Real-world use of multigene signatures in early breast cancer: differences to clinical trials

doi:10.21203/rs.3.rs-3333731/v1

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Research Article

Real-world use of multigene signatures in early breast cancer: differences to clinical trials

https://doi.org/10.21203/rs.3.rs-3333731/v1

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Journal Publication

published 24 Jan, 2024

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Purpose

In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy.

Methods

Among MGAs, OncotypeDX (RS) was used in 97% of cases. Consecutive patients tested with OncotypeDX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low-RS: 0–25, high-RS: 26–100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials.

Results

Out of 1,098 patients identified, 73% had low-RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low-RS, while in patients with both G1 and Ki67 < 20%, 7% had high-RS. The proportion of low-RS in node-positive patients was similar to that in RxPONDER (82%vs83%), while node-negative patients with low-RS were significantly less than in TAILORx (66%vs86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node-positive.

Conclusions

In this real-world series, OncotypeDX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50years tested indicates that oncologists considered OncotypeDX informative also in this population.

ER+/HER2- early breast cancer

adjuvant therapy

multigene assays

Oncotype DX

More than 90% of breast cancer patients are diagnosed with early-stage disease, and around 70% of them have tumors that are estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-)^1,2. In these cases, adjuvant endocrine therapy is typically recommended as it reduces the risk of recurrence by almost half and decreases breast cancer mortality by a third, with a generally favorable risk-benefit ratio³.

Adjuvant chemotherapy further reduces the risk of recurrence and death from breast cancer, and the addition of chemotherapy to adjuvant endocrine therapy is indicated in those patients for whom the estimated residual risk despite endocrine therapy is significant^4,5. The classical clinicopathologic variables are essential for clinicians to estimate the risk of disease recurrence, but they are of limited use in predicting chemotherapy benefit for individual patients⁶.

Advances in the understanding of the molecular biology of breast cancer in the last two decades have led to the development of multigene assays (MGAs) that provide prognostic information independent of that provided by standard clinicopathologic features and help clinicians to better identify those patients with low-risk disease who can be safely spared chemotherapy⁷. All the commercially available MGAs for ER+/HER2 − early breast cancer have been robustly clinically validated⁸ and a plethora of studies consistently showed that their use can decrease chemotherapy recommendation in up to 50% of cases^9–17. Accordingly, major guidelines recommend the use of MGAs as a tool to tailor adjuvant chemotherapy decision^5,18.

Based on this striking evidence, in July 2019, Lombardy was the first Region in Italy to reimburse genomic testing for patients with ER+/HER2- breast cancer¹⁹. Subsequently, on May 2021, the Italian National Health System has approved reimbursement countrywide.

In this study, the Lombardy Genomic Assays for Breast Cancer Working Group reports the pilot experience of six referral cancer centers with the use of MGAs after reimbursement.

We aimed to evaluate the clinicopathologic parameters of the patients who were tested and to compare our real-world data with those from the landmark TAILORx and RxPONDER trials.

Eligibility criteria for genomic testing

Starting from July 2019, patients in Lombardy were considered eligible for reimbursed genomic testing if a formal indication for adjuvant chemotherapy was established by the multidisciplinary team. Excluded from reimbursement were patients meeting the definition of low risk (at least four of the following characteristics: Grade 1, Tumor size ≤ 1 cm, node negative, Ki67 < 15%, ER > 80%) or high risk (at least four of the following characteristics: Grade 3, T3/T4, node positive, Ki67 > 30%, ER < 30%). After the approval of genomic testing reimbursement by the Italian National Health System in May 2021, the indication for testing slightly changed to include ER+/HER2- breast cancer cases that are “considered uncertain, when a further assessment of the actual utility of the addition of chemotherapy to adjuvant endocrine therapy is needed”. MGAs available in Italy included Oncotype DX, MammaPrint, EndoPredict and Prosigna.

