One of the most prevalent potential therapeutic targets for women with endometrioid endometrial cancer (EC) is the estrogen receptor (ER)/progesterone receptor (PR) pathway. Despite a high proportion ...of endometrioid ECs being ER and/or PR positive, endocrine therapy is only effective in a minority of women with EC and ultimately patients progress with resistance developing to treatment. A variety of treatment approaches with progestins, selective ER modulators (SERMs) and aromatase inhibitors (AIs) are available. Exploration of these agents is desirable given their favorable toxicity profile. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and strategies for new therapeutic options. Here we review the clinical efficacy of endocrine therapy in EC, discuss the role of ER and/or PR as prognostic biomarkers, describe disease-specific mechanisms of resistance to endocrine therapy and explore potential strategies to enhance response for the “next generation” of endocrine therapy clinical trials. We also describe the use of endocrine therapy in younger women seeking to pursue fertility sparing options for management of EC.
•A high proportion of endometrioid endometrial cancers are estrogen receptor (ER) and/or progesterone receptor (PR) positive.•Responses of endometrial cancers to single-agent progestins, selective ER modulators and aromatase inhibitors are low.•Understanding mechanisms of resistance to endocrine therapy has generated opportunities to enhance responses to treatment.•Clinical trials evaluating novel combination therapies are highly desirable to optimize ER/PR targeted treatment approaches.
Abstract
Background
Patients with metastatic breast cancer (MBC) are living longer, but the development of brain metastases often limits their survival. We conducted a systematic review and ...meta-analysis to determine the incidence of brain metastases in this patient population.
Methods
Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with human epidermal growth factor receptor-2 positive (HER2+), triple negative, and hormone receptor (HR)+/hormone receptor negative (HER2−) MBC; pooled overall estimates for incidence were calculated using random effects models.
Results
937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2− MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0–34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5–40.6), and 15% among patients with HR+/HER2− MBC (median follow-up: 33.0 months, IQR: 31.9–36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10–0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09–0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03–0.08) for patients with HR+/HER2− MBC.
Conclusion
There is a high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.
Background
Tumor multigene next‐generation sequencing (NGS) is increasingly being offered to cancer patients to guide clinical management and determine eligibility for clinical trials. We undertook a ...review of studies examining the knowledge and attitudes of patients and oncologists regarding the primary results and potential secondary findings of such testing.
Materials and Methods
A search was conducted through the MEDLINE database using the following keywords: “neoplasms” and “molecular sequencing / genome sequencing / tumor profiling / NGS / whole exome sequencing” and “patient / oncologist” and “knowledge / attitudes / satisfaction / experience / evaluation / perspective / practice / preference.” Articles meeting the inclusion criteria and additional relevant articles from their references were selected.
Results
From 1,142 publications identified by the search and 9 from references, 21 publications were included in the final review. Patients generally had positive attitudes toward tumor NGS despite relatively little knowledge of test‐related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes toward disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy; they communicated challenges with tempering patient expectations and deciding what information to disclose.
Conclusion
Patients considering undergoing tumor NGS should be provided with easily understandable resources explaining the procedure, goals, and probable outcomes, whenever possible based on evidence‐based guidelines. Continuing medical education programs on this topic for oncology health care professionals should strive to improve their genomic literacy and instruct them on how to optimally present this information to their patients.
Implications for Practice
Oncologists are increasingly offering tumor multigene testing to patients with advanced cancers to guide more “personalized” treatment and/or determine eligibility for clinical trials. However, patients often have inadequate understanding and unrealistic expectations. Oncologists must ensure that they themselves have sufficient knowledge of the benefits and limitations of testing and must provide their patients with appropriate educational resources. Prior to testing, patients should be told the likelihood of finding a mutation in their specific tumor type for which a targeted treatment or clinical trial is available. Patients also need clear information about the possibility and implications of secondary findings.
This review focuses on patient and/or physicians’ knowledge and attitudes regarding tumor multigene next‐generation sequencing with potential therapeutic intent.
