. METHODS: Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13,404 patients with ER+/PR- tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11,399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan-Meier analyses, and all statistical tests were two-sided. RESULTS: ER+/PR- tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR- tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P < .001) and 50% more overexpressed HER-2 (21% versus 14%; P < .001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1-expressing tumors than with HER-1-negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR- tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence. CONCLUSIONS: ER+/PR- tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER+/PR+ tumors. As in laboratory models, lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials.

BACKGROUND: Fulvestrant is an estrogen receptor antagonist with no agonist effects. In the second-line treatment of advanced breast carcinoma, fulvestrant was shown previously to be as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to disease progression and objective response rates. The authors reported the overall survival results from these studies. METHODS: A prospectively planned, combined, overall survival analysis was performed, including data from two Phase III trials that compared the efficacy and tolerability of fulvestrant (250 mg monthly; n = 428) with anastrozole (1 mg daily; n = 423) in the treatment of postmenopausal women with advanced breast carcinoma who had disease progression after receipt of previous endocrine treatment. RESULTS: At an extended median follow-up of 27.0 months (range, 0-66.9 months), 319 (74.5%) patients in the fulvestrant group and 322 (76.1%) patients in the anastrozole group had died. Prolonged survival was observed with both drugs, with 10-20% of patients still alive > 5 years after randomization. The median overall survival was similar between treatments, being 27.4 months and 27.7 months in fulvestrant and anastrozole-treated patients, respectively (hazards ratio, 0.98; 95% confidence interval, 0.84-1.15; P = 0.809). Fulvestrant continued to be well tolerated, and was associated with a significantly lower incidence of joint disorders compared with anastrozole (P = 0.0234). CONCLUSIONS: The current analysis showed that fulvestrant was similar to anastrozole with respect to overall survival in the second-line treatment of postmenopausal women with advanced breast carcinoma.

HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study.

PURPOSE: Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen. PATIENTS AND METHODS: Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively. RESULTS: HER-2 amplification was correlated with lower ER (P = 0.02), HER-1 positivity (P = 0.004), and HER-2 protein overexpression (P < 0.00001). The response rate was 56% for HER-2 non-amplified versus 47% for HER-2 amplified tumors (P = 0.38), and 58% for HER-1-negative versus 36% for HER-1-positive (P = 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P = 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P = 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P = 0.08) and median survival was 24 versus 31 months (P = 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P = 0.001) and OS (P = 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P

Lobular neoplasia on core-needle biopsy--clinical significance.

BACKGROUND: Approximately 25% of all cases of atypical ductal hyperplasia (ADH) diagnosed on core biopsy of the breast are associated with ductal carcinoma in situ (DCIS) or invasive malignancy at the same site. As a result, surgical excision has become the standard of care for patients with ADH. In contrast, because data on the relation between breast malignancy and lobular neoplasia (LN) detected on core biopsy are limited, clinical management of patients with LN remains controversial. The goal of the current study was to determine the incidence of breast carcinoma at sites of core biopsy exhibiting LN compared with sites of core biopsy exhibiting ADH. METHODS: The results of 2053 core biopsies were reviewed to identify cases of LN and cases of ADH. Follow-up findings on excisional biopsy were categorized as malignancy (DCIS or invasive malignancy) or no malignancy and were compared between the LN group and the ADH group. Mammograms and medical records were reviewed for patients with atypical findings on core biopsy. RESULTS: One hundred six (5.2%) of 2053 biopsy samples exhibited atypia on core biopsy. Among these 106 samples, ADH was found in 49 (46%), LN was found in 45 (42%), and both ADH and LN were found in 12 (12%). Malignant disease was detected on follow-up excisional biopsy in 22% of patients with ADH (9 of 41), 14% of patients with LN (3 of 21), and 33% of patients with both ADH and LN (4 of 12) on core biopsy. In the LN group, two cases of malignant disease were associated with lobular carcinoma in situ, and the third case was associated with atypical lobular hyperplasia. Mammographic and clinical features were unable to distinguish patients with malignant findings on excisional biopsy from patients without malignant findings. CONCLUSIONS: Malignant disease was found in a substantial percentage of excisional biopsy samples (14%) following the detection of LN on core biopsy. Thus, like patients with ADH, patients with LN on core biopsy could be considered candidates for surgical excision, which would allow full assessment of breast carcinoma risk and thereby facilitate the planning of prevention strategies.

Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome.

INTRODUCTION: Invasive lobular carcinoma (ILC) comprises approximately 10% of breast cancers and appears to have a distinct biology. Because it is less common than infiltrating ductal carcinoma (IDC), few data have been reported that address the biologic features of ILC in the context of their clinical outcome. In the present study we undertook an extensive comparison of ILC and IDC using a large database to provide a more complete and reliable assessment of their biologic phenotypes and clinical behaviors. METHODS: The clinical and biological features of 4140 patients with ILC were compared with those of 45,169 patients with IDC (not otherwise specified). The median follow-up period was 87 months. RESULTS: In comparison with IDC, ILC was significantly more likely to occur in older patients, to be larger in size, to be estrogen and progesterone receptor positive, to have lower S-phase fraction, to be diploid, and to be HER-2, p53, and epidermal growth factor receptor negative. It was more common for ILC than for IDC to metastasize to the gastrointestinal tract and ovary. The incidence of contralateral breast cancer was higher for ILC patients than for IDC patients (20.9% versus 11.2%; P < 0.0001). Breast preservation was modestly less frequent in ILC patients than in IDC patients. The 5-year disease-free survival was 85.7% for ILC and 83.5% for IDC (P = 0.13). The 5-year overall survival was 85.6% for ILC and 84.1% for IDC (P = 0.64). CONCLUSION: Despite the fact that the biologic phenotype of ILC is quite favorable, these patients do not have better clinical outcomes than do patients with IDC. At present, management decisions should be based on individual patient and tumor biologic characteristics, and not on lobular histology.

Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.

PURPOSE: To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer. PATIENTS AND METHODS: Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories. RESULTS: In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P <.0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P <.0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P <.0001). CONCLUSION: When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.

A roundtable discussion of aromatase inhibitors as therapy for breast cancer.

This article summarizes the conclusions of a meeting of diverse breast cancer experts who discussed issues, controversies, and new clinical trial results relevant to the use of aromatase inhibitors for treating postmenopausal women with breast cancer. The new generation of aromatase inhibitors (anastrozole, letrozole, exemestane) have largely replaced megestrol acetate as a second-line therapy in postmenopausal women with hormone-responsive advanced breast cancer. In addition, anastrozole and letrozole have been shown to be superior to tamoxifen for first-line therapy. Finally, recent results suggest that anastrozole may be superior to tamoxifen as adjuvant therapy for early stage disease in postmenopausal women with hormone-responsive disease.

Survival of patients with metastatic breast carcinoma: importance of prognostic markers of the primary tumor.

BACKGROUND: Women with metastatic breast carcinoma have a highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary breast tumor may play a role in this variability and may explain it in part. Therefore, the authors tested the hypothesis that the characteristics of primary breast tumors are important determinants of prognosis and survival in patients with metastatic breast carcinoma. METHODS: The prognostic significance of the biology of the primary tumor for outcome in patients with metastatic breast disease was assessed in 346 patients with lymph node positive breast carcinoma who developed distant, recurrent disease. Traditional prognostic indicators (age, tumor size, number of involved lymph nodes, sites of recurrence, disease free interval [DFI], adjuvant treatments, estrogen receptor [ER] expression, progesterone receptor [PgR] expression, S-phase fraction [SPF], and DNA ploidy), together with three newer biologic markers (c-erbB-2, p53, and bcl-2) were assessed. Sites of recurrence were defined as nonvisceral (bone and locoregional lymph nodes) or visceral (lung, liver, brain, and other organs). RESULTS: The median duration of survival was 17.8 months (95% confidence interval, 15.2-21.5 months). Univariate analysis showed that age > 50 years, visceral disease, and shorter DFI were associated significantly with poor outcome (P < 0.05). In addition, the molecular phenotype of the primary breast tumor was significant, with primary tumors that showed ER negativity and PgR negativity, high SPF, aneuploidy, accumulation of p53 protein, and lower bcl-2 expression, together with c-erbB-2 overexpression, all associated with a poorer clinical outcome (P < 0.05). In a multivariate analysis, older age, visceral disease, shorter DFI, PgR negativity, high SPF, and lower bcl-2 expression were significant predictors of worse survival (P < 0.05). CONCLUSIONS: In addition to traditional risk factors, bcl-2 negativity was associated significantly with a worse clinical outcome. Biologic features of primary tumors were correlated independently with outcome after first recurrence in patients with metastatic breast carcinoma and may be used as indicators of prognosis in the metastatic setting.

Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results.

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.

Adenoid cystic carcinoma of the breast: molecular markers, treatment, and clinical outcome.

BACKGROUND: The objective of this study was to comprehensively characterize the clinical and biologic features of adenoid cystic carcinoma (ACC) and to assess the implications for management in a large cohort of patients. METHODS: From a database of 50,000 patients, 28 were identified with ACC for which clinical follow-up and biologic information was available. The biologic features examined included estrogen receptor and progesterone receptor status, DNA ploidy, and S-phase fraction. Median follow-up was 83 months with a range of 29 to 144 months. Overall survival and disease free survival curves were drawn using Kaplan and Meier estimates and were compared by the log-rank test. RESULTS: All but one patient were postmenopausal with a median age at diagnosis of 66 years (range, 40-96 years). One patient had macroscopic metastatic disease at diagnosis. Median tumor size was 1.9 cm (range, 0.5-7.0 cm). Axillary lymph node dissection was performed in 23 patients. Only 1 patient (4%) had histologic positive lymph nodes (2 of 10), and no recurrence was detected for this patient. Forty-six percent were ER positive (median, 16 fmol/mg protein; range, 5-1017 fmol/mg), and 35% were PgR positive (median, 61 fmol/mg protein; range, 6-854 fmol/mg). S-phase fraction and DNA ploidy were assessable in 24 cases. Ninety percent of tumors had low S-phase (median, 3.3%; range, 0.1-34.2%), and 92% were diploid. Simple or modified radical mastectomy was performed in 22 patients, and 6 patients were treated by lumpectomy. Five of these six patients also received radiation therapy after lumpectomy. Despite the different surgical approaches, there were no local recurrences. The 5-year disease free survival rate was 100%, and the 5-year overall survival rate was 85% (95% confidence interval, 71.7-98.6%). CONCLUSIONS: Adenoid cystic carcinomas of the breast have very favorable biologic characteristics and, consistent with this, an excellent prognosis. Good local control can be achieved by lumpectomy with radiation or by simple mastectomy. Axillary lymph node dissection is not helpful in clinical management.