Patients

We conducted a retrospective study including all consecutive patients who were tested with MGAs at six hospitals in Italy between July 2020 and July 2022. In total, 1,133 patients were identified. Given that Oncotype DX was the preferred test in 97% of cases and the sole test used in five of the six centers, we only included Oncotype DX requests in our analysis.

Procedures

We used anonymized aggregated data obtained from the healthcare services' information systems of the six participating cancer centers. Patients were assigned to low (Recurrence Score, RS, 0–25) or high (RS 26–100) RS category according to the TAILORx and RxPONDER thresholds^20,21. The clinicopathologic variables were evaluated by the local pathologists of each center. To evaluate the distribution of RS category according to clinicopathologic features, the following variables were considered: tumor size (T1 vs T2 vs T3), nodal status (N0 vs N1), grade (G1 vs G2 vs G3), Ki67 (< 20% vs 21–30% vs > 30%), and age (≤ 50 years vs > 50 years).

Study Objectives

We aimed to evaluate the clinicopathologic parameters of the patients who were tested, as well as the distribution of RS category according to these features. Additionally, we compared our data with those from the TAILORx and RxPONDER trials^20,21. Secondly, we aimed to examine the trend in test prescription over time, looking at data from four semesters between July 2020 and July 2022. Finally, we aimed to assess whether the clinicopathologic features of tested patients changed over time.

Statistics

Descriptive statistics were used to summarize patient and tumor characteristics. The association of each clinicopathologic feature and RS category was assessed using Pearsonʼs Chi-Squared Test. All p-values were two-sided, and statistical significance was set at p ≤ 0.05. Since the data was aggregated, only univariate analysis was performed.

Ethical issues

The study analyzed aggregated data which has been anonymized from previously collected patient information and did not involve any intervention or impact on patient care. The patients had provided informed consent before undergoing the Oncotype Dx test. The study protocol (ONC/OSS-03/2023) was approved by the Ethics Committee of the coordinating institution (IRCCS Humanitas Research Hospital) and followed local regulation and ethical guidelines.

Patients

Between July 2020 and July 2022, a total of 1,098 patients from six referral centers in Lombardy were tested with Oncotype DX. Among these patients, 642 (58.5%) were older than 50 years old, 655 (59.7%) had tumors < 2 cm, 577 (52.6%) were node-negative, 419 (38.2%) had G3 tumors, and 244 (22.2%) had a Ki67 > 30%. Overall, the requests for patients with tumors > 5 cm or with G1 tumors were rare (3.1% and 3%, respectively) (Table 1).

The clinicopathologic features of patients who have received a genomic test prescription were significantly different between node-negative and node-positive patients.

Genomic test requests for T1, T2 and T3 tumors were 63.6%, 33.8% and 2.6%, respectively, in the node-negative group, and 55.3%, 41.1% and 3.6%, respectively, in the node-positive group (p = 0.018). Regarding tumor grade, G1, G2 and G3 tumors were 0.7%, 48.5% and 50.8%, respectively, in the node-negative group, and 5.6%, 70.2% and 24.2%, respectively, in the node-positive group (p < 0.001). Requests for tumors with Ki67< 20%, Ki67 21-30% and Ki67> 30% were 23%, 45.6% and 31.4%, respectively, in the node-negative group, and 58.2%, 29.8% and 12%, respectively, in the node-positive group (p < 0.001) (Figure 1).

The distribution of clinicopathologic features of patients who were tested with Oncotype DX was significantly different between age groups, except for tumor size. In patients with 50 years or younger, genomic test requests for T1, T2 and T3 tumors were 55.7%, 41.4% and 2.9%, respectively, while in patients older than 50 years, they were 62.5%, 34.3% and 3.2%, respectively (p = 0.053). The requests for G1, G2 and G3 tumors were 3.5%, 64% and 32.5%, respectively, in patients with 50 years or younger, and 2.6%, 55.1% and 42.2%, respectively, in patients older than 50 years (p = 0.004). Tumors with Ki67< 20%, Ki67 21-30% and Ki67> 30% were 44%, 36.4% and 19.6%, respectively, in patients with 50 years or younger, while in patients older than 50 years, they were 36.6%, 39.3% and 24.1%, respectively (p = 0.032) (Figure 2).

