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Multivariable Logistic Regression Analysis
Source publication
Oncotype Dx 21-gene assay recurrence score (RS) predicts recurrence of early-stage breast cancer (ESBC). We investigated whether patient, tumor, or practice characteristics drive its use and explored Oncotype DX RS and chemotherapy use in subgroups.
Patients with ESBC with documented estrogen receptor-positive, lymph node-negative, human epidermal...
Context in source publication
Context 1
... for other covariates (Table 2), for a patient with a low-risk RS, the odds of receiving chemotherapy were 23.2% (95% CI, 0.17% to 0.317%) of the odds for those without a valid RS test. Compared to patients without a valid RS, those with an intermediate-risk RS were 3.19 (95% CI, 2.59 to 3.93) times more likely to undergo chemotherapy, and those with a high-risk RS were 23.79 (95% CI, 14.36 to 39.41) times more likely to undergo chemotherapy. ...
Similar publications
To determine whether multiple primary breast cancers have similar genetic profiles, specifically Oncotype Dx Recurrence Scores, and whether obtaining Oncotype Dx on each primary breast cancer affects chemotherapy recommendations.
A database of patients with hormone receptor-positive, lymph node-negative, breast cancer was created for those tumors t...
Citations
... Postoperative adjuvant systemic treatment for breast cancer is conducted considering various oncological factors, including age, tumor burden, hormone receptor (HR) status (estrogen receptor [ER] or progesterone receptor [PR]), human epidermal growth factor receptor 2 (HER2), and the Ki-67 index [1][2][3][4][5]. Axillary lymph node (ALN) metastases have served as indicators of poor prognosis and criteria for adjuvant systemic treatment [6]. ...
Purpose
The gene expression test (GET) was used to predict the response to chemotherapy and the recurrence risk. Several randomized clinical trials have demonstrated that some patients with node-positive disease can achieve favorable survival outcomes even without adjuvant chemotherapy. This study aimed to predict the results of Oncotype DX (Genomic Health) and MammaPrint (Agendia) using traditional clinicopathological factors.
Methods
We reviewed the records of 311 patients who underwent GET for hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative primary invasive breast cancer with node-positive disease between 2015 and 2022 at Severance Hospital and Gangneung Asan Medical Center. Univariate and multivariate logistic regression analyses assessed the relationships between clinicopathological variables and risk stratification using the GET results.
Results
A simple scoring system was created by assigning integer values to each variable. A score of 3 was assigned for histological grade 3, a score of 2 for pathologic T2 or above, and a score of 1 for a lower progesterone receptor (1–20 or Alled score 3–6), HER2 2-positive, and high Ki-67 (>20). In the validation cohort, overall accuracy was 0.798 (95% confidence interval, 0.744–0.844).
Conclusion
The high GET risk results can be predicted using traditional clinicopathological factors: tumor size, progesterone receptor, histological grade, HER2, and Ki-67. These results will be useful for treatment decision-making among clinically high-risk patients with HR-positive/HER2-negative and node-positive disease, helping to identify patients to whom the GET assay may not apply.
... In patients with ESBC, similar racial/ethnic disparities have been identified with non-Hispanic white women more likely to have genomic profiling than non-Hispanic black or Hispanic women [14][15][16][17]. In contrast to patients with ESBC where genomic profiling is less commonly utilized in older patients [14,18], we found that older women with LABC were more likely to have testing. Genomic profiling was also used more frequently in those with stage IIIA disease or well-/moderately differentiated tumors. ...
Purpose
Genomic profiling in early-stage breast cancer provides prognostic and predictive information. Genomic profiling assays have not been validated in locally advanced breast cancer (LABC). We examined a large cancer registry to evaluate genomic profiling in LABC and its effect on treatment decisions and survival.
Methods
Females with ER+/HER2− LABC who did not receive neoadjuvant therapy were selected from the National Cancer Database 2004–2017. We compared characteristics between patients with and without genomic profiling and with low genomic risk, 21-gene recurrence score ≤ 25 or low-risk 70-gene signature, treated with endocrine therapy ± chemotherapy. Propensity score methods were utilized to account for covariates that may have predicted treatment. Univariable and multivariable survival analyses were performed.
Results
Of 18,437 patients with LABC, 1258 (7%) had genomic profiling and 1022 (81%) had low genomic risk results. 562 patients (55%) with low genomic risk received chemotherapy and endocrine therapy (chemoendocrine). Patients who received chemoendocrine therapy were younger, had fewer comorbidities, presented with higher stage disease, had higher grade tumors, more frequently had partial mastectomy, and more often received radiation than those who received endocrine therapy alone. On multivariable analysis, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy (HR 1.77, 95% CI 1.13–2.78, p = 0.013).
