Erin M. Olson

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab

BACKGROUND Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. METHODS Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. RESULTS A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. CONCLUSIONS Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.

Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era.

BACKGROUND Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. METHODS 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan-Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. RESULTS Median OS was 3.5 years (95% CI 3.0-4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1-5.9, liver/lung: 3.2 years CI 2.5-4.2, other: 4.6 years CI 2.7-8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. CONCLUSIONS The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.

The ethical use of mandatory research biopsies

Increasingly, clinical trials incorporate translational research questions aimed at identifying biomarkers of response or resistance to agents under investigation. Biomarker assays can require tissue samples to be collected through a research biopsy before therapy, during treatment, or at the time of tumor progression. Such biopsy samples will generally not provide a direct benefit to the patient and, given the risks associated with any surgical procedure, ethical concerns have been raised when the participants enrollment on a clinical trial depends on their consent to undergo a research biopsy. In this Perspectives article, we present the rationale for mandatory research biopsies and offer suggestions for standardization to ensure that high-quality, patient-centered, clinical trials continue to be designed with scientific and ethical rigor.

Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer

BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.BACKGROUND Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). PATIENTS AND METHODS We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates. RESULTS We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. CONCLUSIONS In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

Maximizing Human Epidermal Growth Factor Receptor 2 Inhibition: A New Oncologic Paradigm in the Era of Targeted Therapy

ERBB2 (HER2) amplification in breast cancer is a classic example of oncogene addiction in solid tumor oncology; most human epidermal growth factor receptor 2 (HER2) –positive tumors exhibit dependency on signaling pathways downstream of the HER2 receptor tyrosine kinase, even after developing resistance to anti-HER2 drugs. Trastuzumab is a monoclonal antibody that inhibits HER2 and demonstrates efficacy in both treatment-naive patients and those who progress after a prior trastuzumab-based regimen. Serial administration of anti-HER2 therapies in clinical practice has dramatically altered the natural course of HER2positive breast cancer. Previously considered to have a worse prognosis, women with HER2-amplified breast cancer who receive trastuzumab now experience survival outcomes similar to those with HER2-negative disease. Furthermore, recent studies suggest that dual HER2 inhibition (the administration of two anti-HER2 therapeutics simultaneously) may induce more durable tumor responses than sequential HER2-specific monotherapy. In Journal of Clinical Oncology, Cortes et al demonstrate the value of persistent HER2 blockade by reporting a clinical benefit rate of 41.2% after combined treatment with the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in patients with evidence of disease progression while receiving either of the two agents alone. This noteworthy observation suggests that the traditional oncologic paradigm—in which most drugs are used only once and discontinued permanently at the first sign of progression—may require modification in the era of targeted therapy. HER2 is a member of the HER family of transmembrane receptors, which also includes epidermal growth factor receptor, HER3 (ERBB3), and HER4 (ERBB4). In normal tissue, HER proteins mediate cell growth signals transmitted between stromal and epithelial cells. Unlike other members of the family, HER2 does not interact directly with the growth factor ligand. Instead, the receptor functions by a ligand-independent dimerization mechanism that primes HER2 for associations with both itself and other HER kinase family members. In HER2-amplified breast cancers, the overabundance of membrane HER2 further potentiates this ligand-independent mechanism, resulting in “addiction” to HER2 signaling for tumor cell survival. In particular, overexpression of HER2 results in increased HER2 homoand heterodimer formation and augmented signaling through intracellular cascades such as the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathways (Fig 1). Contrary to HER2, HER3 has an impaired intracellular kinase and lacks significant biologic activity when expressed alone. However, when HER3 undergoes heterodimerization with HER2, a potent oncogenic signal may result. The HER2:HER3 heterodimer functions as the most transforming and mitogenic receptor complex of the HER family of proteins and is a robust activator of PI3K pathway signaling. The expression of HER3 can be a rate-limiting step for HER2induced cell growth, because HER2-amplified breast tumors undergo apoptotic cell death when HER3 expression is suppressed. Clinically, patients with high levels of HER2:HER3 heterodimers and low levels of HER2 homodimers exhibit a diminished response to trastuzumab therapy. The dependence on HER2 and pathogenesis of HER2: HER3 heterodimers in HER2-amplified breast cancer provide a scientific rationale for targeting both HER2 and HER3 in the clinical setting (Fig 1). Sequential HER2 blockade aims to achieve an extended and diversified therapeutic blockade of this oncogenic receptor tyrosine kinase. However, as seen in the modest activity of singleagent treatment, demonstrated by Cortes et al and others, repetitive HER2-specific monotherapy is often insufficient to engender long-lasting responses in patients who progress while receiving trastuzumab-based regimens. Trastuzumab-DM1 and pan-HER agents are notable exceptions with reasonable singleagent activity, but these drugs are probably more synonymous to combination treatment than to monotherapy. Trastuzumab-DM1 harnesses the effects of HER2 blockade through its trastuzumab component and simultaneously delivers the cytotoxic agent DM1, and pan-HER drugs are known to affect multiple kinases. Several mechanisms of resistance to single-agent HER2 inhibition have been proposed, including alterations affecting the HER2 receptor, increased interactions with both HER proteins and other membrane-bound receptors, and alternative activation of oncogenic signaling networks such as the PI3K pathway. Dual anti-HER2 regimens, in contrast to monotherapy, show excellent synergy and improved outcome in patients previously JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 30 NUMBER 14 MAY 1

Clinicopathological features among patients with advanced human epidermal growth factor-2-positive breast cancer with prolonged clinical benefit to first-line trastuzumab-based therapy: a retrospective cohort study.