Interestingly, we found that a significant proportion (42%) of node-positive patients who received a genomic test prescription were 50 years old or younger, which is also similar to the proportion in the node-negative group (41.1%). Overall, patients with node-positive tumors who were 50 years old or younger accounted for approximately 20% of the total population receiving a test prescription.

Correlation between clinicopathologic features and Recurrence Score

Overall, the Oncotype DX test identified 803 out of 1,098 patients (73.1%) who had a RS score of 0-25, suggesting potential benefits in terms of chemotherapy sparing and drug costs. The proportion of patients with low RS was similar between age groups (74.8% of patients with 50 years or younger, and 71.8% of patients older than 50 years, respectively, p = 0.27), as well as between subgroups stratified by tumor size (74.7%, 70.4% and 79.4% in patients with T1, T2 and T3, respectively, p = 0.22) (Table 1 and Figure 3).

There were significant differences in the distribution of RS risk groups when tumors were stratified by grading and Ki67 levels. Specifically, low RS was found in 93.9%, 83.3% and 55.6% of G1, G2 and G3 tumors, respectively (p < 0.001), and in 86.5%, 74.4% and 46.7% of tumors with Ki67< 20%, Ki67 21-30% and Ki67> 30%, respectively (p < 0.001) (Table 1 and Figure 3).

The proportion of patients with low RS in the node-negative group was significantly lower than in the node-positive group (65.7% vs 81.6%, p < 0.001) (Table 1 and Figure 3).

The correlation between clinicopathologic features and RS within node-negative and node-positive patients recapitulated what has been observed in the overall population: in both groups, RS significantly correlated with grade and Ki67 levels but not with age or tumor size (Supplementary Figure 1).

Of note, despite the significant correlation of RS with grade and Ki67, Oncotype DX identified a significant proportion of patients with clearly poor biological features having a low RS. Among 179 patients with G3 tumors and Ki67 > 30%, 69 (38.6%) had a RS 0-25 (Figure 4), and this proportion was even higher (50%) within the node-positive patients with these high-risk features (Supplementary Figure 2). On contrary, among 30 patients with G1 tumors and Ki67 < 20%, 2 (6.7%) had a RS higher than 25 (Figure 4).

Temporal trend of test prescription

We observed a progressive increase in genomic testing requests over the two years considered, with the number of requests increasing from 182 between July 2020 and December 2020, to 230 between January 2021 and June 2021, 322 between July 2021 and December 2021, and 364 between January 2022 and June 2022.

The distribution of clinicopathologic characteristics among patients who received a test prescription did not differ significantly between the four semesters, including age, tumor size, nodal status, and Ki67 (Supplementary Table 1). However, there was a trend towards an increase in Oncotype DX requests for node-positive patients after the presentation of RxPONDER trial data. The requests for node-positive patients increased from 41.2% between July 2020 and December 2020 to 49% between January 2021 and July 2022 (p=0.06).

We found a significant variability in the distribution of tumor grade over time. From July 2020 to July 2022, there was a progressive increase in the proportion of patients with G2 tumors who received a test prescription and a corresponding decrease in the proportion of patients with G3 tumors. Specifically, the requests for patients with G2 tumors were 48.9%, 55.2%, 60.2%, and 64.8% in the first to the fourth semester, respectively (p=0.002), while requests for patients with G3 tumors were 47.3%, 41.7%, 36%, and 33.2% in the same period, respectively (p=0.007) (Supplementary Table 1).

Comparison with TAILORx and RxPONDER data

The clinicopathologic characteristics of node-negative patients who underwent genomic testing in our study were significantly different from those of patients included in the TAILORx trial²⁰.

