GMKA
Support

Consensus Statement on the Use of Oncotype DX in Patients With Resected, Hormone Receptor Positive and HER2-Negative, Early Breast Cancer: An Update of the Criteria for Reflex Testing

Oncology
Read in Ukrainian
Acknowledgments: Dario Trapani, MD, and Harold Burstein, MD, PhD, for their leadership in the consensus discussions and in writing of the statements.
Synopsis
The consensus statements for Reflex Testing of OncotypeDX at Dana-Farber Cancer Institute
Clinical QuestionConsensus StatementReflex testing
Can OncotypeDX be implemented as a reflex test in patients beyond 65 years old?OncotypeDX testing is applicable to over-65y patients with early, HR-positive and HER2-negative breast cancer, and can be requested case-by-case. (Medicare restraints may apply).No
Should  OncotypeDX reflex testing be extended to patients with pT1b G2-3 and pT1c G1 tumors?Testing for OncotypeDX applies to pT1c G1-3 pN0 HR-positive and HER2-negative.

Case-by-case consideration and not reflex testing applies to pT1b pN0 G2-3 tumors.		Yes

No
Should OncotypeDX testing be considered in patients with >3 positive axillary lymph nodes?For patients with >3 positive axillary lymph nodes (i.e., pT1-2, pN2), the request for OncotypeDX should be personalized, and not reflex, based on specific patient’s needs and preference, and to inform the shared treatment decision, albeit through careful discussion of the caveats and the nature and limits of the available evidence. No
OncotypeDX-related new tools. Reflex use.

Should RSClin ‡ be implemented in clinical practice for all pN0 breast cancers?		RSClin scoring in clinical practice, in conjunction with the RS, may inform patient preferences by framing the likely benefits of treatment based on clinical and pathology features, and thus help shared decision-making in selected cases.No
Should the reflex testing be kept for premenopausal women, particularly those with 1-3 positive axillary lymph nodes?The reflex testing of OncotypeDX applies to premenopausal women with 1-3 nodes as informing on prognosis, and on choices about chemotherapy and/or OFS.Yes
Should the surgical approach for the axillary management affect the pattern of reflex testing of OncotypeDX in pN1 breast cancer?OncotypeDX test should be done as reflex testing for patients with pN1a breast cancer, regardless the surgical approach for the axillary management (either SLNB or ALND).Yes
Legend: OFS = ovarian function suppression, RS = risk score, SLND = sentinel lymph-node biopsy, ALND = axillary lymph-node dissection.
‡ RSClin® (Genomic Health, Redwood City, CA) is a tool aiming at delivering granular prognostic estimations in patients with early HR-positive and HER2- negative breast cancer by integrating clinicopathological and genomic (RS) information.

Background. Evidence in support of the use of OncotypeDX in the clinical practice

OncotypeDX® (21-gene signature) is laboratory developed genomic test (Genomic Health, Redwood City, CA). It is CLIA-certified and has been accredited by the College of American Pathologists.
It is indicated for prognostication and treatment decision in patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)- negative early breast cancer.[1] OncotypeDX has demonstrated analytical validity (on a 100- unit scale), and clinical validity and utility in the context of pre-clinical assessments, retrospective series and ultimately in randomized clinical trials (ESMO treatment modulation tier A and B). [1,3,4,5,6,7,8,9,10]
The pivotal phase 3 clinical trial TAILORx allocated 10,273 women aged 18-75 years with HR-positive/HER2-negative, resected, pT1-2 pN0 breast cancer to three arms, based on the OncotypeDX estimated risk of recurrence, and randomized patients with mid-range risk score (RS 11-25; 69% of all the population) to receive chemotherapy (CT) plus endocrine treatment (ET) or ET alone.[2]
The study demonstrated the non-inferiority of a risk-informed de-intensified adjuvant treatment with ET alone, on the risk of invasive disease-recurrence (hazard ratio [HaR] 1.08, 9% confidence interval [CI] 0.94-1.24), reporting a 9-year invasive disease-free survival (iDFS) of 83.3% with ET and 84.3% with CT-ET, respectively, in the overall population.
In addition, clinical utility of OncotypeDX was reported in the setting of axillary positive lymph nodes, in the randomized, phase 3 clinical trial RxPONDER, enrolling patients with low- to mid-range RS (i.e., 0-25) and 1 to 3 positive axillary lymph nodes to ET or ET-CT (n= 5,018 women). The study showed no added benefit of adjuvant CT in the overall population, with a 5-year iDFS rate of 92.2% and 91% (HaR 0.86, CI 0.71-1.03). However, an age modifying effect was showed, mostly for pre-menopausal women.
Presently, the use of OncotypeDX is endorsed by the principal oncology societies, including ASCO and ESMO, and the national guidelines for breast cancer treatment NCCN. [11,12,13,14,15,16]

Current Practice of OncotypeDX at Dana-Farber Cancer Institute (DFCI)

Our approach at Dana-Farber has been to recommend reflex testing with OncotypeDX recurrence score when the results will directly inform treatment recommendations. The general expectation is that in such cases a score of < 25 would support endocrine treatment without CT and a score of > 25 would justify CT in most instances.
In 2017, Dana-Farber established an internal guideline to standardize the criteria for reflex testing of OncotypeDX17, that was then updated in 2019 to include node-positive and larger tumors [18,19] based on the available data. Reflex OncotypeDX testing is triggered in case of:
Patient’s age ≤65, AND:
  • T1c N0 tumors grade II-III
  • T2 N0 tumors of any grade
  • T1-T2 N1 tumors of any grade
  • T3 N0/N1 tumors any grade
In March 2022, an internal evaluation of the patterns of OncotypeDX testing for quality improvement suggested that the reflex criteria were commonly utilized, although discrepancies in some of the criteria were common. The analysis of discrepancies between the established criteria and the pattern of use of OncotypeDX showed inconsistency in 36% of testing (n=1,687 test requests), as retrieved from the Clinical Outcomes Quality Database (COQD; Jan 2019-2021; March 2022 query).
The drivers of discrepancies were related to the age and the stage-pertinent criteria for reflex testing. Twenty-six percent of all discrepant cases were ascribed uniquely to age: for patients aged >65 years, the median age was 69 years (IQR: 67-72 years). Among patients ≤65 years of age, the most common instances of discrepancy were grading (pT1c pN0 G1; n=104) and tumor size (pT1b any-grade, pN0; n=86).
Adjuvant treatment decision appeared informed by OncotypeDX for most of the instances of non-concordant test requests.