Conclusion
In women with LABC and low genomic risk, endocrine therapy alone was associated with worse OS compared to chemoendocrine therapy. This suggests that genomic profiling is not predictive in LABC. Accordingly, genomic profiling should not be routinely utilized to make adjuvant treatment decisions in LABC in the absence of further data which shows a benefit.
... Our data is consistent with previous studies [25][26][27][28][29] demonstrating decreased use of ODX RS with increasing age. Similar to previous reports 30 , we found that median ODX RS was similar across age and nodal status. ...
Oncotype DX (ODX) recurrence score (RS) is a validated tool to guide the use of adjuvant chemotherapy (AC) in hormone receptor+/HER2- breast cancer. In this analysis, we examine (1) characteristics associated with ODX testing and (2) the association between ODX RS and receipt of AC across age and nodal status. Women with HR+/HER2–, early-stage (T1-2, N0-1) breast cancers from 2010–2017 in the National Cancer Database were included. 530,125 met inclusion and 255,971 received ODX testing. Older women were less likely to receive testing; however, nodal positivity increased use of testing. High ODX RS was associated with increased mortality, though the association was not consistent across age and was most strongly associated with mortality among younger, node-negative women. Older women with high ODX RS, regardless of nodal status, were less likely to receive AC. Clinicians may be employing ODX RS to support treatment decisions against the receipt of AC.
... The FDA has recently approved the CellSearch system for measuring circulating cancer cells (CTCs), but only in metastatic disease [4,5]. Also, Oncotype DX, a 21-gene transcript-based assay, is currently used as a prognostic tool and for personalized treatment options in early stage ER + BC [6]. As an alternative, ccfDNA is currently the spearhead in biomedical research and provides the choice of non-invasive repetitive sampling for cancer monitoring. ...
Simple Summary
Our research focuses in the elucidation of the nature of circulating cell-free DNA (ccfDNA) as a biological entity and its exploitation as a liquid biopsy biomaterial. Working on breast cancer, it became clear that although a promising biosource, its clinical exploitation is burdened mainly by gaps in knowledge about its biology and specific characteristics. The current review covers multiple aspects of ccfDNA in breast cancer. We cover key issues such as quantity, integrity, releasing structures, methylation specific changes, release mechanisms, biological role. Machine learning approaches for analyzing ccfDNA-generated data to produce classifiers for clinical use are also discussed.
Abstract
Breast cancer (BC) is a leading cause of death between women. Mortality is significantly raised due to drug resistance and metastasis, while personalized treatment options are obstructed by the limitations of conventional biopsy follow-up. Lately, research is focusing on circulating biomarkers as minimally invasive choices for diagnosis, prognosis and treatment monitoring. Circulating cell-free DNA (ccfDNA) is a promising liquid biopsy biomaterial of great potential as it is thought to mirror the tumor’s lifespan; however, its clinical exploitation is burdened mainly by gaps in knowledge of its biology and specific characteristics. The current review aims to gather latest findings about the nature of ccfDNA and its multiple molecular and biological characteristics in breast cancer, covering basic and translational research and giving insights about its validity in a clinical setting.
... The Oncotype DX 21-gene Recurrence Score (RS) was developed in order to determine the likelihood of distant recurrence of early-stage breast cancer patients who initially were diagnosed with node-negative, ER + luminal type breast cancer treated with tamoxifen [44,45]. The RS stratifies the risk of distant recurrence based on an algorithm of the expression levels of 16 cancer-related genes and 5 reference genes. ...
Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy.
... These results, taken together with those that have examined chemotherapy benefit as a function of RS [13,16,20,[57][58][59], suggest that patients with a sufficiently low IHC score are unlikely to benefit from chemotherapy. Recent evidence from the TAILORx trial suggests that a subset of patients with RS scores in the intermediate range are also unlikely to benefit from chemotherapy [60]. ...
Background
The development of molecular techniques to estimate the risk of breast cancer recurrence has been a significant addition to the suite of tools available to pathologists and breast oncologists. It has previously been shown that immunohistochemistry can provide a surrogate measure of tumor recurrence risk, effectively providing a less expensive and more rapid estimate of risk without the need for send-out. However, concordance between gene expression-based and immunohistochemistry-based approaches has been modest, making it difficult to determine when one approach can serve as an adequate substitute for the other. We investigated whether immunohistochemistry-based methods can be augmented to provide a useful therapeutic indicator of risk.
