Early-stage Human Epidermal Growth Research Articles

Safety and efficacy of single-agent adjuvant trastuzumab in older women with early-stage breast cancer.

528 Background: Older adults with multiple comorbidities and poor functional status may not be appropriate candidates for chemotherapy. We conducted a phase II trial to examine the safety and efficacy of single-agent Trastuzumab for older women with early stage Human Epidermal Growth Factor Receptor Type 2 (Her2)-positive breast cancer. Methods: This was a single-arm open label multi-institutional clinical trial of adjuvant single-agent Trastuzumab in women aged ≥ 60 years with stage I-III Her2-positive breast cancer who had either declined chemotherapy or were not chemotherapy candidates. Patients received Trastuzumab monotherapy, (8 mg/kg) for cycle 1 followed by (6 mg/kg) every 3 weeks for 12 months. The primary end point was one-year cumulative incidence of symptomatic congestive heart failure with reduced ejection fraction (HFrEF). Secondary endpoints were disease free survival (DFS) and overall survival (OS) at 5 years. Results: Fifty-six patients were enrolled across four centers with a median follow-up period of 5.0 years, (range 0-6.5). The median age was 72.5 years (range 60-90), 64% had stage I disease, 77% had estrogen-receptor positive disease and 82% had node-negative breast cancer. Only two patients had symptomatic congestive HFrEF with a one-year cumulative incidence of 3.6%; (95% confidence interval [CI], 0.09 to 13.8). Five patients had asymptomatic declines in ejection fraction with a one-year cumulative incidence of 9.1%; (95% CI, 3.9 to 20.1). The 5-year DFS was 86.4%; (95% CI, 73.6 to 93.3). Among seven relapses seen, two were due to distant metastatic breast cancer. The 5-year rate of overall survival was 90.2%; (95% CI, 78.1 to 95.8). Among five deaths, one was due to distant metastatic breast cancer. Conclusions: Among older women with stage I-III HER2-positive breast cancer who decline chemotherapy or are not chemotherapy candidates, treatment with her2 targeted therapy only without chemotherapy may offer a reasonable treatment option without an inordinate rate of cardiac toxicity. Clinical trial information: NCT00796978 .

Correlation between mutation landscape and clinical outcomes of neoadjuvant therapy in HER2-positive breast cancer patients.

579 Background: The standard management of early stage human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer (BC) involves neoadjuvant therapy with combination of chemotherapy and HER2-targeted therapy followed by surgery. However, diverse pathologic responses were observed. We interrogated whether baseline genomic heterogeneity contributes to the varied therapeutic responses. Methods: Capture-based targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6MB of human genome, was performed on tissue biopsy samples, obtained prior to neoadjuvant therapy, of 33 HER2+ women with stage I-III BC. The median age of the cohort was 53. The correlation between genomic alterations and pathologic response were analyzed by multivariate analysis. Results: A majority of them was diagnosed with stage II (67%, 22/33), while 30% (10/33) had stage III and 3% (1/33) had stage I disease. 58% (19/33) were HR+ and 42% (14/33) were HR-. Mutation profiling of baseline samples revealed 349 mutations spanning 145 genes, with TP53, CDK12 and PIK3CA being the top 3 most frequently mutated genes. Neoadjuvant regimen was comprised of trastuzumab and HER2 inhibitor (i.e. pertuzumab or lapatinib). 15 patients used single HER2 inhibitor;18 used dual HER2 inhibitors. Endocrine therapy was also administered to HR+ patients (19/33) in combination with trastuzumab and HER2 inhibitor. Complete pathologic response (pCR) was observed in 45.5% (15/33) of patients. Interestingly, ROS1 copy number amplifications (CANs) were only identified in patients achieved pCR (p = 0.033). In contrast, missense mutations in PIK3CA and CNAs in CCND1, FGF19, FGF3, FGF4, SPOP, HNF1B and BRIP1 showed a trend of being less likely to mutate in pCR patients (p values between 0.05-0.1). Previous reports have suggested that pCR rates in HER2+ patients are associated with HR status. However, our data revealed comparable pathologic response of patients based on either HR status or neoadjuvant regimen. Conclusions: Our data revealed a distinct mutational profile between patients achieved pCR vs patients did not. Further studies with a larger cohort are required to confirm these findings.

A Critical Review of Economic Evaluations of Trastuzumab in the Treatment of Early Stage HER2 Positive Breast Cancer

Eleven years after Trastuzumab was approved for use in the treatment of early stage human epidermal growth factor receptor positive breast cancer (HER2+) its clinical benefit has been demonstrated in short and long term follow up studies. The cost-effectiveness of the therapy in this context remains the subject of debate with a wide range of Incremental Cost Effectiveness Ratios (ICERs) reported in the literature. While several reviews of the literature have been undertaken these have not provided a critical analysis of the factors that might underlie this heterogeneity. In this review we provide a critical overview of the literature and discuss potential sources of heterogeneity in reported ICERs. We identify gaps in the current literature and provide a rationale for filling these gaps.

