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Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.

ABSTRACT: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described.Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy.Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+?hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+?HR- (ER-/PR-) disease (hazard ratio 0.72, P=0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+?HR- compared to HER2+?HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P=0.002 for years 1 to 5). The high early risk of recurrence of HER2+?HR- patients declined sharply over time, so that it was similar to that seen in HER2+?HR+ patients in years 6 to 10 (hazard ratio 0.97, P=0.92 for years 6 to 10).Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+?HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+?HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy.

SUBMITTER: Strasser-Weippl K

PROVIDER: S-EPMC4423419 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.

Strasser-Weippl Kathrin K Horick Nora N Smith Ian E IE O'Shaughnessy Joyce J Ejlertsen Bent B Boyle Frances F Buzdar Aman U AU Fumoleau Pierre P Gradishar William W Martin Miguel M Moy Beverly B Piccart-Gebhart Martine M Pritchard Kathleen I KI Lindquist Deborah D Rappold Erica E Finkelstein Dianne M DM Goss Paul E PE

Breast cancer research : BCR 20150416

<h4>Introduction</h4>Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described.<h4>Methods</h4>Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy.<h4>Re ...[more]

PMID: 25888246

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Project description:Background:In premenopausal patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown. Methods:In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor-positive and -negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided. Results:A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor-positive disease. Median age was 43 (interquartile range = 38-47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab?lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor-positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor-negative patients. Conclusions:In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor-positive/HER2-positive early breast cancer patients.

Project description:PURPOSE:HER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient's live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies. METHODS:The CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2-/HSFs+). RESULTS:HER2-/HSFs+?breast cancer patient samples were identified and showed sensitivity to five approved anti-HER2 therapies. Xenograft studies using both HER2+?and HER2- cell lines confirmed that CELx HER2 signaling status better predicts HER2 inhibitor efficacy than HER2 receptor status. In a study of 114 HER2-negative breast tumor patient samples, 27 (23.7%; 95% CI?=?17-32%) had abnormal HER2 signaling (HSFs+). A ROC curve constructed with this dataset projects the CELx HSF Test would have greater than 90% sensitivity and specificity to detect the HER2-/HSFs+?patient population. CONCLUSIONS:The CELx HSF test is a well-characterized functional biomarker assay capable of identifying dynamic HER2-driven signaling dysfunction in tumor cells from HER2-negative breast cancer patients. This test has demonstrated efficacy of various HER2 targeted therapies in live tumor cells from the HSFs+?population and correlated the test result to HER2 drug response in mouse xenograft studies. The proportion of HER2-negative breast cancer patients found to have abnormal HER2 signaling in a 114 patient sample study, 20-25%, is significant. A clinical trial to evaluate the efficacy of anti-HER2 therapies in this patient population is warranted.