BACKGROUND The magnitude of benefit of trastuzumab for the treatment of advanced HER2-positive breast cancer varies widely. In this retrospective study, we investigated the clinicopathological features associated with prolonged first-line trastuzumab-based treatment duration. PATIENTS AND METHODS A total of 164 patients diagnosed with advanced HER2-positive breast cancer and treated with first-line trastuzumab-based therapy from 1999 to 2009 were identified. Duration of treatment was classified according to tertiles. Different logistic regression models including age, disease-free interval, number of metastatic sites, visceral disease, hormone receptor, and adjuvant trastuzumab were fitted to investigate associations with benefit of prolonged trastuzumab-based therapies. The predictive value of each model was assessed using C-statistics. RESULTS At a median follow-up of 5.8 years (range, 0.7-22.1 years), patients in the short-, intermediate-, and long-term treatment duration groups were given first-line trastuzumab-based therapy for < 7.2 months, 7.2 to 14 months, and > 14 months, respectively. In the multivariate analysis, patients with long-term clinical benefit had a higher likelihood of having hormone receptor-positive tumors (odds ratio [OR]positive vs. negative = 2.39 [95% confidence interval (CI), 1.08-5.31]; P = .032); and a lower likelihood of having received adjuvant trastuzumab (ORadjuvant trastuzumab vs. no adjuvant trastuzumab = 0.30 [95% CI, 0.10-0.96]; P = .043]. C-statistics varied between 0.634 and 0.699. CONCLUSION Long-term benefit of trastuzumab-based therapy is associated with hormone receptor positivity and the absence of previous adjuvant trastuzumab. Nevertheless, clinicopathological features had a low predictive value for prolonged treatment duration. The validation of the current findings and the identification of molecular features associated the magnitude of trastuzumab benefit should be encouraged.

When Standard Therapy Fails in Breast Cancer: Current and Future Options for HER2-Positive Disease

The area of HER2-positive breast cancer is a rapidly changing field. The use of the humanized monoclonal antibody, trastuzumab, significantly improved the prognosis for patients with HER2-positive breast cancer, however, increasing knowledge regarding mechanisms of resistance to trastuzumab have come to light, prompting research into additional methods to target the HER2 protein. The purpose of this article is to discuss evidence for why continued blockade of the HER2 pathway continues to be important despite progression on trastuzumab, as well as to review additional HER2-targeted therapies and progression in the central nervous system. With the availability of new drugs comes the need to determine the appropriate therapeutic combinations and optimal order in which to deliver these therapies. This review summarizes the practice-changing phase III trials and some supporting phase II data regarding the various targeted HER2 therapies available for patients with advanced HER2-positive breast cancer, proposes order for anti-HER2 therapy in the advanced HER2-positive breast cancer patient, and includes information on future strategies. While other reviews on HER2-targeted therapy are available, this review specifically aims at addressing treatment options after trastuzumab failure in the patient with advanced HER2-positive breast cancer.

Incidence and risk of central nervous system (CNS) metastases as a site of first recurrence in patients (pts) with HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab (T).

609 Background: Resistance to conventional chemotherapy remains a major challenge in Stage IV colon cancer. CRM1 inhibition leads to nuclear sequestration of proteins such as tumor suppressor p53, growth regulatory proteins, and chemotherapy targets such as topoisomerase I/II. We examined the effects of combination use of KPT185 (a novel CRM1 inhibitor) with SN38 (active metabolite of irinotecan) and the effect of drug administration sequence in human colon cancer cell lines to determine if CRM1 inhibition enhances the cytotoxic effect of chemotherapy. METHODS We evaluated the combination effect of KPT185 with SN-38 on both Lovo (KPT-sensitive, IC50 = ∼ 500nM) and HT29 cells (KPT-resistant, IC50 = 1000 ∼ 3000nM) by the Chou-Talalay method, an MTT-based assay that interrogates response across a spectrum of drug dosages: KPT185 (0, 1, 10, 100, 1000, 10000 nM) and SN38 (0, 100, 500, 1000 nM). Cell cycle analysis by FACS with propidium iodide (PI) staining was performed. Effects on apoptosis were determined by FACS (Annexin V/PI staining) and Cell Death Detection ELISA assay. RESULTS The Chou-Talalay method determined that there is a synergistic effect when KPT185 is combined with SN38 in both Lovo and HT29 cells (combination index > 1). FACS analysis demonstrated combination use of KPT185 and SN38 induced an increase in the apoptotic sub-G1 fraction and a shift toward G2/M arrest. Combination treatment also significantly increased the Annexin V/PI-positive fraction compared with SN38 alone case (P < 0.05). Treatment sequence studies demonstrated that pretreatment of SN38 followed by KPT185 (KPT-post) produced the maximum synergistic effect compared with pretreatment of KPT185 followed by SN38 (KPT-pre) or concurrent use (KPT-con); Cell Death Detection ELISA assay showed KPT-post increased apoptosis most (4.3-fold) compared with KPT-pre (4.2-fold), KPT-con (3.8-fold) and SN38 alone (1-fold). CONCLUSIONS Our results show KPT185, a novel CRM1 inhibitor, sensitizes the response to SN38 in KPT-sensitive as well as KPT-resistant colon cancer cells. This method of sensitizing colon cancer cells warrants further evaluation in preclinical models of colon cancer.

