Perez, Edith A.

Purpose It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Results Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). Conclusion In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

Purpose Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials. Initial data of the combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial were reported in 2005. Long-term follow-up results on disease-free survival (DFS) and overall survival (OS) have been awaited. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials. The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis. Results At 3.9 years of median follow-up, there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm (P < .001). Similarly, there continues to be a statistically significant 39% reduction in death rate in favor of the trastuzumab-containing arm (P < .001). Conclusion These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time, with the longest follow-up reported to date. The clinical benefits continue to outweigh the risks of adverse effects.

Abstract Background: In 2007, the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) recommended new guidelines to define HER2 positivity by immunohistochemistry (3+ IHC: uniform intense membrane staining of &gt;30% of invasive tumor cells) or fluorescent in situ hybridization (FISH+: HER2/CEP17 ratio &gt;2.2). The original criteria used for enrollment in the pivotal N9831 trial conducted from 2000-2005 were IHC&gt;10% (3+) or FISH ≥2.0.Purpose: To investigate the impact of the ASCO/CAP guidelines on patient (pt) eligibility and disease free survival (DFS) compared to the originally used FDA-approved definitions.Patients/Methods: This analysis included 2268 patients from the HER2+ N9831 adjuvant trastuzumab phase III trial. IHC was centrally performed at the Mayo Clinic using the DAKO HercepTest™ and was re-analyzed to determine the percent of tumor cells with 0, 1+, 2+, and 3+ staining intensities. DFS was compared between pts randomized to standard chemotherapy +/- concurrent trastuzumab (Arms A and C of the trial) within IHC/FISH subgroups using Cox proportional hazards regression stratified by hormone receptor and nodal status.Results: Based on 2268 pts, 83 pts (3.7%) were 3+ by FDA-approved guidelines but not 3+ by the ASCO/CAP guidelines. Among these pts, 77% (64/83) were FISH amplified centrally by ASCO/CAP guidelines. Only 1.5% (34/2268) of pts eligible under FDA-approved definitions from N9831 in this sample set would not meet the ASCO/CAP guidelines. In 1441 patients randomized to standard chemotherapy +/- concurrent trastuzumab, the exploratory DFS hazard ratio (HR) associated with trastuzumab in IHC/FISH subgroups were as follows: ASCO/CAP HER2+ HR=0.59 (95% CI: 0.47-0.75; p&lt;0.001); FDA-approved HER2+ HR=0.60 (95% CI: 0.47-0.75; p&lt;0.001); ASCO/CAP HER2 normal(not positive) HR=0.74 (95% CI: 0.35-1.57; p=0.43); and FDA-approved HER2 normal HR=0.53 (95% CI: 0.22-1.26; p=0.15).Conclusions: A small percentage (1.5%) of N9831 patients did not meet ASCO/CAP 2007 guidelines when applied retrospectively. Trastuzumab effect appeared similar for HER2+ patients regardless of ASCO/CAP or FDA-approved guidelines. Additional DFS analyses by IHC/FISH subgroups will be presented. We gratefully acknowledge support from the Breast Cancer Research Foundation, Genentech, and NIH CA25224 for this study. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 701.

Abstract Background: Microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves and the binding of paclitaxel to tubulin may lead to neuropathy. Peripheral neuropathy is a common dose limiting toxicity of paclitaxel. We hypothesized that the occurrence of peripheral neuropathy may correlate with outcome (disease-free survival; DFS).Methods: This analysis sought to describe incidence of peripheral neuropathy following paclitaxel and its association to outcome (DFS) in patients who received paclitaxel (weekly x 12) in the adjuvant HER2+ intergroup trial N9831. Only eligible pts who initiated paclitaxel and did not have peripheral neuropathy at initiation of paclitaxel that were randomized to arms A (955 pts; chemotherapy alone) and C (889 pts; chemotherapy plus concurrent trastuzumab) of N9831 were included. Cox regression analysis stratified by ER/PR status and nodal status was used to compare DFS within arm between patients with and without peripheral neuropathy.Results: Out of 1844 eligible pts, 379 developed neuropathy (20.5%). For pts in arm A, those who developed neuropathy had better DFS than pts who did not (3 yr DFS: 86.2% vs 81.8%; HR 0.65; p=0.01), despite lower doses of paclitaxel in the pts with neuropathy. Grade of neuropathy did not appear to impact DFS. No statistical difference was noted for pts treated in the trastuzumab-containing arm (3 yr DFS: 92.8% vs 91.1% for pts with neuropathy vs not; HR 0.79; p=0.34). There were no differences in paclitaxel dose intensity between arms A and C.Conclusion: Patients with early stage HER2+ breast cancer who received adjuvant paclitaxel-containing chemotherapy in arm A and developed peripheral neuropathy had a better DFS than pts who did not develop neuropathy. This effect was possibly abrogated by the use of trastuzumab in Arm C. This side effect may represent effective bindings of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site and/or lack of selective overexpression of β-III tubulin. This is a hypothesis generating study and additional analysis needs to be conducted from other large taxane-based trials.Partial support from Genentech and the Breast Cancer Research Foundation Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2100.

