W.R. Miller

Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial

PURPOSE Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively. PATIENTS AND METHODS Postmenopausal patients with estrogen- and/or progesterone receptor-positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria. RESULTS For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P =.004), and fewer patients underwent breast conservation (36%, P =.036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P =.0004). CONCLUSION ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.

Recommendations From an International Expert Panel on the Use of Neoadjuvant (Primary) Systemic Treatment of Operable Breast Cancer: An Update

Neoadjuvant (primary systemic) treatment is the standard treatment for locally advanced breast cancer and a standard option for primary operable disease. Because of new treatments and new understandings of breast cancer, however, recommendations published in 2003 regarding neoadjuvant treatment for operable disease required updating. Therefore, a second international panel of representatives of a number of breast cancer clinical research groups was convened in September 2004 to update these recommendations. As part of this effort, data published to date were reviewed critically and indications for neoadjuvant treatment were newly defined.

Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics

Background Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estrogen receptor–positive (ER+) breast cancer. Methods Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before surgery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer–specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided. Results Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial (P = .002). Conclusions Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy.

The importance of local synthesis of estrogen within the breast.

Tumor aromatase has been correlated with clinical response to treatment with aminoglutethimide in patients with estrogen receptor-positive advanced breast cancer. There was a significant positive relationship between aromatase status and likelihood of response to therapy, none of five patients with aromatase-negative tumors responding compared with 11 of 18 having aromatase-positive cancers. Measurement of in vitro aromatase in sequential biopsies of large primary tumors before and during treatment with aminoglutethimide-hydrocortisone showed a marked but paradoxical rise in activity following therapy. Assays of aromatase in adipose tissue from the different quadrants of mastectomy specimens from patients with breast cancer indicate that activity was always higher in quadrants associated with tumor as compared with non-involved quadrants. These results emphasize the importance of local estrogen synthesis within the breast in terms of both the natural history and behavior of breast cancers.

OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients

OX40 is a potent costimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells. Preclinical studies have shown that OX40 agonists increase antitumor immunity and improve tumor-free survival. In this study, we performed a phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12 of 30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4(+) FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, and increased the antitumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in patients with cancer, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells, and intratumoral regulatory T cells.

The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.

The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole

PURPOSE To investigate the impact of human epidermal growth factor receptor (HER) 1 and HER2 gene amplification on endocrine therapy responsiveness, a fluorescence in situ hybridization (FISH) study was conducted on tumor samples from 305 postmenopausal patients with stage II and III estrogen receptor (ER) -positive (ER > or = 10%) breast cancers treated on two independent neoadjuvant endocrine therapy trials. PATIENTS AND METHODS FISH analysis focused on HER1 and/or HER2 immunohistochemistry (IHC) -positive patients and a random selection of HER1/2 IHC-negative patients. HER2 FISH status was correlated with response and changes in the proliferation marker Ki67. RESULTS HER1 was rarely amplified (< 1%), and HER2 amplification was observed in 9.2% of patients. Letrozole response by clinical measurement (71% HER2 FISH positive v 71% HER2 FISH negative), mammogram (44% HER2 FISH positive v 47% HER2 FISH negative), or ultrasound (47% HER2 FISH positive v 54% HER2 FISH negative) was not impaired by HER2 FISH-positive status. In contrast, HER2 FISH-positive tumors showed higher histologic grade (P = .009), higher pretreatment Ki67 (P = .005), and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors (P = .0001). Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors. CONCLUSION Neoadjuvant letrozole is clinically effective in ER-positive HER2 FISH-positive tumors, indicating sensitivity to short-term estrogen deprivation. However, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive samples (88%) could imply therapeutic resistance that may manifest later in the clinical course of the disease. Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes.

Aromatase activity in breast tissue

Aromatase activity may be detected both in breast adipose tissue and breast cancer in levels similar to or greater than those in other peripheral tissues. Factors influencing such local biosynthesis have been sought. Of 247 primary breast cancers investigated, 178 showed evidence of oestrogen biosynthesis. No significant relationships were found between either the presence or levels of activity and tumour histopathology, patient characteristics (such as age and menopausal status), disease stage and prognosis (determined by disease-free interval and survival after primary treatment). Aromatase was more likely to be found in cellular cancers and those which were oestrogen receptor-positive, but these were not absolute associations, activity being detected in tumours with all degrees of cellularity and both receptor-positive and receptor-negative cancers. However, in a small group of patients with metastatic oestrogen receptor-positive tumours, response to the aromatase inhibitor, aminoglutethimide, seemed confined to tumours with aromatase activity. Oestrogen biosynthesis was detected in all specimens of breast adipose tissue examined. Activities were higher in fat from breast cancer patients compared with that from women with benign breast disease. In breasts with cancer, levels were higher in quadrants bearing tumour compared with those without evidence of malignancy. It is suggested that either enhanced aromatase in breast fat promotes the appearance of overt cancer or tumour factors induce aromatase in surrounding fat. Finally, although no significant correlations were detected in postmenopausal women between local aromatase activity and endogenous oestrogens in breast cancer, perfusion studies show that in situ oestrogen biosynthesis is primarily responsible for oestrogen levels in the majority of breast tissues. These data suggest that local aromatase activity may influence events within the breast and may be associated with the natural history and progression of certain malignancies.

Irinotecan Plus Gemcitabine Induces Both Radiographic and CA 19-9 Tumor Marker Responses in Patients With Previously Untreated Advanced Pancreatic Cancer

PURPOSE This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.