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Cancer Treatment Reviews Apr 2022Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment... (Review)
Review
BACKGROUND
Adjuvant and neoadjuvant breast cancer treatments can reduce breast cancer mortality but may increase mortality from other causes. Information regarding treatment benefits and risks is scattered widely through the literature. To inform clinical practice we collated and reviewed the highest quality evidence.
METHODS
Guidelines were searched to identify adjuvant or neoadjuvant treatment options recommended in early invasive breast cancer. For each option, systematic literature searches identified the highest-ranking evidence. For radiotherapy risks, searches for dose-response relationships and modern organ doses were also undertaken.
RESULTS
Treatment options recommended in the USA and elsewhere included chemotherapy (anthracycline, taxane, platinum, capecitabine), anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab, trastuzumab emtansine, neratinib), endocrine therapy (tamoxifen, aromatase inhibitor, ovarian ablation/suppression) and bisphosphonates. Radiotherapy options were after breast conserving surgery (whole breast, partial breast, tumour bed boost, regional nodes) and after mastectomy (chest wall, regional nodes). Treatment options were supported by randomised evidence, including > 10,000 women for eight treatment comparisons, 1,000-10,000 for fifteen and < 1,000 for one. Most treatment comparisons reduced breast cancer mortality or recurrence by 10-25%, with no increase in non-breast-cancer death. Anthracycline chemotherapy and radiotherapy increased overall non-breast-cancer mortality. Anthracycline risk was from heart disease and leukaemia. Radiation-risks were mainly from heart disease, lung cancer and oesophageal cancer, and increased with increasing heart, lung and oesophagus radiation doses respectively. Taxanes increased leukaemia risk.
CONCLUSIONS
These benefits and risks inform treatment decisions for individuals and recommendations for groups of women.
Topics: Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Mastectomy; Neoadjuvant Therapy; Tamoxifen
PubMed: 35367784
DOI: 10.1016/j.ctrv.2022.102375 -
CJC Open Nov 2021Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The... (Review)
Review
BACKGROUND
Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2-positive cancer who are receiving pertuzumab.
METHODS
We performed a systematic review of phase 2 and 3 randomized controlled trials in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2-positive cancer was evaluated, and cardiac adverse effects reported. We searched MEDLINE (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models.
RESULTS
Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants' median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF; RR [95% CI]: 1.97 [1.05-3.70]; I = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I = 19%).
CONCLUSIONS
Pertuzumab increases the risk of clinical HF, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity.
PubMed: 34901806
DOI: 10.1016/j.cjco.2021.06.019 -
Cureus May 2023Patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer require treatment upfront because of the aggressive nature of this type of... (Review)
Review
Pathologic Complete Response Achieved in Early-Stage HER2-Positive Breast Cancer After Neoadjuvant Therapy With Trastuzumab and Chemotherapy vs. Trastuzumab, Chemotherapy, and Pertuzumab: A Systematic Review and Meta-Analysis of Clinical Trials.
Patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer require treatment upfront because of the aggressive nature of this type of cancer. Patients with early-stage HER2-positive breast cancer are usually treated with neoadjuvant therapy. This neoadjuvant therapy comprises targeted therapy and chemotherapy. Targeted therapy is given with trastuzumab. Pertuzumab is either administered or not with trastuzumab as a targeted therapy. This systematic review and meta-analysis aim to find out and compare the benefit achieved in terms of pathologic complete response (pCR) by adding pertuzumab to the neoadjuvant treatment regimen for early-stage HER2-positive breast cancer patients. Various databases were searched to find out relevant clinical trials. After going through PubMed, Embase, and Cochrane, three clinical trials were shortlisted for this systematic review and meta-analysis. These three clinical trials were double-armed. Pertuzumab was present in one arm while being absent in one arm to assess the benefit of adding pertuzumab in terms of pCR achieved. Data were analyzed using RevMan Web (Cochrane, London, UK). The odds ratio and 95% confidence interval were calculated for the outcome. The Mantel-Haenszel method and random effect model were used for analysis. The risk of bias in studies was evaluated using the Cochrane risk of bias tool for randomized controlled trials (ROB2). The summary statistics showed that the incidence of pCR was more in the experimental group (having pertuzumab) as compared to the control group (without pertuzumab) with an odds ratio of 2.10 (95% CI: 1.56-2.83) with I2 = 0%. In three double-arm trials, there were 840 participants, 445 in the experimental group and 395 in the control group. A total of 203 (45%) patients out of 445 in the experimental group achieved pCR, whereas 127 (32%) patients out of 395 in the control group achieved pCR. Through the results of this study, it can be concluded that the rate of pCR achieved was higher in that arm in which pertuzumab was present compared to the study arm in which only trastuzumab was given as targeted therapy. Thus, it can be suggested that pertuzumab be added to the neoadjuvant regimen for early-stage HER2-positive breast cancer patients. This would result in achieving a better pCR. And by improving pCR rates, the survival outcomes of patients can be significantly improved.