Abstract Long-term outcomes and hence the role of adjuvant therapy in patients with small (≤1 cm), node-negative breast cancer remain unclear. This study's objective was to evaluate whether human epidermal growth factor receptor (HER)-2 status is an independent, poor prognostic marker in patients with these tumors and to identify a subgroup of patients with these small tumors who might benefit from adjuvant systemic therapy. All patients with a diagnosis of a node-negative breast tumor measuring ≤1 cm and available HER-2 test results between January 1, 2001, and December 31, 2005, at the three Mayo Clinic sites were identified. Clinicopathologic data were compared in three groups: HER-2−, HER-2+, and triple-negative (TN) tumors. Of the 421 tumors identified, 364 (86.5%) were HER-2−, 28 (6.7%) were HER-2+, and 29 (6.9%) were TN. The median follow-up time was 1,015 days (range, 1–2,549 days). Groups were balanced in terms of patient age and tumor histology. Eleven patients with HER-2− tumors (3.0%), seven with HER-2+ tumors (25.0%), and eight with TN tumors (27.6%) received adjuvant chemotherapy. Follow-up data were available for 357, 28, and 28 patients in the three groups, respectively. Death rates in the three groups were 6.4% (23 of 357) (one recurrence-related death), 0% (0 of 28), and 7.1% (2 of 28) (one recurrence-related death), respectively. During follow-up, the tumor recurred in nine patients: four were HER-2− tumors (1.1%), two were HER-2+ tumors (7.1%), and three were TN tumors (10.7%). Patients with small, node-negative breast tumors have an excellent prognosis, but HER-2+ and TN tumors appear to have a higher recurrence rate, warranting consideration for broad use and optimization of systemic adjuvant treatments.

AbstractLearning ObjectivesAfter completing this course, the reader will be able to: Describe the potential therapeutic advantages of tyrosine kinase inhibitors (TKIs) over antibody mediated inhibition with trastuzumab, such as oral bioavailability and ability to cross the blood–brain barrier.Explain the ability of TKIs to overcome resistance to and synergize with trastuzumab.Discuss the multiple tyrosine kinase inhibitors currently in development and their spectrum of targets and toxicities.This article is available for continuing medical education credit at CME.TheOncologist.com.HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti–HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood–brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti–HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available.

Abstract Up to one fourth of women diagnosed with early breast cancer (EBC) have tumors that are human epidermal growth factor receptor 2 (HER-2) positive. This is associated with a high risk of relapse and death from meta-static disease. Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER-2, improves survival and quality of life in women with HER-2-positive metastatic breast cancer receiving chemotherapy. Four major adjuvant trials—Herceptin® Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006—including between them &gt;13,000 women with HER-2-positive EBC, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this population. The benefit was similar across the trials despite differences in patient populations, chemotherapy regimens, and sequencing of treatment. At a 2-year follow-up, interim results from the combined analysis of the NSABP B-31 and NCCTG N9831 trials showed a one third lower mortality for trastuzumab, and there was a trend toward an overall survival benefit in the HERA and BCIRG trials. A small Finnish trial, FinHer, investigating another regimen of trastuzumab, has also shown similarly positive results. Further follow-up of the major adjuvant trials will clarify the survival benefit for women receiving trastuzumab, as well as the optimal treatment duration (1 or 2 years). Notably, cardiac events in the trastuzumab-containing arms of these trials have remained within acceptable levels, with a slightly higher (0.6%–3.3%) incidence of congestive heart failure that mostly responded to treatment. Further follow-up will provide information on long-term cardiac safety. Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies.

Purpose This review provides an update on the current understanding of the clinical cardiac tolerability of trastuzumab, a humanized monoclonal antibody effective in the treatment of patients with advanced breast cancer overexpressing or amplifying HER2. Methods and Results We produced a summary of currently available information regarding the incidence and natural history of trastuzumab-associated cardiac dysfunction. Data from new, prospective clinical studies that incorporate close cardiac monitoring and standardized follow-up in patients with either advanced or earlier stages of breast cancer are also presented, and hypotheses regarding potential mechanisms of trastuzumab-related cardiotoxicity are discussed. Patients treated with trastuzumab in the pivotal trials were found to have increased risk for cardiac dysfunction, mostly when used concurrent with anthracyclines. Recent trials have required more stringent and consistent cardiac monitoring criteria and excluded patients with abnormal cardiac function, pre-existing heart disease, and/or high cumulative doses of anthracyclines. Decreases of ejection fraction and a few cases of congestive heart failure (CHF) requiring medical therapy have been detected. Improvements in ejection fraction and the symptoms of CHF have been subsequently noted in a significant number of these patients. Conclusion Trastuzumab is associated with an increased risk of asymptomatic decreases in ejection fraction, and, in a small number of patients, CHF that is almost always responsive to medical management. This risk is greatest in patients receiving concurrent anthracyclines. More data are needed to help elucidate the pathophysiology of this syndrome.