We tested a higher percentage of patients aged 50 years or younger (41.1% vs 31.4%, p < 0.001), a lower percentage of patients with tumors < 2 cm (63.6% vs 74.8%, p < 0.001), a higher percentage of patients with G3 tumors (50.6% vs 17.8%, p < 0.001), and a lower percentage of patients with G1 tumors (0.7% vs 26.6%, p < 0.001) (Table 2). As expected, given the poorer biological characteristics of node-negative patients in our series, the proportion of low RS was also significantly lower than that observed in TAILORx (65.7% vs 85.7%, p < 0.001).

We also observed significant differences in the distribution of patients age and tumor grade within the node-positive group of patients tested in our series compared to patients enrolled in the RxPONDER trial²¹. We found a higher proportion of node-positive patients who were 50 years of age or younger (42% vs 24.4 %, p < 0.001), a lower proportion of patients with G1 tumors (5.6% vs 24.7%, p < 0.001) and, a higher proportion of patients with G3 tumors (24.2% vs 10.3%, p < 0.001) (Table 2). However, it should be noted that the distribution of tumor grade in RxPONDER refers to patients enrolled in the trial (therefore, with RS 0-25). Considering the total population screened for RxPONDER, the proportion of node-positive patients with low RS was similar to that observed in our series (83.1% vs 81.6%, p=0.38) (Table 2).

The incorporation of MGAs in clinical practice has profoundly changed the decision-making process for the adjuvant therapy of patients with ER+/HER2- early breast cancer.

Several real-world studies have consistently shown that the use of these signatures can alter treatment recommendation in approximately one-third of patients^9,11,17,22, and there is a large body of evidence supporting the cost-effectiveness of MGAs in various community practice settings^23–25. As a result, many health systems worldwide have approved the reimbursement of these tests for ER+/HER2- breast cancer patients since 2006, but reimbursement in Italy was not approved until July 2019 in Lombardy¹⁹ and then later countrywide in May 2021.

To the best of our knowledge, this is the first report of the use of MGAs in Italy after reimbursement, and it is the largest real-world study conducted after the availability of data from the large TAILORx, RxPONDER, and MINDACT trials. Our study has uncovered several interesting findings.

First, among the commercially available genomic assays, Oncotype DX resulted by far the preferred test. Prescribing oncologists chose Oncotype DX for 1,098 out of 1,133 patients who received an indication for genomic testing, and Oncotype DX was the only test used in five out of six centers. These findings likely reflect that clinicians perceive the predictive information for chemotherapy benefit provided by Oncotype DX as one of the most relevant aspects driving their choice of assay. They also indicate that prescribing oncologists generally adhere to Guidelines recommendations²⁶. Indeed, Oncotype DX is the only test recommended by current Guidelines with a level of evidence and a grade of recommendation of I, A for both node-negative and node-positive postmenopausal patients and for node-negative premenopausal patients¹⁸.

Second, the number of genomic test requests progressively increased throughout the considered time frame. We observed a trend towards an increase in requests for node-positive patients, which accounted for about half of the total requests after RxPONDER results were presented. Moreover, the proportion of requests for patients with G2 tumors progressively increased, while those for patients with G3 tumors progressively decreased. These trends are unlikely to reflect a change of the number of eligible patients or of their baseline characteristics. Rather, they might indicate a learning curve for prescribing oncologists during time. In Italy, the use of Oncotype DX and other MGAs remains quite scattered to date, but these data suggest that Italian physicians are coming to have greater “trust” in genomic test results.