Clinical Questions

Q1: Can OncotypeDX be implemented as a reflex test in patients beyond 65 years old?

Evidence in support. The pivotal clinical trials TAILORx and RxPONDER included patients aged 18-75 years and patients receive ET or CT-ET treatments. In TAILORx, median age at enrollment was 55 years, with an IQR of 25-75 years: 27% of the population with RS 11-25 receiving CT-ET had an age 61-70 years and 4% were older than 71 years. The subgroup analysis for iDFS of patients aged >65 years did not reveal inconsistent findings when compared to the overall population.
In RxPONDER, 30.6% of the enrolled population was 60-69 years old, and 11.6% was ≥70 years old. The subgroup analysis for patients aged >65 years was consistent with the findings in the overall population. The prognostic information retrieved with OncotypeDX is still valuable, and an absolute contraindication for CT for patients older than 65 years is not presently supported by oncogeriatric breast cancer recommendations, albeit such a shared decision[20] should be integrated in the context of a multidimensional health status evaluation, and CT tolerance could be anticipated with validated tools (SIOG and EUSOMA).[21,22]
In fact, clinical evidence suggest that CT can portend improvement in DFS in older patients, and that age should not be the sole determinant of the treatment choice.[23,24,25,26,27,28]
Of note, recently presented data in over-70 years old women have not shown improvement of the survival outcomes with chemotherapy compared with hormonal therapy, including in the setting of high genomic risk.
For example, in the ASTER trial, those ages 70 and older did not experience an improvement survival with the addition of CT to ET. However, interpreting these data may require additional scrutiny given the small benefit seen among those receiving their assigned therapy.
This trial was limited to women ages 70y or older who had high clinical-genomic risk breast cancer [but determined with a different tool than OncotypeDX, that is an important caveat to remind] (HR 0.85 [0.64-1.13], p=0.2538): 4-year OS was 90.5% and 89.7% with CT-ET and ET alone.[29]
Policy considerations. A note on the use of OncotypeDX in patients older than 65 years who perform breast surgery as inpatients is about regulations, falling under the Medicare “14 days rule” for reimbursement, as part of the Centers for Medicare & Medicaid Services’ [CMS] Date of Service Regulation (42 C.F.R. Section 414.510).[30]
The test is eligible to CMS’ reimbursement if it is ordered by the patient’s physician at least 14 days following the date of the patient’s discharge from the hospital, for specimens which collection is inappropriate in another setting.
OncotypeDX is commonly applied to the surgical specimens, obtained from inpatient procedures (i.e., breast surgery), therefore the “Date of Service Regulation” applies.
Consensus Statement 1.
OncotypeDX testing can be applicable to patients with early, HR-positive and HER2- negative breast cancer aged ≤72 years old (based on the internal data of limited use of OncotypeDX beyond 72 years and indication for chemotherapy) on a case-by-case manner, based on a multi-dimensional geriatric assessment and shared decision. Reflex testing to all comers >65y does not apply.

Q2: Should OncotypeDX reflex testing be extended to patients with pT1b G2-3 and pT1c G1 tumors?

Evidence in support. The pivotal clinical trial TAILORx enrolled patients with tumors 1-5cm (any grade) and of 0.5-1cm grade 2-3 or presenting lymphovascular invasion. The cohort of patients with mid-range RS included 423 patients in the CT-ET arm and 446 in the ET arm with pT1b pN0 tumors, corresponding to 13% of the overall population. However, no disaggregation was performed at the subgroup analysis level for the threshold of 1cm, to the survival analysis.
The central question is whether some small HR-positive breast tumors might have an aggressive biological behaviour, and if CT could provide a meaningful benefit on iDFS for RS>25. Evidence from retrospective series and real-life evidence suggest that up to 18% of pT1b tumors present with RS>25, in the “high risk” range for recurrence.[31]
The estimate is consistent with the COQD analysis for pT1b tumors. In the overall COQD dataset, 818 patients had pT1b pN0 tumors (G1=383; G2=331; G3=104). Of them, only 97 were referred for OncotypeDX (11.9%), with RS>25 reported in 19.6% (n=19). For pT1b G1 tumors, RS>25 was reported in 9.1% of tested patients, while for G2 and G3 it was 13.3% and 60%, respectively. Chemotherapy was received in 60 patients.
Limits due to the small sample size of patients tested are acknowledged. Robust evidence of a clear benefit of CT for pT1b luminal B-like breast cancer is not available in the literature. However, the principal treatment guidelines and consensus documents include consideration of selected patients with pT1b “high risk” for discussion of CT.[32]
A large, US-based study from the National Comprehensive Cancer Network Database showed high survival rates for pT1a-b breast cancer treated with ET alone.32 However it is unclear if a potential effect of CT is diluted in historical cohorts not comprehensively characterized with OncotypeDX or other genomic tools of prognostication. A possible estimation of the risk of recurrence and CT benefit for pT1b G2-3 tumors can be derived from OncotypeDX-based tools like RSClin (which will be expanded on below). Based on RSClin algorithm, patients with pT1b tumors can derive meaningful benefits from adjuvant CT when RS≥25, with a distant-disease free survival gain consistently above 3% (4-9%)
[Note: 3% is considered a clinical trade-off to indicate an “acceptable” loss of benefit in trials of treatment de-intensification and improved safety profile, as agreed in multi- stakeholder consensus and applied to ongoing trials: an increase in the risk of distant metastasis above 3% is commonly considered “not acceptable” for de-intensification].[33,34,10]
Overall, a consensus for pT1c G1 was reached, and these tumors can be eligible to reflex OncotypeDX testing. However, uncertainties on a clinically meaningful benefit of chemotherapy in pT1b pN0 tumors is acknowledged, as data are mostly speculative or based on modelling exercises. Accordingly, case-by-case consideration will be done.
Estimation of the benefit of chemotherapy on the risk of distant recurrence across the spectrum of OncotypeDX scores and tumour dimensions. The estimates are based on the RSClin model. The benefit of adjuvant chemotherapy in pT1b tumours with RS>25 appears consistently above 3% i.e., +4% for RS=28 and +9% for RS=40. Similar considerations are drawn for pT1c G1 tumours (data not shown). Overestimation of the benefit cannot be excluded. Source: Sparano et al, 2021.