Abstract P4-15-10: Initial therapy among patients newly diagnosed with operable early stage human epidermal growth factor receptor 2-overexpressed (HER2+) breast cancer in the US: A real-world retrospective study

Abstract BACKGROUND: Prognosis and appropriate treatment of breast cancer patients (pts) is influenced by tumor molecular characteristics. However, few existing retrospective studies have investigated the treatment patterns and outcomes of breast cancer pts by tumor biomarkers. The objective of this study was to assess the current real-world treatment patterns associated with resected non-metastatic HER2+ breast cancer in the US. METHODS: This was a retrospective study of physician-reported clinical information (including date and stage at diagnosis, HER2 status and hormone receptor (HR) status) for commercially insured breast cancer pts from the Oncology Management Registry linked with medical and pharmacy claims from a large, national health plan in the US from 01/2008 to 8/2013. The date of initial diagnosis was the index date. The inclusion criteria were: adult pts (≥18 years old), enrolled in the health plan for ≥6 months after the index date, diagnosed with HER2+ Stage I-III disease, known HR status, received breast cancer specific surgery (mastectomy or lumpectomy) and anti-cancer systemic therapy (ACST) and/or radiation within 6 months of index date. Pts with other primary cancers during the study period were excluded. The initial phase of care included initial therapy (surgery and ACST and/or radiation) until 30 days after the last therapy received (surgery, ACST or radiation) prior to a 90-day gap in treatment. Treatment patterns during the initial phase of care by HR status were examined. RESULTS: Among 915 pts who met all study criteria, 662 (72%) and 253 (28%) were HR+ and HR-, respectively. Mean age was 52 years (standard deviation=9) and was not significantly different by HR cohort. Approximately 82% (n=749) were diagnosed with Stage I/II disease. Most pts (80%, n=732) received adjuvant therapy only, 19% (n=177) received both neo-adjuvant and adjuvant therapy, and <1% (n=6) were observed to have neo-adjuvant therapy only. Among pts who received neo-adjuvant therapy, mean time from diagnosis to ACST was 21 days (median=21). Among pts who received only adjuvant therapy, mean time from diagnosis to initial breast cancer specific surgery was 24 days (median=20). Overall, 72% of pts received HER2 targeted therapy (69% HR+, 80% HR-; p<0.01) during their initial phase of care. During neo-adjuvant therapy, 72% of pts received trastuzumab (67% HR+, 81% HR-; p<0.05). During adjuvant therapy, 72% of pts received trastuzumab (69% HR+, 81% HR-; p<0.05). The most common neo-adjuvant regimen regardless of HR status was carboplatin+docetaxel+trastuzumab (>40% pts). The most common regimens during the adjuvant therapy period were carboplatin+docetaxel+trastuzumab with or without hormone therapy (∼30% of pts). CONCLUSION: In this real-world population of commercially insured breast cancer pts treated for operable, early stage HER2+ disease in the US, 28% of pts did not receive targeted therapy. More pts with HR- status received targeted therapy than those with HR+ status. Further studies are warranted to examine whether pts that have not received targeted therapy are eligible and would benefit from an HER2 targeted approach. Citation Format: Stacey DaCosta Byfield, Philip O Buck, Cori Blauer-Peterson, Sara A Poston. Initial therapy among patients newly diagnosed with operable early stage human epidermal growth factor receptor 2-overexpressed (HER2+) breast cancer in the US: A real-world retrospective study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-10.

Health related quality of life of women in TEACH, a randomised placebo controlled adjuvant trial of lapatinib in early stage Human Epidermal Growth Factor Receptor (HER2) overexpressing breast cancer