Third, our data confirm that no individual clinicopathologic feature was precisely and robustly predictive of RS category. The significantly lower proportion of patients with a low RS in the node-negative compared to the node-positive group (65.7% vs 81.6%) is not surprising, as node-negative patients in our cohort had poorer biological features (more G3 and more Ki67 > 30%) than node-positive patients. This is most likely due to the indication for reimbursed genomic testing, which was for patients with a formal recommendation for adjuvant chemotherapy. Although RS correlated significantly with grade and Ki67, a substantial proportion of patients with G3 tumors (55.6%) or with Ki67 > 30% (46.7%) had a low RS. Moreover, 39% of patients with both G3 tumors and Ki67 > 30% still had a low RS. According to the International Ki67 in Breast Cancer Working Group recommendations, a Ki67 threshold of 30% or greater could be used to proceed with chemotherapy without the need for more expensive commercial multi-parameter gene expression assays²⁷. However, our findings indicate that a chemotherapy recommendation based solely on high Ki67 values may be at least questionable and suggest that, if available, genomic assays should be employed also in those cases with high Ki67 levels when uncertainty on the chemotherapy benefit still remains. Oppositely, we have found that a low but not negligible proportion (1 out of 15) of patients with biological features indicative of clearly low risk (i.e. G1 and low Ki67) had a high RS and therefore may derive a benefit from chemotherapy. Although limited by the small numbers, these data pose the question of how many patients missed the opportunity of the test during the early period (when the indication was for patients with formal recommendation to adjuvant chemotherapy) and corroborate the utility of genomic assays not only for treatment de-escalation but, more in general, for treatment tailoring, especially for those cases that may fall in a “grey zone” for chemotherapy recommendations.

Fourth, we found that a substantial proportion (41.5%) of patients who have received a genomic test prescription were 50 years old or younger. More importantly, almost half of these young patients had node-positive tumors, representing about 20% of the overall population.

These data indicate that, despite Guidelines do not recommend the use of Oncotype DX or other genomic assays to tailor adjuvant therapy decisions in node-positive premenopausal patients (or patients ≤ 50 years), the oncologists prescribing Oncotype DX considered the test informative also in this population²⁶. The role of age and menopausal status has been quite neglected in the development of Oncotype DX and other MGAs. However, both TAILORx and RxPONDER trials have found significant interaction for outcome between chemotherapy effect and age or menopausal status^21,28, leading to different interpretations of RS based on these factors.

Some data suggested that among the luminal subtype, tumors arising in young women may be biologically distinct^29,30. For example, it was found that tumors of young women showed upregulation of biological processes related to growth factor signaling and downregulation of apoptosis-related genes²⁹. More recently, Qing et al. have found that tumors in patients 50 years or younger have lower expression of ER-related genes and higher expression of immune-related genes that may determine higher chemo-sensitivity³⁰. Although one might speculate that these biological characteristics could lead to a greater cytotoxic effect of chemotherapy and some data suggest that ER+/HER2- tumors in younger women may be more responsive to chemotherapy³¹, evidence from TAILORx and RxPONDER support the hypothesis that most of the observer chemotherapy benefit in young women with low RS might be due to its endocrine effect of ovarian suppression. In fact, in TAILORx, the chemotherapy benefit observed in women 50 years old or younger was primarily limited to women between 40 and 50 years old and waned in younger and older age groups. Additionally, women between 46 and 50 years old appeared to derive a benefit only before menopause, while postmenopausal women in the same age group did not experience any benefit²⁸. In RxPONDER, the only subgroup of premenopausal women who didn't seem to benefit from the addition of chemotherapy were those who were 50 years of age or older, namely women who are likely to reach menopause soon, even without chemotherapy²¹. Importantly, the rate of ovarian function suppression for premenopausal women in the endocrine therapy alone arm was limited in both trials, which hinders the full applicability of the results in current clinical practice. This could explain why clinicians in our series used Oncotype DX so often in young women with node-positive tumors. Nonetheless, there is an urgent need for prospective data to fill the knowledge gap in this field.

Strengths of our study include a large sample size and the evaluation of real-world MGAs use in a time frame when results from prospective trials were available. Additionally, the reliability of our histological reports, which were conducted in referral cancer centers by pathologists specialized in breast cancer, adds to the validity of our findings.