Source: Sparano JA, Crager MR, Tang G, Gray RJ, Stemmer SM, Shak S. Development and Validation of a Tool Integrating the 21-Gene Recurrence Score and Clinical-Pathological Features to Individualize Prognosis and Prediction of Chemotherapy Benefit in Early Breast Cancer. J Clin Oncol. 2021;39(6). doi:10.1200/JCO.20.03007. Reprinted under the Free Creative Commons License https://creativecommons.org/licenses/by/4.0/
Consensus Statement 2A
Reflex testing for OncotypeDX applies to pT1c G1-3 pN0 tumors.
Consensus Statement 2B.
Reflex testing does not apply to pT1b pN0 G2-G3 and decisions should be done case-by- case.

Q3: Should OncotypeDX testing be considered in patients with >3 positive axillary lymph nodes?

Evidence in support. There is no evidence from randomized, prospective, controlled clinical studies that OncotypeDX retains prognostic and predictive value, in patients with >3 positive lymph nodes. Retrospective translational studies from prospective cohorts suggest that the distribution of RS scores is not a function of the number of involved lymph nodes, meaning that patients presenting with >3 lymph nodes have a likelihood to have a low- to intermediate RS comparable to patients with pN0 breast cancer.[9]
A re-analysis of the SWOG-8814 clinical trial (i.e., tamoxifen with/without adjuvant CT in node-positive breast cancer; 34% had >3 positive lymph nodes) reported that 40% of patients with positive lymph nodes at diagnosis had a low RS, and 28% had a mid-range RS.[7]
The retrospective translational re-analysis of the prospective cohort from SWOG-8814 suggested a prognostic significance of OncotypeDX: the 10-year DFS rates were 60%, 49%, and 43% for low, intermediate, and high RS. In addition, adjuvant CT was associated with no survival benefit in the setting of low RS (defined here as RS<18), but there was a potential benefit for RS≥31 (log-rank p=0.033; HaR 0.59, 0.35-1.01), after adjustment for the number of positive nodes. In patients with >3 positive lymph nodes, extrapolation from the Kaplan- Meier suggest that for low-risk patients, the benefit of chemotherapy is unlikely to be meaningful.
The indication of OncotypeDX in the setting of >3 positive lymph nodes is not presently supported in clinical guidelines, and has been recommended against in a consensus statement from ASCO, for the lack of clinical validation in prospective studies.[13] Therefore, the indication for reflex testing is discouraged at moment.[18]
Consensus Statement 3.
For patients with >3 positive axillary lymph nodes (i.e., T1-2 N2), the request for OncotypeDX should be personalized, and not reflex, based on specific patient’s needs and preference, and to inform the shared treatment decision, albeit through careful discussion of the caveats, and the nature and limits of the available evidence.

Q4: Should RSClin be implemented in clinical practice for pN0 breast cancer?

Evidence in support. RSClin® (Genomic Health, Redwood City, CA) is a tool aiming at delivering granular prognostic estimations in patients with early HR-positive and HER2- negative breast cancer by integrating clinicopathological and genomic (RS) information.[33]
RSClin was developed by incorporating prognostic independent factors like tumor grade, tumor size, and age to RS, based on a patient-specific metanalysis of TAILORx (all arms), B-14 and B-20 trials; the tool was validated against an external cohort of real-life (Clalit Research Institute, Israel), showing an ultimate high concordance. RSClin is accessible via an online interface, and is able to provide prognostic estimates (risk of distant recurrence at 10 years), and calculate the absolute benefit of adjuvant CT on the risk of recurrence.
A potential caveat about the tool regards the model for the age as a prognostic variable: based on the information provided in the methodology paper, pre-menopausal women had received mostly tamoxifen as adjuvant treatment in the cohorts of reference (i.e., 50-60% of patients aged <40y had tamoxifen alone): therefore, the tool could provide a systematic estimate of higher benefit of CT for premenopausal women, resulting from OFS (expanded below), as commented in the original publication by the authors. RSClin may help inform the treatment decision, especially in controversial scenarios (e.g., pT1b tumors).
The tool is based on a modelling exercise derived from trial-based data, but has no prospective validation (“Tier C” in the ESMO framework for treatment de-intensification). Of note, OncotypeDX is conceptualized as a continuous score in RSClin, and not in score-ranges, and is contextualized in an integrated, multi-variable prognostication, aiming at providing patient-granular data.
No strong consensus was reached for the routinary, reflex clinical implementation of RSClin, for potential inflated estimates of the CT effect, based on the methodology of development, the mechanism to retrieve the benefit of CT and the mixed populations and treatments included.
A: Simulation extracted from RS clin, of a postmenopausal woman with a pT1c pN0 across the spectrum of tumor grading. The algorithm shows an increasing risk of distant recurrence for high-grade breast cancer, suggesting that the overall outcome can be better predicted with a multi-variable model as opposed to be recapitulated by the RS alone.
B: The absolute benefit of chemotherapy might be superior to the one anticipated with the use of the RS alone. For a patient with a pT1c G3 tumor and a RS of 23 (mid-range), the benefit of adjuvant CT on risk-reduction of distant recurrence is estimated to be 6%, that is a benefit for which CT is commonly considered as an option.
Source for A and B: Sparano JA, Crager MR, Tang G, Gray RJ, Stemmer SM, Shak S. Development and Validation of a Tool Integrating the 21-Gene Recurrence Score and Clinical-Pathological Features to Individualize Prognosis and Prediction of Chemotherapy Benefit in Early Breast Cancer. J Clin Oncol. 2021;39(6). doi:10.1200/JCO.20.03007. Reprinted under the Free Creative Commons License https://creativecommons.org/licenses/by/4.0/
Statement 4.
RSClin scoring in clinical practice, in conjunction with the RS, might inform treatment decisions by framing the likely benefits of treatment based on clinical and pathology features.