Abstract 5586: Phase I study of PARP inhibitor ABT-888 and carboplatin with novel imaging in metastatic breast cancer (MBC) (NCI-8609)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Purpose: ABT-888 is an oral inhibitor of PARP 1 and 2 and potentiates activity of platinums in preclinical models. We are conducting a phase I study of ABT-888 on 2 different schedules (7 and 14 day) plus q 3 week carboplatin (C) to identify the recommended phase II dose schedules (RPTD-7and 14 day) for this regimen in patients (pts) with MBC who are: (1) triple negative (TN); or (2) estrogen receptor positive (ER+) with defective Fanconi Anemia (FA) pathway (no FANCD2 foci in tumor). Study design: Eligible pts received C-AUC 5 Q 3weeks (except dose level 1-AUC 6) plus escalating doses of ABT-888 BID on a 7 or 14-day schedule using a 3+3 dose escalation design. Blood samples were collected during cycles 1 and 2 for PAR assay and CTCs isolated to measure gamma H2Ax. We performed 3′-[F-18] Fluoro-3′-deoxythymidine(FLT) PET scans to assess cellular tumor proliferation at baseline, cycle 1 day 7 and 14 and after cycle 3. FDG-PET-CT scans were used to assess response. Results: 22 pts (20-TN, 2-ER+ w/FA defect) with median age of 56.5 yrs (range 31-69) were enrolled on 5 dose levels. Dose level 1 with C at AUC 6 was too toxic with 3 DLTs (Table 1). Further dose escalations were performed with C at AUC-5. Dose reductions in C were made in subsequent cycles for thrombocytopenia, anemia and fatigue. Maximum reduction in thymidine uptake in tumors was seen on day 7 FLT scans. CTCs were isolated using an immunomagnetic negative depletion method on 8 pt samples to date (median-59, range 0-684 CTCs). Gamma H2Ax analysis on sequential samples is ongoing. Four pts have had an unconfirmed partial response (PR) with > 50% tumor shrinkage; 2 of the 4 pts had a defective FA pathway. Conclusions: Thrombocytopenia is the major DLT when ABT-888 is given in combination with C, where lower AUC of C is better tolerated and shows promising activity of this combination. FA deficiency (5/14=27%) seen in this group is consistent with our previous reports. The study is supported U01 CA076576. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5586. doi:1538-7445.AM2012-5586 [1]: pending:yes

Abstract P5-18-17: Impact of compliance with National Comprehensive Cancer Network guidelines on adjuvant trastuzumab administration for patients with HER2-positive breast cancer.

Background: The National Comprehensive Cancer Network (NCCN) breast cancer guidelines recommend trastuzumab as a component of adjuvant therapy for patients with stage I-III HER2-positive breast cancer. Reasons for noncompliance with adjuvant trastuzumab therapy and the impact of noncompliance with national guidelines are unknown. Methods: We retrospectively identified 331 patients with stage I-III HER2 -positive breast cancer treated at the Ohio State University James Cancer Hospital 2005–2011 who were eligible for adjuvant trastuzumab. Medical records were reviewed to obtain age at diagnosis, race, co-morbidity score, stage, hormone positivity, type of therapy administered, date of disease recurrence, vital status and date of last follow up. Available clinician-documented reasons for not administering adjuvant trastuzumab were also recorded. Multivariate logistic regression modeling was used to examine the effect of these variables on completion of 1 year of adjuvant trastuzumab. Cox regression modeling was used to estimate the effect of completing 1 year of trastuzumab on disease-free and overall survival, respectively. Results: Median follow up was 39.9 months (range 12.0–85.1). Of the 331 patients, the majority of (289; 87%) received at least 1 dose of trastuzumab while 251 (76%) patients completed the recommended 1 year of trastuzumab therapy. In multivariate modeling, age ≥ 70 years (Odds Ratio 0.18, 95% CI 0.07 to 0.47; p Conclusion: Age ≥ 70 years and stage I disease are predictors of noncompliance with NCCN guidelines recommending administration of adjuvant trastuzumab therapy for one year. Failure to complete one year of adjuvant trastuzumab is significantly associated with disease recurrence and worse overall survival in patients with stage I-III HER2-amplified breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-17.