However, our study clearly has limitations. For instance, we were unable to capture other clinicopathologic variables such as menopausal status or progesterone receptor status, and our use of an age cutoff to determine menopausal status may be imprecise. Additionally, the reproducibility of certain clinicopathologic features such as Ki67 can be variable across labs, which limits the generalizability of our findings. Furthermore, our use of anonymized aggregated data prevented us from collecting treatment and follow-up information, so we could not estimate the exact amount of chemotherapy sparing in our series.

Nevertheless, several decision-impact studies available in literature consistently showed significant chemotherapy sparing effect of Oncotype DX^{9,11,12,14,17}, and given the initial indication of test prescription in Lombardy, it is likely that also in our series Oncotype DX use has led to a substantial reduction in chemotherapy use and drug cost, with remarkable benefits for both patients and the healthcare system.

In summary, this study highlights the contemporary use of MGAs in clinical practice and showed that Oncotype DX was by far the preferred test adopted by clinicians. Our findings confirm that individual clinicopathologic features do not robustly predict RS category and suggest that, despite Guidelines recommendation, clinicians view Oncotype DX as a useful tool for guiding treatment decisions, even in young patients with node-positive disease.

Acknowledgements

The authors thank Exact Sciences and Editree for their unconditional support

This work was supported by an unrestricted grant from Exact Sciences

LL has served on the advisory boards for: Lilly, Exact Sciences, AstraZeneca, Italfarmaco and Daiichi Sankyo; has received consulting fee from: Exact Sciences, Helsinn and Eisai; honoraria for speakers’ bureaus from: Gilead and Exact Sciences; support for travel, accommodations, expenses from: Lilly and Gilead.

RDS has served on the advisory boards for: Novartis, Lilly, Istituto Clinico Gentili, Ipsen, Amgen, EISAI.

AV reports honoraria from Roche and Lilly

ELS has received consulting fee and served on the advisory boards for: Exact Sciences, Seagen.

EM has received consulting fee and served on the advisory boards for: Exact Sciences, EISAI, MSD Oncology, Daiichi Sankyo/Astra Zeneca, Pfizer, Seagen; support for travel, accommodations, expenses from: Roche, Pfizer, Lilly, Novartis.

EGR has received advisory fee from AstraZeneca, Exact Sciences, GSK, Novartis, Roche; honoraria from AstraZeneca, GSK, Novartis, Thermo Fisher Scientific; travel accommodation and expenses from AstraZeneca, GSK, LCM Genect, Novartis, Roche, Thermo Fisher Scientific; grants and non-financial support from Thermo Fisher Scientific, Roche.

CT has received consulting fee and served on the advisory boards for: Myriad Genetics, MSD Oncology and Amgen; honoraria for speakers’ bureaus from: Amgen; support for travel, accommodations, expenses from: Takeda, Amgen, MSD, Eli Lilly Italia SPA, Roche, Pfizer.

AZ has received personal fees and non-financial support from Novartis, AstraZeneca, Lilly, Pfizer, Daiichi Sankyo, MDS (Merck Sharp&Dome), Roche, Seagen, Exact Sciences, Gilaed, Istituto Gentili.

GP has served on the advisory boards for: ADS Biotec; has received honoraria for speakers’ bureaus and travel funding from: Lilly, AstraZeneca, Exact Sciences, Novartis.