PubMed: 37398703
DOI: 10.7759/cureus.39780 -
European Journal of Cancer (Oxford,... Sep 2023The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The recommended preoperative approach for HER2-positive breast cancer is unclear. We aimed to investigate the following: i) what is the optimal neoadjuvant regimen and ii) whether anthracyclines could be excluded.
METHODS
A systematic literature search in Medline, Embase and Web of Science databases was performed. Studies had to satisfy the following criteria: i) randomised controlled trials (RCTs), ii) enroled patients treated preoperatively for HER2-positive BC (breast cancer), iii) at least one treatment group received an anti-HER2 agent, iv) available information of any efficacy end-point and v) published in English. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR), event-free survival (EFS) and overall survival (OS) were the efficacy end-points of interest, and selected safety end-points were also analysed.
RESULTS
A total of 11,049 patients with HER2-positive BC (46 RCTs) were included in the network meta-analysis, and 32 different regimens were evaluated. Dual anti-HER2-therapy, with pertuzumab or tyrosine kinase inhibitors, combined with chemotherapy was significantly superior to trastuzumab and chemotherapy in terms of pCR, EFS and OS. However, a higher risk of cardiotoxicity was observed with dual anti-HER2-therapy. Anthracycline-based chemotherapy was not associated with better efficacy outcomes in comparison with non-anthracycline-based chemotherapy. In anthracycline-free regimens, the addition of carboplatin presented numerically better efficacy outcomes.
CONCLUSION
Dual HER2 blockade with chemotherapy is the recommended choice as neoadjuvant therapy for HER2-positive breast cancer, preferably by omitting anthracyclines in favour of carboplatin.
Topics: Humans; Female; Neoadjuvant Therapy; Carboplatin; Network Meta-Analysis; Receptor, ErbB-2; Breast Neoplasms; Trastuzumab; Antibiotics, Antineoplastic; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37142539
DOI: 10.1016/j.ejca.2023.03.042 -
Frontiers in Oncology 2022Although dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab, has shown promising results in patients with HER2-positive breast cancer (BC), it is still unclear...
Pertuzumab combined with trastuzumab compared to trastuzumab in the treatment of HER2-positive breast cancer: A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
Although dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab, has shown promising results in patients with HER2-positive breast cancer (BC), it is still unclear whether dual therapy will increase adverse effects (AEs) while ensuring the efficacy compared with trastuzumab monotherapy. We conducted a systematic review and meta-analysis to compare the efficacy and safety of combined therapy with monotherapy.
METHODS
A systematic search was performed to identify eligible randomized controlled trials (RCTs) that evaluated the administration of dual anti-HER2 therapy [pertuzumab plus trastuzumab or trastuzumab emtansine (T-DM1)] versus monotherapy (trastuzumab or T-DM1). The primary endpoints were overall survival (OS) and progression-free survival (PFS).