Project description:BACKGROUND: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. METHODS: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. RESULTS: 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. CONCLUSIONS: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Project description:BackgroundUnderstanding the survival outcomes associated with breast-conserving therapy (BCT) and mastectomy after preoperative systemic therapy (PST) enables clinicians to provide more personalized treatment recommendations. However, lack of firm survival benefit data limits the breast surgery choices of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive PST. We sought to determine whether BCT or mastectomy after PST for early operable HER2-positive breast cancer is associated with better long-term survival outcomes and determine the degree to which PST response affects this association.MethodsIn this observational cohort study, we compared the long-term survival outcomes of BCT and mastectomy after PST for HER2-positive breast cancer and evaluated the impact of PST response on the relationship between breast surgery performed and survival outcomes. Our cohort included 625 patients with early operable HER2-positive breast cancer who received PST followed by BCT or mastectomy between January 1998 and October 2009. These patients also received standard postoperative radiation, trastuzumab, and endocrine therapy as indicated clinically. We used propensity score matching to assemble mastectomy and BCT cohorts with similar baseline characteristics and used Kaplan-Meier plots and Cox proportional hazards regression to detect associations between surgery types and outcomes. Furthermore, in this study, we analyzed the original data of 625 patients using the inverse probability of treatment weighting (IPTW) method to enhance the reliability of the comparison between the mastectomy and BCT cohorts by addressing potential confounding variables.FindingsPropensity score matching yielded cohorts of 221 patients who received BCT and 221 patients who underwent mastectomy. At the median follow-up time of 9.9 years, compared with BCT, mastectomy was associated with worse overall survival (hazard ratio, 1.66; 95% confidence interval [CI]: 1.08-2.57; P = 0.02). In patients who had axillary lymph node pathological complete response, mastectomy was associated with worse overall survival before matching (hazard ratio, 2.17; 95% CI: 1.22-3.86; P < 0.01) and after matching (hazard ratio, 2.12; 95% CI: 1.15-3.89; P = 0.02). Among patients with pathological complete response in the breast, the survival results did not differ significantly between BCT and mastectomy patients. IPTW method validated that BCT offers better overall survival in patients who had axillary lymph node pathological complete response.InterpretationPeople with HER2-positive breast cancer who have already had PST are more likely to survive after BCT, especially if they get a pathological complete response in the axillary lymph nodes. These findings underscore the necessity for further investigation into how responses to PST can inform the choice of surgical intervention and the potential impact on overall survival. Such insights could lead to the development of innovative tools that support personalized surgical strategies in the management of breast cancer.FundingThis work was supported by grants from the Nantong Science and Technology Project (JCZ2022079), Nantong Health Commission Project (QA2021031, MSZ2023040) and National Natural Science Foundation of China (No. 82394430).

Project description:BACKGROUND:An increasing proportion of human epidermal growth receptor 2 (HER2) positive (HER2+) metastatic breast cancer (MBC) is diagnosed as de novo stage IV disease. We hypothesize that a subset of these patients who achieve no evidence of disease (NED) status after multimodality HER2-targeted treatments may have prolonged progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS:Patients with de novo stage IV, HER2+ MBC (n = 483) diagnosed between 1998 and 2015 were identified at two institutions (Yale and MD Anderson Cancer Centers). Clinical variables, treatment details, and survival outcomes were compared between those who achieved NED and those who did not. RESULTS:All patients received trastuzumab, and 20% also received pertuzumab as first-line therapy. The median OS was 5.5 years (95% confidence interval [Cl]: 4.8-6.2). Sixty-three patients (13.0%) achieved NED; their PFS and OS rates were 100% and 98% (95% CI: 94.6%-100%), respectively, at 5 years and remained the same at 10 years. For patients with no NED (n = 420), the PFS and OS rates were 12% (95% CI: 4.5%-30.4%) and 45% (95% CI: 38.4%-52.0%) at 5 years and 0% and 4% (95% CI, 1.3%-13.2%) at 10 years, respectively. NED patients more frequently had solitary metastasis (79% vs. 51%, p = .005) and surgery to resect cancer (59% vs. 22%, p ≤ .001). In multivariate analysis, NED status (hazard ratio [HR]: 0.014, p = .0002) and estrogen receptor positive status (HR: 0.72; p = .04) were associated with prolonged OS. CONCLUSION:Among patients with de novo stage IV, HER2+ MBC, those who achieve NED status have a very high PFS and OS. Further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes. IMPLICATIONS FOR PRACTICE:In this retrospective review at two institutions, it was demonstrated that 13% of patients with de novo stage IV, human epidermal growth receptor 2 positive metastatic breast cancer achieved no evidence of disease (NED) status with trastuzumab-based therapy plus/minus local therapies, and these patients had a very high progression-free survival (100%) and overall survival (98%) at both the 5- and 10-year time points. Achieving NED status may be an important therapeutic goal. However, further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes.

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Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.

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Long-term hazard of recurrence in HER2+ breast cancer patients untreated with anti-HER2 therapy.

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