Q5: Should the reflex testing be forgone for premenopausal women, particularly those with 1-3 positive axillary lymph nodes?

Evidence in support. The use of OncotypeDX in premenopausal women in the setting of node-negative lymph nodes is not dissimilar to post-menopausal women.[16]
Post-hoc exploratory analyses from TAILORx reported that the risk-grouping might not be entirely reproducible in women aged <50 years: an interaction between age and benefit of CT was reported, with a gain of 1.6% in the 9-year iDFS for RS 16-20 and more pronounced for RS 21-25 (ΔiDFS: +6.5%), however with no impact on the overall survival (OS).
Of note, most of the patients had received tamoxifen alone as ET, with a use of ovarian suppression (OFS) in only 13% of premenopausal women. The post hoc analysis of TAILORx suggested that some women with intermediate RS might benefit from the addition of CT.
In the setting of 1-3 positive lymph nodes, the RxPONDER trial analysed the data based on the menopausal status, that was a stratification factor for the randomization. While the group of post-menopausal women had no benefit from the addition of CT (HaR 1.02, 0.82- 1.26), for premenopausal women there was evidence toward better iDFS, with a 5-year iDFS of 93.9% vs 89% (HaR 0.60, 0.43-0.83). The subgroup analysis per age-range showed consistent results for patients aged <45 and 45-49 years, and no benefit beyond 50 years. Of relevance, the use of OFS was provided in 6% in the group of premenopausal patients treated with CT and 20% in the group with ET alone. The poor uptake of OFS cannot be disregarded in defining the potential, absolute benefit of CT on iDFS.[35,36]
The pivotal SOFT and TEXT trials [35], the Korean ASTRRA [37,38] study and, more recently, the EBCTCG metanalysis[39] showed that the addition of OFS (to tamoxifen or with an aromatase inhibitor) is associated with a significant risk reduction of iDFS events. In the EBCTCG metanalysis, the estimated absolute risk reduction of disease recurrence at 5 years with OFS and aromatase inhibitors is of 3.2%, with a magnitude of benefit more pronounced in patients with positive lymph nodes (+4%) versus node-negative (2.2%). In the combined analysis of SOFT and TEXT trials [35] , women receiving tamoxifen with OFS experienced an 8-year rate of DFS of 83.2% versus tamoxifen alone (8-year DFS: 78.9%), with an absolute gain of +4.2% (HRa 0.76; 0.62-0.93). Exemestane plus OFS showed to provide an iDFS improvement at 8y of +7% (HaR 0.65; 0.53-0.81).
An improvement of the survival of 4.3% was also showed with the addition of OFS in SOFT, in higher-risk cancers, in the post-CT setting. Notably, compliance in SOFT and TEXT was not optimal, as one-fifth of the patients stopped OFS earlier, and almost a third of patients did not complete 5 years of exemestane.
CT-induced amenorrhea has demonstrated a prognostic significance in women with early breast cancer. CT can exert OFS, thus accounting for part of the iDFS benefit through an endocrine effect, and not merely cytotoxic per se. For example:
  1. CT can induce persistent ovarian suppression, variously reported in literature (e.g., 30- 42% of patients are amenorrhoeic at 52 weeks post-CT, 33% have undetectable anti- Mullerian hormone beyond 2 years, 73% show no ovarian function full-recovery after 2 years); [40,41,42,43,44,45,46,47]

    The risk seems lower but still substantial with “modern” CT regimens, as showed in “The Young Women’s Breast Cancer Study (HOHO)” prospective cohort: rates of treatment-related amenorrhea was in the range of 41-44% with TC or AC-T chemotherapy regimens.
  2. In head-to-head comparisons in the early setting, CT and OFS (with GnRH regulators or ovariectomies) deliver the same benefit on DFS and OS; [48,49,50]
  3. There is evidence that neoadjuvant CT alone might exert a downregulation of the oestrogen-dependent gene transcription in premenopausal but not postmenopausal women[51,52] suggesting that the antineoplastic activity could be attributed to both a cytotoxic and an endocrine effect (explored in ongoing trials).[11,53,54]
  4. Women experiencing CT-induced amenorrhea have improved cancer-related outcomes.[55,56] The NSABP B-30 trial tested a strategy of sequential vs concurrent AC-T chemo versus AC alone, and assessed the outcomes in relation to persistent treatment- emerging amenorrhea at 6 months from the CT.[54]

    Menopausal status alone was not a determinant of CT efficacy, both with AC-T and AC regimens. However, CT-induced amenorrhea seemed to correlate with an improvement of the outcome, defining a potential mechanism affecting the outcome (P-value interactions according to menopausal status for OS and DFS ranged between 0.08 and 0.47). NSABP B-30 included a sub-protocol analysis called the “menstrual history study”, that collected data on 97% of the pre-menopausal women enrolled in the trial (n=2,343).