The molecular mechanism underlying the CNS activity of trastuzumab deruxtecan remains elusive and is an area of active investigation, as it is known that trastuzumab administered intravenously ...reaches the cerebrospinal fluid in the CNS at only 1–10% of its serum concentration.5 Nonetheless, trastuzumab deruxtecan has demonstrated intracranial objective response rates of up to 73% in patients with metastatic HER2-positive breast cancer and active CNS metastases in the TUXEDO trial.4 Patients with HER2-expressing metastatic NSCLC with active CNS disease represent a distinct population primed to derive benefit from trastuzumab deruxtecan. Given the relative rarity of patients with HER2-expressing metastatic NSCLC with active brain or leptomeningeal metastases, the engagement of international clinical trial networks might improve feasibility of such approaches. KJJ has been a consultant, speaker, or advisory board member for Amgen, AstraZeneca, Apo Biologix, Daiichi Sankyo, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics, Organon, Seagen (now Pfizer), Roche, Novartis, and Viatris; has received research funding from AstraZeneca, Eli Lilly, and Seagen (now Pfizer); has received support for attending meetings or travel from AstraZeneca and Daiichi Sankyo; has a patent regarding compounds for treating cancer and methods of use thereof (US patent 10 576 056; Europe patent 3 393 466); and has received drug supply from Viatris for an investigator initiated clinical trial.
Objective
To examine the association between Karnofsky Performance Status (“KPS”) and brain-specific progression-free survival (“bsPFS”) among patients with breast cancer brain metastases (“BCBrM”).
...Methods
Using a previously compiled retrospective cohort of 683 patients who were treated for BCBrM with surgery and/or radiotherapy at the Sunnybrook Odette Cancer Centre from 2008-2018, electronic records were reviewed to impute KPS scores at the time of BCBrM diagnosis. Patients were then grouped into KPS ≤60 and KPS >60 cohorts. The dataset was analyzed to identify variables that were prognostic for bsPFS and/or overall survival (“OS”) using univariable and multivariable Cox proportional hazards models.
Results
The mean age of patients was 57 (range 24-93). Most patients (
n
=622, 91%) had extracranial metastatic disease and 174 (25%) had leptomeningeal disease. 247 patients (36%) had hormone receptor (“HR”)-positive/human endothelial growth factor receptor 2 (“HER2”)-negative tumours, 189 (28%) had HER2-positive disease, and 153 (22%) had triple-negative breast cancer. Of the 331 patients (48%) who could be assigned a KPS cohort, 102 (31%) had KPS ≤60. Most patients were treated with whole brain radiotherapy (
n
=498, 73%) and/or stereotactic radiosurgery (“SRS”) (
n
=128, 19%). Median bsPFS was 9 months (95% CI 8-10 months) and median OS was not reached. In univariable analyses, KPS ≤60, presence of leptomeningeal disease, neurological symptoms, ≥2 brain metastases, and not undergoing SRS were factors associated with shorter bsPFS. In a multivariable analysis, KPS ≤60 was the only statistically significant determinant of bsPFS (HR 1.86, 95% CI 1.20-2.88). Although survival data was limited, KPS ≤60 was associated with shorter OS in both univariable (HR 3.12, 95% CI 1.85-5.26) and multivariable (HR 2.95, 95% CI 1.55-5.58) analyses.
Conclusion
Patients with BCBrM who have a KPS ≤60 have significantly shorter bsPFS and OS than those with KPS >60. KPS should be documented routinely at the time of diagnosis of brain metastases to improve prognostication.
The approval of CDK4/6 inhibitors has dramatically improved care for the treatment of HR+/HER2- advanced breast cancer, but navigating the rapidly-expanding treatment evidence base is challenging. In ...this narrative review, we provide best-practice recommendations for the first-line treatment of HR+/HER2- advanced breast cancer in Canada based on relevant literature, clinical guidelines, and our own clinical experience. Due to statistically significant improvements in overall survival and progression-free survival, ribociclib + aromatase inhibitor is our preferred first-line treatment for de novo advanced disease or relapse ≥12 months after completion of adjuvant endocrine therapy and ribociclib or abemaciclib + fulvestrant is our preferred first-line treatment for patients experiencing early relapse. Abemaciclib or palbociclib may be used when alternatives to ribociclib are needed, and endocrine therapy can be used alone in the case of contraindication to CDK4/6 inhibitors or limited life expectancy. Considerations for special populations-including frail and fit elderly patients, as well as those with visceral disease, brain metastases, and oligometastatic disease-are also explored. For monitoring, we recommend an approach across CDK4/6 inhibitors. For mutational testing, we recommend routinely performing ER/PR/HER2 testing to confirm the subtype of advanced disease at the time of progression and to consider
and
testing for select patients. Where possible, engage a multidisciplinary care team to apply evidence in a patient-centric manner.