Methods
We studied whether the Oncotype DX breast cancer recurrence score can be predicted from routinely acquired immunohistochemistry of breast tumor histology. We examined the effects of two modifications to conventional scoring measures based on ER, PR, Ki-67, and Her2 expression. First, we tested a mathematical transformation that produces a more diagnostic-relevant representation of the staining attributes of these markers. Second, we considered the expression of BCL-2, a complex involved in regulating apoptosis, as an additional prognostic marker.
Results
We found that the mathematical transformation improved concordance rates over the conventional scoring model. By establishing a measure of prediction certainty, we discovered that the difference in concordance between methods was even greater among the most certain cases in the sample, demonstrating the utility of an accompanying measure of prediction certainty. Including BCL-2 expression in the scoring model increased the number of breast cancer cases in the cohort that were considered high certainty, effectively expanding the applicability of this technique to a greater proportion of patients.
Conclusions
Our results demonstrate an improvement in concordance between immunohistochemistry-based and gene expression-based methods to predict breast cancer recurrence risk following two simple modifications to the conventional scoring model.
... Several studies have examined the impact of age and menopausal status on the distribution and validity of oDX scores, although most are either reports from a single institution or lack clinical data (such as chemotherapy use) and are therefore not generalizable. [13][14][15][16] We hypothesize that there are likely differences in both the use of oDX in the\ 50 and C 50 years of age patient populations and that RS is weighed more heavily in chemotherapy use/recommendations in older ([ 50 years) versus younger (\ 50 years) patients. We aimed to use the National Cancer Database (NCDB) to evaluate practice trends in the use of oDX and its impact on chemotherapy use in patients \ 50 years of age compared with those C 50 years of age. ...
Background:
Oncotype DX (oDX) is used to predict recurrence and indicate response to chemotherapy in patients with early-stage breast cancer (BC). We evaluated the relationship between age (< 50 vs. ≥ 50 years), recurrence score (RS), chemotherapy use, and trends of oDX testing over time.
Methods:
Using the National Cancer Database, we identified women with T1/T2, N0, estrogen receptor-positive BC from 2009 to 2014. We stratified patients by age (< 50 and ≥ 50 years) and RS (low: < 18; intermediate: 18-30; and high: > 30), and compared demographics, tumor characteristics, and chemotherapy recommendations. Management trends were also assessed.
Results:
From 2009 to 2014, a total of 377,725 cases met the eligibility criteria for oDX testing; 115,052 (30.5%) patients had oDX, and 60,804 (16.1%) were < 50 years of age. The majority had low RS and T1N0 disease. Patients < 50 years of age were more likely to be recommended chemotherapy than those ≥ 50 years of age, regardless of RS (p ≤ 0.001), and were more likely to ultimately undergo chemotherapy (p < 0.001). When stratified by year, oDX utilization increased. There was a decreasing trend in chemotherapy recommendations in both the low- and intermediate-RS groups for both age groups (all p = 0.001), with no change in the high-RS group (< 50 years: p = 0.52; ≥ 50 years: p = 0.67). Univariate and multivariate analyses demonstrated that patients < 50 years of age and those with a higher RS were more likely to be recommended chemotherapy (p < 0.001).
Conclusions:
The testing of oDX in BC has significantly increased since first implemented. Results from additional studies such as TAILORx will clarify the current discordant practice patterns between low oDX RSs and adjuvant chemotherapy recommendations.
... They can help patients to avoid the potential adverse toxicity from chemotherapy when the recurrence risk and treatment benefit is low [24]. On the other hand, such prognostic genomic assays should not miss to identify patients that are at high risk of recurrence and could benefit from chemotherapy [25]. ...
There had been several studies using gene-expression profiling in predicting distant recurrence in breast cancer. In this study, we developed an 18-gene classifier (18-GC) to predict distant recurrence of breast cancer and compared it with the 21- gene panel (Oncotype DX®, ODx) in performance. Included were 224 breast cancer patients with positive hormonal receptor (HR+) and negative human epidermal growth factor receptor 2 (HER2-). We compared the demographic, clinical, and survival information of the patients, and further compared the prediction of recurrence risk obtained by using the 18-GC with that by ODx. To have the best combined sensitivity and specificity, receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff values for several breakpoint scores. For the new 18-GC, a breakpoint score of 21 was adopted to produce a combined highest sensitivity (95%) and specificity (39%) in detecting distant recurrence. At this breakpoint score, 164 of the 224 patients were classified by the 18-GC in the same risk level as by ODx, giving a concordance rate of 73%. Along with patient age and tumor stage, this 18- GC was found to be an independent significant prognostic factor of distant metastasis of breast cancer. We have thus created a new gene panel assay for prediction of distant recurrence in HR+ and HER2- breast cancer patients. With a high concordance rate with ODx, this new assay may serve as a good tool for individual breast cancer patients to make an informed decision on whether adjuvant chemotherapy should be performed post-surgery.