    Full-adjusted analyses showed an improved OS (relative risk [RR] 0.76, p=0.04) and DFS (RR 0.70, p<0.001) for patients with no menstruation for ≥6 months during 24 months of follow- up (panel C-D and E-F below). Caveats for immortal-time bias might be addressed in analyses of this type. [57]

    However, the absence of correlation with menopausal status alone and the signal of significant benefit in patients experiencing treatment-induced amenorrhea can suggest a mechanistic link of DFS improvement with a well-known effect of CT. Of note, amenorrhea alone is still only a proxy of optimal ovarian suppression. Estradiol levels in the premenopausal range can be detected in amenorrhoeic patients despite cessation of menstruation, suggesting persisting ovarian function.[58,59]

    Better ovarian suppression can be achieved with pharmacological OFS or ultimately with ovarian ablation. Conversely, resumption or persistence of menstruation after CT has been associated with adverse survival outcomes.[44]
NSABP B-30 trial54, data on OS (C) and DFS (D) for premenopausal women participating to the “Menstrual History” sub-study. Analyses are adjusted for ER status, age, lymph-node status, tumor size and use of endocrine treatment.
From: N Engl J, Swain SM, Jeong J-H, Geyer CE, Costantino JP, Pajon ER, Fehrenbacher L. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. 2010 Jun;362(22):2053–2065. Copyright © (2022) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Subgroup analyses for multiple potential confounders are provided in the forest plots E and F.
From: N Engl J, Swain SM, Jeong J-H, Geyer CE, Costantino JP, Pajon ER, Fehrenbacher L. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. 2010 Jun;362(22):2053–2065. Copyright © (2022) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
It cannot be concluded, but only speculated, that the effect on iDFS of adjuvant CT in premenopausal women with 1-3 node-positive and low-mid-range RS breast cancer in RxPONDER is driven by the OFS effect of CT.
It is notable that the use of OFS with GnRH (LHRH) agonists or ovarian ablation is very limited in the pivotal trials for clinical validation of OncotypeDX, both in patients enrolled to CT-ET and ET alone, including RxPONDER.
Accordingly, it can be assumed, or at least hypothesized that premenopausal women with 1-3 positive lymph nodes and mid-range RS could derive comparable benefit from CT or OFS. Speculatively, the absolute benefit of CT can be minimal for patients with positive lymph nodes and RS<11, albeit the relative benefit might be comparable (as expressed with HaR, e.g., in RxPONDER).[19,60]
In WSG PlanB, the 5-year DFS for RS ≤ 11 was 94% with ET alone (in both pN0 and pN1), meaning that the absolute improvement of iDFS might be negligible, considering the data from RxPONDER (+40% relative improvement), that is possibly lower than 3%[61] Similarly, a SEER-based study showed a 5-year BCSS of 97.2%- 99.7%, in case of pN0-1 (any T) and RS<18.[62]
Consensus Statement 5.
The reflex testing of OncotypeDX applies to premenopausal women with 1-3 nodes as informing choices about chemotherapy and/or OFS.

Q6: Should the surgical approach to the axillary management affect the pattern of reflex testing of OncotypeDX in pN1 breast cancer?

Evidence in support. The axillary lymph node dissection in case of 1-2 positive sentinel lymph nodes can be safely skipped, for patients with cT1-2 cN0 early breast cancer.[63,11,64]
The surgical clinical trial ACOSOG Z0011 demonstrated that the more conservative sentinel lymph node dissection (SLND) is non inferior to the axillary lymph node dissection (ALND).[65]
The 10-year DFS rates reported for SLND and ALND were 86.3% and 83.6% (HaR 0.85, 0.10-1.6), with an OS of 80.2% and 78.2% (HaR 0.85, 0.62-1.17), respectively. The 10- year cumulative rates of locoregional recurrences and of axillary nodal recurrences were 5.3% / 1.5% with SLND and 6.2% / 0.5% with ALND.[65]
Pre-ACOSOG Z0011 algorithms showed that the anticipated risk of an additional lymph node in the axilla after SLNB (1 out of 2, and 2 out of 3) ranges between 3% and 21%, based on the pT and the tumor grade.[66,67,68]
Estimates for figure derived from the MSK algorithm (for illustrative purpose).[66,67,68]
What are the implications of the surgical approach on the outcome, and the interaction with the treatment benefit in patients with pN1 breast cancer and RS≤25 has been a key question in RxPONDER. The type of axillary surgery (SLND [37.4% of the enrolled population] vs ALND [62.6%]) was in fact a stratification factor for the randomization. The trial reported no difference in the outcome, based on the surgical approach.
The consensus was not to change the reflex testing approach based on the surgical management of the axilla.[69,70]
From: N Engl J Med, From 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer, Kalinsky, M.D., Barlow WE. Gralow JR, Meric-Bernstam F, Albain KS, et al. 2021; 385:2336-2347 DOI: 10.1056/NEJMoa2108873 Copyright © (2022). Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Consensus Statement 6.
OncotypeDX test should be done as reflex testing for patients with pN1 breast cancer, regardless the surgical approach for the axillary management.

Synopsis of the consensus statements

Reflex testing applies to:
Patient’s age ≤65, AND:
  • T1c-T3, N0-1 tumors, any grade, pre- and post-menopausal status
Ad hoc testing can be requested to:
  • Patient’s age 66-72 ¶
  • pT1b pN0 G2-3
  • pT1-2 pN2
¶ based on the COQD analysis and the ASTER 70s study.
  • Routinary use of RSClin, at this moment, is not endorsed. Case-by-case use can be considered to inform treatment decision.

