| 1. |
- Bergh, Jonas C. S., et al.
(författare)
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Docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer : results from the Swedish PREDIX HER2 trial identifying a new potential de-escalation standard?
- 2019
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15, s. 501-501
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neoadjuvant therapy produces high rates of pathological complete response (pCR) and is the standard of care in HER2 positive breast cancer; however, the optimal treatment regimen remains to be established. Methods: In this randomized phase II study patients ≥18 years with HER2 positive breast cancer > 20mm or verified lymph node metastases were randomized to 6 courses of docetaxel, trastuzumab and pertuzumab (DTP, group A) or trastuzumab emtansine (T-DM1, group B), q 21 days. The protocol allowed switch to the competing treatment upon lack of response or drug-related severe toxicity. Patients received postoperative epirubicin+cyclophosphamide, trastuzumab for a total of one year and endocrine therapy. Accrual was completed in October 2018 after randomization of 202 patients, data on pCR were available for 190 at the time for this abstract submission. Median age, 52 years (26-74), menopausal status, histological type and grade were well balanced between the treatment groups. 62.6% of the tumors were hormone receptor (HR) positive. Results: Primary endpoint was pathological objective response. 190 patients completed the protocol-specified preoperative treatment. pCR was achieved in 45.3% of patients, 46.4% in patients treated with DTP and 44.1% with T-DM1 (chi-sq., p = 0.75). In HR-positive tumors, pCR was obtained in 35.3% of patients, 35.9% in group A vs. 34.6% in group B (p = 0.87); in HR-negative tumors, the overall pCR rate was 62.0%, 66.7% in group A vs. 57.9% in group B (p = 0.45). Severe (grade 3/4) toxicity was reported at 68 occasions related to DTP, compared with 16 related to T-DM1, 26 vs. 3 caused by febrile neutropenia. Significantly better quality of life was reported by patients treated with T-DM1. Conclusions: Our data on TDM-1 demonstrates similar efficacy and less toxicity, in particular for patients with HER2 and HR positive cancers, being a potential new standard for neoadjuvant therapy. Clinical trial information: NCT02568839.
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| 2. |
- Brandberg, Yvonne, et al.
(författare)
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Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer.
- 2019
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15, s. 583-583
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.). Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses. Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables. Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity. Clinical trial information: NCT02568839.
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| 3. |
- Foukakis, Theodoros, et al.
(författare)
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Immune gene expression and response to chemotherapy in advanced breast cancer
- 2018
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 118:4, s. 480-488
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Tidskriftsartikel (refereegranskat)abstract
- Background:Transcriptomic profiles have shown promise as predictors of response to neoadjuvant chemotherapy in breast cancer (BC). This study aimed to explore their predictive value in the advanced BC (ABC) setting.Methods:In a Phase 3 trial of first-line chemotherapy in ABC, a fine needle aspiration biopsy (FNAB) was obtained at baseline. Intrinsic molecular subtypes and gene modules related to immune response, proliferation, oestrogen receptor (ER) signalling and recurring genetic alterations were analysed for association with objective response to chemotherapy. Gene-set enrichment analysis (GSEA) of responders vs non-responders was performed independently. Lymphocytes were enumerated in FNAB smears and the absolute abundance of immune cell types was calculated using the Microenvironment Cell Populations counter method.Results:Gene expression data were available for 109 patients. Objective response to chemotherapy was statistically significantly associated with an immune module score (odds ratio (OR)=1.62; 95% confidence interval (CI), 1.03-2.64; P=0.04). Subgroup analysis showed that this association was restricted to patients with ER-positive or luminal tumours (OR=3.54; 95%, 1.43-10.86; P=0.012 and P for interaction=0.04). Gene-set enrichment analysis confirmed that in these subgroups, immune-related gene sets were enriched in responders.Conclusions:Immune-related transcriptional signatures may predict response to chemotherapy in ER-positive and luminal ABC.
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| 4. |
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| 5. |
- Hatschek, Thomas, et al.
(författare)
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Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer A Phase 2 Randomized Clinical Trial
- 2021
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 7:9, s. 1360-1367
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown.OBJECTIVE: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer.DESIGN, SETTING, AND PARTICIPANTS: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis.INTERVENTIONS: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (F-18-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles.MAIN OUTCOME AND MEASURES: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery.RESULTS: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with F-18-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by more than 31.3% (median) was associated with pCR (odds ratio, 6.67, 95% CI, 2.38-20.00; P < .001).CONCLUSIONS AND RELEVANCE: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1.
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| 6. |
- Kimbung, Siker, et al.
(författare)
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Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer
- 2016
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:1, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. (C)2015 AACR.
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| 7. |
- Suzuki, Chikako, et al.
(författare)
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Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy
- 2013
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Ingår i: Medical Oncology. - : Humana Press. - 1357-0560 .- 1559-131X. ; 30:1
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p andlt; 0.001). A decrease by andgt;30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p andlt; 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.
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| 8. |
- Tobin, Nicholas P., et al.
(författare)
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PAM50 provides prognostic information when applied to the lymph node metastases of advanced breast cancer patients
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:23, s. 7225-7231
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting. Experimental Design: Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable locoregional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan–Meier and/or multivariate Cox regression analyses. Results: The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P < 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan–Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer–specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance. Conclusions: Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients.
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| 9. |
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| 10. |
- Zhu, Yajing, et al.
(författare)
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The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer : biomarker analysis from the swedish phase ii randomized predix HER2 trial
- 2024
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Ingår i: Breast Cancer Research and Treatment. - : Springer. - 0167-6806 .- 1573-7217.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown.Methods: In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated.Results: No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis.Conclusion: sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation.Trial registration: ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.
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