RESULTS
Fourteen RCTs (8,378 patients) were identified. Compared to monotherapy, dual therapy significantly improved the OS (HR = 0.77, 95% CI: 0.59-0.99) and PFS (HR = 0.74, 95% CI: 0.63-0.86) in advanced BC. In neoadjuvant therapy, dual blockade has a higher ORR rate than monotherapy. Grade 3 or higher febrile neutropenia, diarrhea, and anemia as well as heart failure were more frequently reported in dual therapy compared to monotherapy. No significant difference in serious AEs was observed between the two groups. In the subgroup analysis, compared to single-target therapy, dual-target therapy has higher OS and PFS rates in Asian patients with advanced therapy; however, total grade ≥3 AEs and serious AEs were significantly higher in the dual group in Asian patients.
CONCLUSIONS
Our study confirms that the combination of pertuzumab and trastuzumab therapy could substantially improve the outcome of patients with HER2-positive breast cancer and was well tolerated compared to trastuzumab monotherapy.
PubMed: 36249045
DOI: 10.3389/fonc.2022.894861 -
Breast (Edinburgh, Scotland) Jun 2023Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM.
METHODS
We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint.
RESULTS
7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine.
CONCLUSIONS
The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Trastuzumab; Meningeal Neoplasms
PubMed: 37156650
DOI: 10.1016/j.breast.2023.04.008 -
BMC Cancer Oct 2019Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although the dual anti-HER2 therapy, namely, pertuzumab plus trastuzumab and docetaxel, has shown promising results in HER2+ breast cancer patients, whether the dose, efficacy and safety of this treatment differs from those of other pertuzumab-based dual anti-HER2 therapies remain controversial. This systematic review evaluates the efficacy and safety of H (trastuzumab or trastuzumab emtansine ± chemotherapy) + P (pertuzumab) compared with those of H in HER2+ breast cancer patients.
METHODS
A comprehensive search was performed to identify eligible studies comparing the efficacy and safety of H + P versus H. The pathologic complete response (pCR), median progression-free survival (PFS) and overall survival (OS) were the primary outcomes, and safety was the secondary outcome. A subgroup analysis of pCR according to hormone receptor (HR) status was performed. All analyses were conducted using STATA 11.0.
RESULTS
Twenty-six studies (9872 patients) were identified. In the neoadjuvant setting, H + P significantly improved the pCR [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.08-1.63; p = 0.006]. In the metastatic setting, H + P significantly improved PFS [hazard ratios (HRs) = 0.75; 95% CI, 0.68-0.84; p < 0.001]. There was a trend towards better OS but that it did not reach statistical significance (HRs = 0.81; 95% CI, 0.64-1.03; p = 0.082). A subgroup analysis revealed that the HER2+/HR- patients who received H + P showed the highest increase in the pCR. Rash, diarrhea, epistaxis, mucosal inflammation, and anemia were significantly more frequently observed with H + P than with H, whereas myalgia was less frequent (OR = 0.91; 95% CI, 0.82-1.01; p = 0.072), and no significant difference in cardiac toxicity was observed between these therapies (OR = 1.26; 95% CI, 0.81-1.95; P = 0.309).
CONCLUSIONS
Our study confirms that H + P is superior to H in the (neo)adjuvant treatment of HER2+ breast cancer, and increase the risk of acceptable and tolerable toxicity (rash, diarrhea, epistaxis, mucosal inflammation, and anemia).
TRIAL REGISTRATION
A systematic review protocol was registered with PROSPERO (identification number: CRD42018110415 ).
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Diarrhea; Docetaxel; Epistaxis; Exanthema; Female; Humans; Molecular Targeted Therapy; Neoadjuvant Therapy; Progression-Free Survival; Receptor, ErbB-2; Trastuzumab
PubMed: 31638935
DOI: 10.1186/s12885-019-6132-0 -
Biomedicines Aug 2022Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated... (Review)
Review
Trastuzumab is a monoclonal antibody used in the treatment of breast cancer in cases where the tumor overexpresses the HER2 receptor, a cell membrane receptor activated by the epidermal growth factor. Intravenous and subcutaneous administration of trastuzumab have comparable clinical and pharmacological characteristics, but trastuzumab biosimilars are currently only available in intravenous form. Trastuzumab biosimilars are ultimately preferred by a proportion of patients, especially in cases where co-administration of other chemotherapeutic agents, such as trastuzumab and tucatinib, a small molecule of tyrosine kinase inhibitor, is required in patients with HER-positive metastatic breast cancer. Oncologists should be well-aware of the advantages of intravenously administered trastuzumab biosimilars over subcutaneous administration, certainly also taking into account the patient's preferences. Further cost-effectiveness analyses will be very important, along with expectations regarding successful concomitant subcutaneous administration of trastuzumab with other anticancer drugs, such as pertuzumab. This systematic review describes and analyzes the so-far published studies concerning the use of the available trastuzumab biosimilars in HER-positive early and metastatic breast cancer in terms of efficacy, safety, and cost-benefit ratio. An attempt was also made to draw some conclusions and to comment on future needs and perspectives.