Development of the Consensus Statements

The preparatory materials for the group discussion were developed initially by Dr. Trapani, Dr. Burstein and Dr. Tolaney; the COQD queries were provided by Dr. Tarantino, Dr. Jin and Dr. Tayob. Coordination and editorial support were performed by Mr. Scorzoni and Mrs. Bak.
The evidence in support and consensus statements were presented for discussion to a multidisciplinary group, which includes physicians, nurses, clinical investigators, lab investigators, translational researchers, administrators, and patient advocates, at the Breast Oncology Center weekly staff meeting on 4/15/2022 and 6/1/2022. The discussion and suggestions for improvements continued via email exchanges following the meeting. The final consensus statements were consolidated in June 2022.
The consensus statements can be subject to future variations and periodic updates, based on emerging evidence and new reports from ongoing clinical studies. Therefore, the information provided in this document should not be considered as being complete or inclusive of all proper assessments, treatments or methods of care, or as a statement of the standard of care.
This information does not mandate any particular course of medical care and is not intended to be a substitute for the independent professional judgment of a health care provider. The document is based on the opinion of a multidisciplinary team at Dana-Farber but does not represent the official institutional position, and overall must be considered as a consensus based on the positions and ideas of the Dana-Farber providers.
The graphic material was extracted from the peer-reviewed publications or produced de novo, for the purpose of data presentation.