... One of the pillars in cancer treatment, chemotherapy has played a significant role in improving the outcomes of breast cancer patients over the years. Traditionally, chemotherapy was offered to premenopausal women with early-stage node-negative breast cancer based primarily on tumor size (e.g., > 1 cm) and receptor status (e.g., triple-negative or HER2-positive) [1][2][3][4]. ...
Background:
The recommendation for chemotherapy in early-stage breast cancer patients has been refined by the 21-gene Recurrence Score. However, uncertainty remains whether patients in the Intermediate Risk category benefit from chemotherapy.
Methods:
We analyzed female patients from the National Cancer Database from 2006 to 2012 who had pT1c-T2N0M0 breast cancer, were ER/PR-positive and HER2-negative, received endocrine therapy, and had a 21-gene Recurrence Score from 11 to 25. We performed univariate and multivariate logistic regression analyses to see what impacted chemotherapy receipt. We compared overall survival using Kaplan-Meier curves and the log-rank test. A multivariable Cox proportional hazards regression model was used to assess what variables impacted overall survival.
Results:
Of 21,991 patients who met all inclusion and exclusion criteria, 4646 (21.1%) received chemotherapy and 17,345 (78.9%) did not. Chemotherapy was more often received by patients who were younger (adjusted odds ratios (aORs) compared to age < 40 years, 0.48 for 40s, 0.34 for 50s, 0.20 for 60s, 0.10 for 70s, and 0.07 for 80+), had private insurance vs Medicare (aOR = 1.37), were from metro vs urban counties (aOR = 1.15), and were treated in community cancer centers vs academic programs (aOR = 1.26), and those with tumors of higher grade (grade 2 vs 1, aOR = 1.72; grade 3 vs 1, aOR = 3.76), higher tumor stage (pT2 vs pT1c, aOR = 1.62), or presence of lymphovascular invasion (LVI) (aOR = 1.41). At a median follow-up of 46.4 months, there was no significant difference in overall survival between patients who received chemotherapy vs those who did not (5-year estimated overall survival, 97.4% vs 97.8%, p = 0.89). On multivariable analysis, worse overall survival was associated with Black race, treatment at a community program, Medicaid, high-grade tumors, pT2 vs pT1c, higher Charlson-Deyo score, and no radiotherapy. Utilization trends showed that chemotherapy receipt in these patients has been decreasing from 25.8% in 2010 to 18.4% in 2013 (p < 0.001).
Conclusions:
In these patients where the benefit of chemotherapy remains uncertain, current practices see chemotherapy more likely to be used in patients with younger age, higher pathologic T stage, higher grade tumors, and LVI. No apparent difference was seen in overall survival between those who received chemotherapy and those who did not.
... However, existing research has not produced clear guidance on how to maximize the effectiveness of such opinion leaders in disseminating new technology [9]. This analysis has several important strengths including the large, integrated healthcare setting, linked patient, [3,6,8,[25][26][27] and has increased from earlier reported rates in this setting [5]. On balance, the variability we observed in testing rates among practice groups suggests that financial access alone will not ensure consistent use of cancer genomic tests. ...
Purpose:
Multigene testing for breast cancer recurrence risk became available in 2007, yet many eligible patients remain untested. This study evaluated variation in testing rates, and oncologist and organizational factors associated with variation, in a setting without financial influences on testing.
Methods:
We conducted a retrospective cohort study using electronic data and oncologist surveys within Kaiser Permanente Northern California, a large integrated health care system. Analyses included all 2974 test eligible patients from 2013 to 2015, 113 oncologists, and 15 practice groups. Receipt of multigene testing was evaluated with generalized linear mixed models.
Results:
Overall, 39% of eligible patients had multigene testing, but rates varied widely among practice groups, ranging from 24 to 48% after case mix adjustment. This 24% difference among practices was greater than the variation associated with most patient characteristics, including comorbidities and race/ethnicity, and similar to that associated with tumor size. Practice group and oncologist factors were statistically significant contributors to the variation in testing after adjusting for patient factors. Patients were more likely to be tested if they had a female oncologist (aOR 1.60, 95% CI 1.21-2.12) or were in a practice whose chief had a high testing rate (aOR 1.20, 95% CI 1.12-1.29 per 10% increase in the percent tested).
Conclusions:
Oncologist and leadership practices play a key role in the variation in genomic test use for cancer recurrence risk even in a healthcare system without financial barriers to testing and could be a leverage point for implementing desired practice changes for new genomic advances.