Importance:
Metastatic breast cancer with central nervous system (CNS) metastases carries a poor prognosis. Recently, CDK4/6 inhibitors have demonstrated a progression free survival (PFS) and overall ...survival benefit when combined with standard endocrine therapy in advanced hormone receptor (HR)+/HER2- breast cancer. Pre-clinical data suggests possible activity of CDK4/6 inhibitors in the brain, but their CNS-specific benefit has not been explored in clinical practice.
Methods:
We reviewed clinical trials investigating the efficacy of CDK4/6 inhibitors for advanced or metastatic HR+/HER2- breast cancer. We also reviewed pre-clinical studies that demonstrated the ability of CDK4/6 inhibitors to cross the blood-brain barrier (BBB) and halt the growth of brain metastases in animal models.
Findings:
An ongoing phase II trial (NCT02308020) was designed to investigate the safety and tolerability of abemaciclib for treatment of patients with CNS metastases, with preliminary data showing partial response in some patients. Review of key randomized phase III trials revealed a scarcity of data pertaining to the development of new CNS metastases. Pre-clinical models demonstrate that CDK4/6 inhibitors are able to cross the BBB and can delay the growth of brain metastases.
Conclusions:
Despite encouraging pre-clinical evidence, there is a lack of clinical data to inform CNS-specific response rates to CDK4/6 inhibitors among patients with metastatic breast cancer. Given that the treatment of patients with breast cancer brain metastases represents an area of unmet medical need, enrollment of patients with CNS metastases in ongoing clinical trials should be encouraged; innovative trials that examine response of CNS metastases to CDK4/6 inhibitors are also of interest.
PURPOSE Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). The inability to accurately estimate an individual's risk of local ...recurrence (LR) and invasive LR using clinicopathologic factors (CPF) contributes to the overtreatment of DCIS. We examined the impact of the 12-gene DCIS Score (DS) and the 21-gene Recurrence Score (RS) on the accuracy of predicting LR and invasive LR. METHODS A population-based cohort diagnosed with pure DCIS treated with BCS ± RT from 1994 to 2003 was used. All patients had expert pathology review and assessment of the DS and RS. Predictive models (CPF alone, DS + CPF, and RS + CPF) were developed using multivariable Cox regression analyses to predict 10-year LR and invasive LR risks. Models were evaluated on the basis of c-statistic, –2log likelihood estimate (–2LLE), and Akaike information criterion. Calibration was performed using bootstrap resamples, with replacement. RESULTS The cohort includes 1,226 women treated with BCS; 712 received RT. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive. Models including the DS or RS performed better in predicting the 10-year risk of LR compared with models on the basis of CPF alone with excellent calibration. The two molecular-based models also performed better in predicting invasive LR compared with the CPF model but the model incorporating the RS did not perform better in the prediction of invasive LR compared with the DS-based model. CONCLUSION Models incorporating the DS or RS more accurately predicted the 10-year risk of LR and invasive LR after BCS compared with models on the basis of CPF alone. Inclusion of the RS, compared with DS, did not improve the prediction of the 10-year risk of invasive LR.
Clinical data supporting the best therapeutic approach in leptomeningeal disease (LMD; also known as leptomeningeal metastases or leptomeningeal carcinomatosis) are lacking. Despite the development ...of new agents and increasing incidence of central nervous system metastases, patients with LMD are often excluded from clinical trials in breast cancer, with very few conducted specifically in LMD. Consequently, current evidence may not provide an accurate reflection of real-world clinical practice. This review aims to provide further insight into the treatment strategies for patients with breast cancer and LMD. We explore differences between clinical and real-world studies, considering inclusion criteria, levels of evidence for LMD diagnosis, and time between diagnosis of LMD and LMD-specific treatment initiation. Patient prognosis is poor; median overall survival is limited to several months, with approximately 10% of patients alive at 12 months. Efficacy results have been reported for various systemic and intrathecal agents in LMD to date. Systemic therapies under investigation for LMD in breast cancer include tucatinib, trastuzumab deruxtecan, and paclitaxel trevatide; trastuzumab is the main intrathecal agent currently under investigation. Recent trials investigating systemic or intrathecal therapies are typically small, single-arm studies, and most are restricted to patients with human epidermal growth factor receptor 2-positive breast cancer. Moreover, the variability among inclusion criteria and response assessment tools makes the interpretation of results difficult. Large retrospective cohorts with various inclusion criteria and treatment regimens provide some real-world data. However, there remains an urgent need for randomised clinical trials which include patients with LMD across all breast cancer subtypes.
Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary ...results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression.
Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status.
At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94). Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status.
Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
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