References

  1. Trosman JR, Van Bebber SL, Phillips KA. Coverage policy development for personalized medicine: Private payer perspectives on developing policy for the 21-gene assay. J Oncol Pract. 2010;6(5). doi:10.1200/JOP.000075
  2. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMOA1804710/SUPPL_FILE/NEJMOA1804710_DISCLOSURES.PDF
  3. Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in NodePositive Breast Cancer. https://doi.org/101056/NEJMoa2108873. Published online December 1, 2021. doi:10.1056/NEJMOA2108873
  4. Paik S, Shak S, Tang G, et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, NodeNegative Breast Cancer. N Engl J Med. 2004;351(27). doi:10.1056/nejmoa041588
  5. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with nodenegative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23). doi:10.1200/JCO.2005.04.7985
  6. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: A TransATAC study. J Clin Oncol. 2010;28(11). doi:10.1200/JCO.2009.24.4798
  7. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11(1). doi:10.1016/S1470-2045(09)70314-6
  8. Cronin M, Sangli C, Liu ML, et al. Analytical validation of the oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptorpositive breast cancer. Clin Chem. 2007;53(6). doi:10.1373/clinchem.2006.076497
  9. Buus R, Sestak I, Kronenwett R, et al. Molecular drivers of oncotype DX, prosigna, endopredict, and the breast cancer index: A TransATAC study. J Clin Oncol. 2021;39(2). doi:10.1200/JCO.20.00853
  10. Trapani D, Franzoi MA, Burstein HJ, et al. Risk-adapted modulation through de-intensification of cancer treatments: an ESMO classification. Ann Oncol Off J Eur Soc Med Oncol. Published online May 2022. doi:10.1016/J.ANNONC.2022.03.273 1
  11. Burstein HJ, Curigliano G, Thürlimann B, et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021;32(10). doi:10.1016/j.annonc.2021.06.023
  12. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidel
  13. Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline updateintegration of results from TAILORx. J Clin Oncol. 2019;37(22). doi:10.1200/JCO.19.00945
  14. NCCN clinical practice guidelines in oncology. Breast Cancer. V2-2022. Available at NCCN.org (last access 22 April, 2022).
  15. Burstein HJ. Systemic Therapy for Estrogen Receptor–Positive, HER2-Negative Breast Cancer. N Engl J Med. 2020;383(26). doi:10.1056/nejmra1307118
  16. Sella T, Ruddy KJ, Carey LA, Partridge AH. Optimal Endocrine Therapy in Premenopausal Women: A Pragmatic Approach to Unanswered Questions. JCO Oncol Pract. 2022;18(3). doi:10.1200/op.21.00482
  17. Losk K, Freedman RA, Lin NU, et al. Implementation of Surgeon-Initiated Gene Expression Profile Testing (Onco type DX) Among Patients With Early-Stage Breast Cancer to Reduce Delays in Chemotherapy Initiation. J Oncol Pract. 2017;13(9):e815-e820. doi:10.1200/JOP.2017.023788
  18. Natsuhara KH, Losk K, King TA, et al. Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria. Oncologist. 2019;24(5):595- 602. doi:10.1634/THEONCOLOGIST.2018-0154
  19. Losk K, Freedman RA, Laws A, et al. Oncotype DX testing in node-positive breast cancer strongly impacts chemotherapy use at a comprehensive cancer center. Breast Cancer Res Treat. 2021;185(1). doi:10.1007/s10549-020-05931-9
  20. Minami CA, Freedman RA, Karamourtopoulos M, et al. Acceptability of a patient decision aid for women aged 70 and older with stage I, estrogen receptor-positive, HER2-negative breast cancer. J Geriatr Oncol. 2021;12(5). doi:10.1016/j.jgo.2021.02.028
  21. Biganzoli L, Battisti NML, Wildiers H, et al. Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG). Lancet Oncol. 2021;22(7). doi:10.1016/S1470-2045(20)30741-5
  22. Freedman RA, Winer EP. Adjuvant Chemotherapy for Older Patients with Breast Cancer: When Is the Pain Worth the Gain? J Natl Cancer Inst. 2020;112(6). doi:10.1093/jnci/djz192
  23. Kizy S, Altman AM, Marmor S, et al. 21-gene recurrence score testing in the older population with estrogen receptor-positive breast cancer. J Geriatr Oncol. 2019;10(2). doi:10.1016/j.jgo.2018.07.006
  24. Muss HB, Polley MYC, Berry DA, et al. Randomized trial of standard adjuvant chemotherapy regimens versus capecitabine in older women with early breast cancer: 10-year update of the CALGB 49907 trial. J Clin Oncol. 2019;37(26). doi:10.1200/JCO.19.00647
  25. Elkin EB, Hurria A, Mitra N, Schrag D, Panageas KS. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: Assessing outcome in a population-based, observational cohort. J Clin Oncol. 2006;24(18). doi:10.1200/JCO.2005.03.6053
  26. Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Goodwin JS. Use and outcomes of adjuvant chemotherapy in older women with breast cancer. J Clin Oncol. 2006;24(18). doi:10.1200/JCO.2005.02.3028
  27. Tamirisa N, Lin H, Shen Y, et al. Association of Chemotherapy with Survival in Elderly Patients with Multiple Comorbidities and Estrogen Receptor-Positive, Node-Positive Breast Cancer. JAMA Oncol. 2020;6(10). doi:10.1001/jamaoncol.2020.2388
  28. Caputo R, Cianniello D, Giordano A, et al. Gene Expression Assay in the Management of Early Breast Cancer. Curr Med Chem. 2019;27(17). doi:10.2174/0929867326666191205163329
  29. E. B. Final results from a phase III randomized clinical trial of adjuvant endocrine therapy ± chemotherapy in women ≥ 70 years old with ER+ HER2- breast cancer and a high genomic grade index: The Unicancer ASTER 70s trial. J Clin Oncol 40, 2022 (suppl 16; abstr 500).
  30. 42 CFR 414.510 – Laboratory date of service for clinical laboratory and pathology specimens. 71 FR 69786, Dec. 1, 2006, as amended at 72 FR 66402, Nov. 27, 2007. Available at: https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSch.
  31. Nguyen TTA, Postlewait LM, Zhang C, Meisel JL, O’Regan R, Badve S, Kalinsky K, Li X. Utility of Oncotype DX score in clinical management for T1 estrogen receptor positive, HER2 negative, and lymph node negative breast cancer. Breast Cancer Res Treat. 2022.
  32. Vaz-Luis I, Ottesen RA, Hughes ME, et al. Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: A multi-institutional study. J Clin Oncol. 2014;32(20). doi:10.1200/JCO.2013.53.1608
  33. Sparano JA, Crager MR, Tang G, Gray RJ, Stemmer SM, Shak S. Development and Validation of a Tool Integrating the 21-Gene Recurrence Score and Clinical-Pathological Features to Individualize Prognosis and Prediction of Chemotherapy Benefit in Early Breast Cancer. J Clin Oncol. 2021;39(6). doi:10.1200/JCO.20.03007
  34. Piccart MJ, Hilbers FS, Bliss JM, et al. Road map to safe and well-designed de-escalation trials of systemic adjuvant therapy for solid tumors. J Clin Oncol. 2020;38(34). doi:10.1200/JCO.20.01382
  35. Francis PA, Pagani O, Fleming GF, et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med. 2018;379(2). doi:10.1056/nejmoa1803164
  36. Pagani O, Francis PA, Fleming GF, et al. Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: Results from TExT and Soft. J Clin Oncol. 2020;38(12). doi:10.1200/JCO.18.01967
  37. Kim HA, Lee JW, Nam SJ, et al. Adding ovarian suppression to tamoxifen for premenopausal breast cancer: A randomized phase III trial. J Clin Oncol. 2020;38(5):434-443. doi:10.1200/JCO.19.00126
  38. Baek SY et al. Adding ovarian function suppression to tamoxifen in young women with hormonesensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: 8- year follow-up of the randomized ASTRRA trial. Abstr #506 J Clin Oncol 40, 2022 (suppl 16; abstr 506) DOI 101200/JCO 20224016_suppl506.