To evaluate health related quality of life (HRQOL) in TEACH, a phase III randomized placebo controlled trial of 12 months of adjuvant lapatinib in HER2 positive (HER2+) early breast cancer which demonstrated marginal benefit in disease-free survival. Women on TEACH completed the Short Form 36-item health survey (version2; SF-36v2) at the baseline, six and 12 months after therapy initiation and six monthly thereafter. Mean changes were compared between treatment groups for two summary measures (Physical and Mental Component Summary scores; PCS and MCS) and eight domain measures (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), and in patients discontinuing therapy. A five-point change was deemed a Minimally Clinically Important Difference (MCID). Response analysis compared the proportion of patients demonstrating a MCID in HRQOL, and a regression analysis identified predictors of worsening HRQOL. 3074 (97%) subjects completed baseline SF-36v2. During the initial 12 months, summary SF-36v2 scores decreased in both arms but did not reach Minimally Clinically Important Difference (MCID) despite significant incidences of diarrhoea and rash in lapatinib treated patients. At six months, women receiving lapatinib had more significant reductions (p < 0.01 versus placebo) in social functioning. Early treatment discontinuations were more frequent on lapatinib (32% versus 18%), and were associated with more substantial decrements of HRQOL in both arms. For those discontinuing primarily due to adverse events, decrements in HRQOL reached MCID in Mental Summary scores (MCS) only. Lower baseline HRQOL was a significant predictor of worsening HRQOL (p < 0.05). Despite frequent but usually mild toxicities, adjuvant lapatinib is not associated with clinically significant decreases in overall HRQOL. These placebo-controlled results may also help to inform physicians and patients using lapatinib in metastatic HER2 positive breast cancer. GlaxoSmithKline. The AVON Foundation NY supported PEG, DF and BM and The Friends of the Mater Foundation supported FB.

Neoadjuvant therapy of early stage human epidermal growth factor receptor 2 positive breast cancer: latest evidence and clinical implications.

Neoadjuvant therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer is exactly the paradigm of targeted therapy and a suitable setting to develop and test rapidly novel therapies in early stages. Moreover, neoadjuvant approaches provide a significant source of tumour tissue to identify molecular heterogeneity and potential predictive biomarkers of response. The addition of trastuzumab to primary chemotherapy revolutionized the treatment of this tumour subtype, increasing pathological complete response rate (pCR) that, even with its limitations, has also been shown to be an early marker of survival in HER2-positive disease. HER2-positive breast cancer is a biological heterogeneous disease with different characteristics and clinical outcomes. Multiple promising anti-HER2 drugs with nonoverlapping mechanisms of action have recently been developed. Combined administration of two different HER2-targeted agents, that is, trastuzumab with lapatinib or pertuzumab, and primary chemotherapy shows enhanced antitumour activity, with an increase in pCR to values never reached in the past. Moreover, results of recent studies show that the combination of targeted therapy alone (dual HER2 blockade with or without endocrine therapy) also has activity in a substantial percentage of patients, eradicating HER2-positive tumours without chemotherapy and with a favourable toxicity profile. It is still necessary to be able to select the appropriate group of patients who can avoid chemotherapy (approximately 25%), and to establish robust predictive biomarkers of response or resistance to the anti-HER2 approach. Neoadjuvant therapy represents an enormous step forward in HER2-positive breast cancer. The results of the most relevant neoadjuvant studies and latest evidence are described in this review, though new questions have emerged.

Reply to V. Pitini et al

We appreciate the comments of Pitini et al regarding our recent report of 7-year follow-up of cardiac function in National Surgical Adjuvant Breast and Bowel Project protocol B-31, which is evaluating the benefits and risks of adding trastuzumab to standard chemotherapy for the adjuvant treatment of women with early stage human epidermal growth factor receptor 2–positive breast cancer. We agree that a dynamic evaluation of cardiac function, for example by echocardiogram, provides more detailed assessment of myocardial function than multigated acquisition (MUGA) scans, and clearly all imaging modalities carry a margin of error. It is worth pointing out that for the first 1,000 patients enrolled onto B-31, the primary end point of the protocol was not the clinical efficacy of trastuzumab but cardiac safety. As such, patients with any significant cardiac condition were excluded from participation, including those with any arrhythmia requiring medication. The cardiac risk score applies only to those patients who would have met the eligibility requirements of the protocol from which it was developed. As we mentioned in the Methods section, MUGA scans were chosen over echocardiograms in order to write rules for holding or stopping trastuzumab and to minimize observer variability across institutions. We also agree that the accuracy of the baseline left ventricular ejection fraction (LVEF) measurement is critical, not only for the cardiac risk score, but also because it serves as the comparison point for subsequent LVEF measurements in determining whether to hold or continue trastuzumab. For instance, if a patient is dehydrated when her baseline LVEF study is performed, the value obtained may be higher than a true reflection of her level of systolic function, and the difference between baseline and subsequent measurements then may be exaggerated, in some cases potentially affecting decisions about whether to hold or continue trastuzumab. Finally, we welcome the important work that is being done using biomarkers such as ultrasensitive troponin, and we cite two such studies in our discussion. In the end, however, any indicators of potential cardiac risk, whether by risk score, biomarkers, or genetics, must be integrated into clinical decision algorithms regarding optimal use of trastuzumab in the treatment of patients with breast cancer.

Herceptin therapy in pregnancy: Continuation of pregnancy in the presence of anhydramnios

Herceptin (Trastuzumab) is licensed for use in recurrent as well as early stage human epidermal growth factor receptor (HER) 2 positive breast cancer. It is recommended that Herceptin be used with ...