GB has received consulting fee from Roche, AstraZeneca, Novartis, MSD, Sanofi, Daiichi Sankyo, and Exact Sciences; honoraria for speakers’ bureaus from Roche, Pfizer, Astra- Zeneca, Lilly, Novartis, Neopharm Israel, MSD, Chugai, Daiichi Sankyo, EISAI, and Exact Sciences; support for travel, accommodations, expenses from Roche, Pfizer, and AstraZeneca; is co-inventor of ‘European patent Application N. 12195182.6 and 12196177.5 titled “PDL-1 expression in anti-HER2 therapy” -Roche- Issued (no compensation provided); and has served on the advisory boards for Roche, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis, AstraZeneca, Genomic Health, EISAI, Gilead, and Seagen.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Luca Licata and Rita De Sanctis. The first draft of the manuscript was written by Luca Licata and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Sung H, Ferlay J, Siegel RL, et al: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209-249, 2021
Cardoso F, Spence D, Mertz S, et al: Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). Breast 39:131-138, 2018
Group EBCTC: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687-717, 2005
Henry NL, Somerfield MR, Abramson VG, et al: Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: Update of the ASCO Endorsement of the Cancer Care Ontario Guideline. J Clin Oncol 37:1965-1977, 2019
Cardoso F, Kyriakides S, Ohno S, et al: Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 30:1194-1220, 2019
Group EBCTC: Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. The Lancet 379:432-444, 2012
Sotiriou C, Pusztai L: Gene-expression signatures in breast cancer. N Engl J Med 360:790-800, 2009
Kwa M, Makris A, Esteva FJ: Clinical utility of gene-expression signatures in early stage breast cancer. Nat Rev Clin Oncol 14:595-610, 2017
Lo SS, Mumby PB, Norton J, et al: Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol 28:1671-6, 2010
Martín M, González-Rivera M, Morales S, et al: Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer. Curr Med Res Opin 31:1129-37, 2015
Albanell J, Svedman C, Gligorov J, et al: Pooled analysis of prospective European studies assessing the impact of using the 21-gene Recurrence Score assay on clinical decision making in women with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative early-stage breast cancer. Eur J Cancer 66:104-13, 2016
Kuchel A, Robinson T, Comins C, et al: The impact of the 21-gene assay on adjuvant treatment decisions in oestrogen receptor-positive early breast cancer: a prospective study. Br J Cancer 114:731-6, 2016
Wuerstlein R, Kates R, Gluz O, et al: Strong impact of MammaPrint and BluePrint on treatment decisions in luminal early breast cancer: results of the WSG-PRIMe study. Breast Cancer Res Treat 175:389-399, 2019
Curtit E, Vannetzel JM, Darmon JC, et al: Results of PONDx, a prospective multicenter study of the Oncotype DX(®) breast cancer assay: Real-life utilization and decision impact in French clinical practice. Breast 44:39-45, 2019
Soliman H, Shah V, Srkalovic G, et al: MammaPrint guides treatment decisions in breast Cancer: results of the IMPACt trial. BMC Cancer 20:81, 2020
Penault-Llorca F, Kwiatkowski F, Arnaud A, et al: Decision of adjuvant chemotherapy in intermediate risk luminal breast cancer patients: A prospective multicenter trial assessing the clinical and psychological impact of EndoPredict® (EpClin) use (UCBG 2-14). Breast 49:132-140, 2020
Cognetti F, Masetti R, Fabi A, et al: PONDx: real-life utilization and decision impact of the 21-gene assay on clinical practice in Italy. NPJ Breast Cancer 7:47, 2021
Andre F, Ismaila N, Allison KH, et al: Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. Journal of Clinical Oncology 40:1816-1837, 2022
Pruneri G, Tondini CA: The use of genomic tests in patients with breast cancer in Lombardy: a successful healthcare model. Tumori Journal 107:166-170, 2021
Sparano JA, Gray RJ, Makower DF, et al: Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 379:111-121, 2018
Kalinsky K, Barlow WE, Gralow JR, et al: 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med 385:2336-2347, 2021
Carlson JJ, Roth JA: The impact of the Oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis. Breast Cancer Res Treat 141:13-22, 2013
Chandler Y, Schechter CB, Jayasekera J, et al: Cost Effectiveness of Gene Expression Profile Testing in Community Practice. J Clin Oncol 36:554-562, 2018
Wang SY, Dang W, Richman I, et al: Cost-Effectiveness Analyses of the 21-Gene Assay in Breast Cancer: Systematic Review and Critical Appraisal. J Clin Oncol 36:1619-1627, 2018
Yang M, Rajan S, Issa AM: Cost effectiveness of gene expression profiling for early stage breast cancer: a decision-analytic model. Cancer 118:5163-70, 2012
Licata L, Cosentini D, De Sanctis R, et al: Multigene signatures for early breast cancer in clinical practice: A report of the Lombardy genomic assays for breast cancer working group. Frontiers in Oncology 13, 2023
Nielsen TO, Leung SCY, Rimm DL, et al: Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst 113:808-819, 2021
Sparano JA, Gray RJ, Ravdin PM, et al: Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. N Engl J Med 380:2395-2405, 2019
Azim HA, Jr, Michiels S, Bedard PL, et al: Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling. Clinical Cancer Research 18:1341-1351, 2012
Qing T, Karn T, Rozenblit M, et al: Molecular differences between younger versus older ER-positive and HER2-negative breast cancers. NPJ Breast Cancer 8:119, 2022
Loibl S, Jackisch C, Lederer B, et al: Outcome after neoadjuvant chemotherapy in young breast cancer patients: a pooled analysis of individual patient data from eight prospectively randomized controlled trials. Breast Cancer Res Treat 152:377-87, 2015