PubMed: 36009592
DOI: 10.3390/biomedicines10082045 -
Journal of Clinical Oncology : Official... Jul 2014To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)... (Review)
Review
Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline.
PURPOSE
To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.
METHODS
The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events.
RESULTS
A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer.
RECOMMENDATIONS
HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.
Topics: Ado-Trastuzumab Emtansine; Anastrozole; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Comorbidity; Docetaxel; Drug Administration Schedule; Evidence-Based Medicine; Female; Health Status Disparities; Healthcare Disparities; Humans; Lapatinib; Letrozole; Maytansine; Molecular Targeted Therapy; Nitriles; Quinazolines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Societies, Medical; Taxoids; Trastuzumab; Treatment Outcome; Triazoles; United States
PubMed: 24799465
DOI: 10.1200/JCO.2013.54.0948 -
The Lancet. Oncology Mar 2019Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated... (Meta-Analysis)
Meta-Analysis
Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: a systematic review and meta-analysis.
BACKGROUND
Although frequently used as a primary endpoint, disease-free survival has not been validated as a surrogate for overall survival in early breast cancer. We investigated this surrogacy in the adjuvant setting of treatment with anti-HER2 antibodies.
METHODS
In a systematic review and meta-analysis, we identified published and non-published randomised controlled trials with completed accrual and available disease-free survival and overall survival results for the intention-to-treat population as of September 2016. Bibliographic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials), clinical trial registries (Clinicaltrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, and PharmNet.Bund), and trial registries from relevant pharmaceutical companies were searched. Eligibility for treatment of HER2-positive early breast cancer required at least one group to have an anti-HER antibody treatment (ie, trastuzumab, pertuzumab, or trastuzumab emtansine) planned for 12 months, and at least one control arm with chemotherapy without the antibody, a lower total dose or duration of the antibody, or observation alone. Units of analysis were contrasts: two-group trials gave rise to one contrast, whereas trials with more than two groups gave rise to more than one contrast. We excluded trials enrolling patients with recurrent, metastatic, or non-invasive disease, and those testing neoadjuvant therapy exclusively. Our primary objective was to estimate patient-level and trial-level correlations between disease-free survival and overall survival. We measured the association between disease-free survival and overall survival using Spearman's correlation coefficient (r), and the association between hazard ratios (HRs) for disease-free survival and overall survival using R. We computed the surrogate threshold effect, the maximum HR for disease-free survival that statistically predicts an HR for overall survival less than 1·00 in a future trial.
FINDINGS
Eight trials (n=21 480 patients) gave rise to a full set (12 contrasts). Patient-level associations between disease-free and overall survival were strong (r=0·90 [95% CI 0·89-0·90]). Trial-level associations gave rise to values of R of 0·75 (95% CI 0·50-1·00) for the full set. Subgroups defined by nodal status and hormone receptor status yielded qualitatively similar results. Depending on the expected number of deaths in a future trial, the surrogate threshold effects ranged from 0·56 to 0·81, based on the full set.
INTERPRETATION
These findings suggest that it is appropriate to continue to use disease-free survival as a surrogate for overall survival in trials in HER-2-positive, early breast cancer. The key limitation of this study is the dependence of its results on the trials included and on the existence of an outlying trial.
FUNDING
Roche Pharma AG.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Neoplasm Staging; Proportional Hazards Models; Receptor, ErbB-2; Treatment Outcome
PubMed: 30709633
DOI: 10.1016/S1470-2045(18)30750-2