Abstract Background Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival ...of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer. Materials and methods A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included. Results This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. Conclusion Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.
Abstract Background Initial treatment for advanced ER-positive/HER2-negative breast cancer involves a CDK 4/6 inhibitor (CDK 4/6i). Recent overall survival (OS) analyses led the Danish Medical ...Council to exclude palbociclib as preferred option. This study aimed to evaluate the real-world effectiveness of abemaciclib, palbociclib, and ribociclib in a Danish context. Additionally, to compare the inhibitors to identify potential endpoint differences. Material and methods Patients undergoing first or second line CDK 4/6i treatments from January 1st, 2017, until December 31st, 2021 were included. The primary endpoint was progression free survival (PFS). Results Among 2069 Danish patients, 1554 received first line treatment, 515 received second line treatment. In first line, abemaciclib’s median PFS was unreached; palbociclib had a median PFS of 32.0 months (95% CI: 28.9–35.3); ribociclib 42.4 months (95% CI: 35.1–52.9). First-line median OS was 37.8 months (95% CI: 32.5–NA); 49.7 months (95% CI: 44.7–54.1); and 54.4 months (95% CI: 47.9–NA) for abemaciclib, palbociclib and ribociclib, respectively. No significant differences in OS were observed, nor in PFS in second line. Conclusion This study confirms first-line CDK 4/6i effectiveness, with abemaciclib and ribociclib showing prolonged PFS vs. palbociclib. This study could not confirm a ranking of the three CDK 4/6i.
Introduction:
Despite the significant gains in the treatment of breast cancer over the last decade, further improvements in survival using traditional chemotherapeutic agents have begun to plateau. ...Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has provided promise for continued gains in therapy efficacy.
Areas covered:
The authors review Phase III data concerning the safety of bevacizumab in breast cancer, summarize data on efficacy and discuss the risk:benefit ratio of the drug. The data for this review were obtained by searching in the PubMed database. This review enables the reader to overview current knowledge on the efficacy and safety of bevacizumab in breast cancer.
Expert opinion:
Insight into complex risk-benefit calculations for bevacizumab is missing. In unselected patients with HER2-negative metastatic breast cancer, the risk of serious side effects of bevacizumab overshadows the benefit of the drug. However, increased response rates and progression-free survival in the majority of Phase III trials suggest that the drug is of benefit in a subgroup of patients. Although requiring close monitoring, most side effects are manageable. Reliable, validated predictive biomarkers are of utmost importance to improve the likelihood of clinical benefit.
Abstract Angiogenesis is a key component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive strategy for the treatment of cancer. We systematically ...describe phase II and III clinical trials of bevacizumab for the treatment of breast cancer. Methods A computer-based literature search was carried out using PUBMED and conference databases. Original phase II and III studies reporting ⩾15 patients who received bevacizumab were included. Results 41 phase II trials were identified in the metastatic setting. Most trials found bevacizumab treatment feasible. Response rates (RR) varied from 0% to 76.5%, time to progression (TTP)/progression free survival (PFS) from 2.4 to 25.3 months and overall survival from 11.5 to more than 38 months. 14 phase III trials including more than 4400 patients with MBC unanimously showed increased RR and PFS, however, no trials demonstrated an OS benefit. In the neoadjuvant setting 23 phase II and III trials were identified. All studies found increased pCR/tpCR but no benefit in terms of OS could be demonstrated. The only study conducted in the adjuvant setting failed to show any survival benefit of bevacizumab. Conclusion Despite increased response rates in both the metastatic and neoadjuvant setting, bevacizumab has failed to show any OS benefit. Future trials should include identification of robust predictive biomarkers in order to improve our understanding of molecular biomarkers and mechanisms.
Cancer is a leading cause of mortality worldwide and matters are only set to worsen as its incidence continues to rise. Traditional approaches to combat cancer include improved prevention, early ...diagnosis, optimized surgery, development of novel drugs, and honing regimens of existing anti-cancer drugs. Although discovery and development of novel and effective anti-cancer drugs is a major research area, it is well known that oncology drug development is a lengthy process, extremely costly and with high attrition rates. Furthermore, those drugs that do make it through the drug development mill are often quite expensive, laden with severe side-effects and unfortunately, to date, have only demonstrated minimal increases in overall survival. Therefore, a strong interest has emerged to identify approved non-cancer drugs that possess anti-cancer activity, thus shortcutting the development process. This research strategy is commonly known as drug repurposing or drug repositioning and provides a faster path to the clinics. We have developed and implemented a modification of the standard drug repurposing strategy that we review here; rather than investigating target-promiscuous non-cancer drugs for possible anti-cancer activity, we focus on the discovery of novel cancer indications for already approved chemotherapeutic anti-cancer drugs. Clinical implementation of this strategy is normally commenced at clinical phase II trials and includes pre-treated patients. As the response rates to any non-standard chemotherapeutic drug will be relatively low in such a patient cohort it is a pre-requisite that such testing is based on predictive biomarkers. This review describes our strategy of biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy, taking the repurposing of topoisomerase I (Top1) inhibitors and Top1 as a potential predictive biomarker as case in point.
Abstract Therapies targeting the human epidermal growth factor receptor (HER) 2 are effective in metastatic breast cancer (MBC). We review the efficacy of HER2-directed therapies, focussing on ...monoclonal antibodies and tyrosine kinase inhibitors targeting HER2 that have been tested in phase II–III studies in MBC. Trastuzumab is an important component of first-line treatment of HER2-positive MBC. New anti-HER2 drugs have the potential to change clinical practice. The potential role of the different drugs and regimens is yet to be determined. The response rate for trastuzumab-DM1 of 26–64% is comparable to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome. The future challenges include understanding HER2 functions, designing rational combinations and optimal selection of patients.
Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the ...topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan.
Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/- trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months.
The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD.
The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC.
Eudract registration numbers 2012-002348-26 and 2012-002347-23 . Registration date August 20th 2012.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases. Current HER2-targeted therapies have limited potential to cross the ...blood–brain-barrier. We performed a systematic review to investigate data on HER2-targeting therapies in the treatment of brain metastases in breast cancer. We searched PUBMED for all human studies published 1998–2012 using the following search terms: breast neoplasm/cancer, human epidermal growth factor receptor 2/HER2, ErbB2, trastuzumab, lapatinib, brain/cerebral neoplasm/metastases and blood–brain barrier. We identified few and mostly small clinical studies. Study designs were very heterogeneous making comparisons on endpoints difficult. Overall survival for patients treated with trastuzumab varied from 8 to 25 months and 5.5 to 11 months for patients receiving lapatinib. The majority of studies were retrospective thus possibly biasing data. Only three studies were identified comparing trastuzumab to lapatinib. Conclusively, no solid data exist on how to treat patients with HER2-positive disease and brain metastases. Although continuous HER2-blockade is recommended by international consensus guidelines, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur. The choice of chemotherapy to accompany the blockade is not obvious and we do not know if dual is better than single blockade. Further clinical trials are urgently needed.
The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and ...adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases.
Patients with HER2-positive mBC, diagnosed between 01.01.2014-31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function.
631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2-48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2-NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1-14.8), 6.6 (95% Cl, 5.8-7.6) and 5.8 (95% Cl, 4.9-6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49-0.98), p = 0.047 and 2.69 (95% CI, 1.45-5.00), p = 0.002, respectively.
We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased ...until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented.
This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up.
Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis.
Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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