Table 1. Distribution of Oncotype DX RS according to clinicopathologic features

Characteristic

All (%)

RS 0-25 (%)

RS 26-100 (%)

p-value

Age

≤ 50 y

> 50 y

456 (41.5)

642 (58.5)

341 (74.8)

461 (71.8)

115 (25.2)

181 (28.2)

0.274

Tumor size

655 (59.7)

409 (37.2)

34 (3.1)

488 (74.7)

288 (70.4)

26 (79.4)

167 (25.3)

121 (29.6)

8 (20.6)

0.309

Nodal status

577 (52.6)

521 (47.4)

377 (65.3)

425 (81.6)

200 (34.7)

96 (18.4)

< 0.001

Grade

33 (3)

646 (58.8)

419 (38.2)

31 (93.9)

538 (83.3)

233 (55.6)

2 (6.1)

108 (16.7)

186 (44.4)

< 0.001

Ki67

0-20%

21-30%

> 30%

436 (39.7)

418 (38.1)

244 (22.2)

377 (86.5)

311 (74.4)

114 (46.7)

59 (13.5)

107 (25.6)

130 (53.3)

< 0.001

Total

1098 (100)

802 (73)

296 (27)

Table 2. Comparison of clinicopathologic features and RS results of our series with TAILORx and RxPONDER

Characteristic

Lombardy series (N0) (n=577)

TAILORx (n=9719)

p-value

Age

≤ 50 y

> 50 y

237 (41.1)

340 (58.9)

3054 (31.4)

6665 (68.6)

< 0.001

Tumor size

367 (63.6)

195 (33.8)

15 (2.6)

7271 (74.8)

2448 (25.2)

< 0.001

Grade*

4 (0.7)

281 (48.7)

292 (50.6)

2512 (25.8)

5242 (53.9)

1676 (17.2)

< 0.001

0-25

26-100

380 (65.7)

197 (34.3)

8330 (85.7)

1389 (14.3)

< 0.001

Characteristic

Lombardy series (N1) (n=521)

RxPONDER (n=5018)

p-value

Age †

≤ 50 y

> 50 y

219 (42)

302 (58)

1224 (24.4)

3794 (75.6)

< 0.001

Tumor size

288 (55.3)

214 (41.1)

19 (3.6)

2923 (58.3)

1843 (36.7)

252 (5.0)

0.084

Grade*

29 (5.6)

366 (70.2)

126 (24.2)

1218 (24.3)

3215 (64.3 )

507 (10.1)

< 0.001

RS ‡

0-25

26-100

425 (81.6)

96 (18.4)

5083 (83.1)

1035 (16.9)

0.380

* tumor grade was unknown for some pts in TAILORx and RxPONDER

† In RxPONDER, age cut-offs were: < 50 and > 50 years old

‡ In RxPONDER, numbers include all pts screened for the trial (n=6118)

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published 24 Jan, 2024

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Real-world use of multigene signatures in early breast cancer: differences to clinical trials

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