  39. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 wo.
  40. Jonat W, Kaufmann M, Sauerbrei W, et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the zoladex early breast cancer research association study. Int J Cl.
  41. Del Mastro L, Boni L, Michelotti A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011;306(3):269–276.
  42. Moore HC, Unger JM, Phillips KA, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;37210:923–932.
  43. Anderson RA, Su HI. The Clinical Value and Interpretation of Anti-Müllerian Hormone in Women With Cancer. Front Endocrinol (Lausanne). 2020;11. doi:10.3389/fendo.2020.574263
  44. Jacobson MH, Mertens AC, Spencer JB, Manatunga AK, Howards PP. Menses Resumption After Cancer Treatment-Induced Amenorrhea Occurs Early or Not At All. Fertil Steril (2016) 105(3):765–72. doi: 10.1016/J.Fertnstert.2015.11.020.
  45. Petrek JA, Naughton MJ, Case LD, Paskett ED, Naftalis EZ, Singletary SE, et al. Incidence, Time Course, and Determinants of Menstrual Bleeding After Breast Cancer Treatment: a Prospective Study. J Clin Oncol (2006) 24(7):1045–51. doi: 10.1200/JCO.2005.03
  46. Partridge AH, Ruddy KJ, Gelber S, Schapira L, Abusief M, Meyer M, et al. Ovarian Reserve in Women Who Remain Premenopausal After Chemotherapy for Early Stage Breast Cancer. Fertil Steril (2010) 94(2):638–44. doi: 10.1016/J.Fertnstert.2009.03.045.
  47. Dowsett M, Richner J. Effects of cytotoxic chemotherapy on ovarian and adrenal steroidogenesis in pre-menopausal breast cancer patients. Oncol. 1991;48(3). doi:10.1159/000226930
  48. Kaufmann M, Jonat W, Blamey R, et al. Survival analyses from the ZEBRA study: Goserelin (ZoladexTM) versus CMF in premenopausal women with node-positive breast cancer. Eur J Cancer. 2003;39(12). doi:10.1016/S0959-8049(03)00392-7
  49. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy’s Hospital, London. Lancet. 1993 May 22;341(8856):1293-.
  50. Freedman RA, Partridge AH. Management of breast cancer in very young women. Breast. 2013;22(S2). doi:10.1016/j.breast.2013.07.034
  51. Chic N, Schettini F, Brasó-Maristany F, et al. Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy: ER activity in pre-menopausal HR+ breast cancer during CT. EBioMedicine. 2021;69. doi:10.1016/j.ebiom.2021.103451
  52. Enomoto Y, Morimoto T, Nishimukai A, Higuchi T, Yanai A, Miyagawa Y. Impact of biomarker changes during neoadjuvant chemotherapy for clinical response in patients with residual breast cancers. Int J Clin Oncol. 2016;21(2):254–261.
  53. Burstein HJ. Unmet challenges in systemic therapy for early stage breast cancer. The Breast. 2021;56. doi:10.1016/s0960-9776(21)00044-8
  54. Swain SM, Jeong J-H, Geyer CE, Costantino JP, Pajon ER, Fehrenbacher L. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun;362(22):2053–2065.
  55. Poorvu PD, Hu J, Zheng Y, Gelber SI, Ruddy KJ, Tamimi RM, Peppercorn JM, Schapira L, Borges VF, Come SE, Warner E, Lambertini M, Rosenberg SM, Partridge AH. Treatment-related amenorrhea in a modern, prospective cohort study of young women with breast canc.
  56. Del Mastro L, Venturini M, Sertoli MR, Rosso R. Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications. Breast Cancer Res Treat. 1997 Apr;43(2):183-90. doi: 10.1023/a:1005792830054. PMID: 913.
  57. Yadav K, Lewis RJ. Immortal Time Bias in Observational Studies. JAMA. 2021;325(7):686-687. doi:10.1001/JAMA.2020.9151
  58. Durrani, Sajid, and Humariya Heena. “Controversies Regarding Ovarian Suppression and Infertility in Early Stage Breast Cancer.” Cancer management and research vol. 12 813-817. 5 Feb. 2020, doi:10.2147/CMAR.S231524.
  59. Tesch M et al. Estradiol (E2) levels in premenopausal women with hormone receptor-positive (HR+) breast cancer (BC) on ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa). ASCO 2022 Abstr #524 J Clin Oncol 40, 2022 (suppl 16; abstr 524).
  60. Laws A, Garrido-Castro AC, Poorvu PD, Winer EP, Mittendorf EA, King TA. Utility of the 21-gene recurrence score in node-positive breast cancer. Oncol (United States). 2021;35(2). doi:10.46883/ONC.2021.3502.0077
  61. Nitz U, Gluz O, Christgen M, et al. Reducing chemotherapy use in clinically high-risk, genomically lowrisk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial. Breast Cancer Res Treat. 2017;165(3). doi:10.1007/s10549-017-4358-6
  62. Kantor O, King TA, Shak S, et al. Expanding Criteria for Prognostic Stage IA in Hormone Receptor– Positive Breast Cancer. JNCI J Natl Cancer Inst. 2021;113(12). doi:10.1093/jnci/djab095
  63. Brackstone M, Baldassarre FG, Perera FE, et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline. J Clin Oncol. 2021;39(27). doi:10.1200/JCO.21.00934
  64. Grossmith S, Nguyen A, Hu J, et al. Multidisciplinary Management of the Axilla in Patients with cT1-T2 N0 Breast Cancer Undergoing Primary Mastectomy: Results from a Prospective Single-Institution Series. Ann Surg Oncol. 2018;25(12). doi:10.1245/s10434-018-6525-3
  65. Giuliano AE, Ballman K V., McCall L, et al. Effect of axillary dissection vs no axillary dissection on 10- year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA – J Am Med Assoc. 2017;318(10). doi:10.1001/jama.2017.11470
  66. Specht MC, Kattan MW, Gonen M, Fey J, Van Zee KJ. Predicting nonsentinel node status after positive sentinel lymph biopsy for breast cancer: clinicians versus nomogram. Ann Surg Oncol. 2005 Aug;12(8):654-9. doi: 10.1245/ASO.2005.06.037. Epub 2005 Jun 16. .
  67. Van Zee KJ, Manasseh DM, Bevilacqua JL, Boolbol SK, Fey JV, Tan LK, Borgen PI, Cody HS 3rd, Kattan MW. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol. .
  68. MSKCC. Nomogram for Breast Additional Non SLN Metastases. Avaiilable https//nomograms.mskcc.org/Breast/BreastAdditionalNonSLNMetastasesPage.aspx (last access June 23, 2022).
  69. Mittendorf EA, King TA, Tolaney SM. Impact of RxPONDER and monarchE on the Surgical Management of the Axilla in Patients With Breast Cancer. J Clin Oncol. Published online June 8, 2022:JCO2200173. doi:10.1200/JCO.22.00173
  70. Kantor O, Weiss A, Burstein HJ, Mittendorf EA KT. Sentinel Lymph Node Biopsy Alone is Adequate for Chemotherapy Decisions in Postmenopausal Early-Stage Hormone-Receptor Positive, HER2-Negative Breast Cancer with 1-3 Positive Sentinel Lymph Nodes. Ann Surg Oncol [in Press.

List of abbreviations

  • AC-T chemotherapy, anthracycline- and taxane-containing ASCO, American Society of Clinical Oncology
  • ALND, axillary lymph node dissection BCSS, breast cancer specific survival CI, confidence interval
  • CLIA, Clinical Laboratory Improvement Amendments CMS, Centers for Medicare & Medicaid Services COQD, Clinical Outcomes Quality Database
  • CT, chemotherapy
  • DFS, disease-free survival
  • ESMO, European Society for Medical Oncology ET, endocrine treatment
  • EUSOMA, European Society of Breast Cancer Specialists FISH, fluorescent in-situ hybridization
  • G, tumor grade HaR, hazard ratio
  • HER2, human epidermal growth factor receptor 2 (HER2)-
  • HR, hormone Receptor
  • iDFS, invasive disease-free survival IHC, immunohistochemistry
  • IQR, interquartile range
  • NCCP, National Comprehensive Cancer Network OFS, ovarian function suppression
  • SIOG, International Society of Geriatric Oncology SLND, sentinel lymph node dissection
  • TC chemotherapy, docetaxel-cyclophosphamide