How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women With Early-Stage HR+/HER2− Breast Cancer In the Post-RxPONDER Era?

Abstract

Background:

The RxPONDER trial reported no benefit to chemotherapy among postmenopausal patients with HR+/HER2− tumors, 1-3 positive nodes, and low recurrence scores, questioning the role of axillary staging in this population. Here we evaluate the impact of SLNB results on adjuvant therapy decisions in postmenopausal women with HR+/HER2− breast cancer.

Methods:

Postmenopausal women with cT1-2N0, HR+/HER2− breast cancer treated with lumpectomy and SLNB from 2012-2018 were identified. Receipt of nodal irradiation, indication for axillary lymph node dissection (ALND) and chemotherapy, and partial breast irradiation (PBI) eligibility were reviewed with pre- and post- SLNB results.

Results:

786 women were identified: median age 62 years, 84% with pT1 tumors, and 16% pT2-3. 85% (n=1525) remained pN0, 14% (n=244) were pN1, and 1% (n=17) were pN2-3. 20 (1%) patients had >2 positive SLNs, necessitating ALND. Pre-SLNB, 1478 women were considered PBI eligible; post-SLNB, 227 (13%) converted to PBI ineligible. 58 node-positive patients received nodal irradiation representing 3% of the entire cohort and 22% of pN+ patients. Overall, 1401 patients had an Oncotype DX recurrence score available, including 1273 pN0 patients and 128 pN1 patients, with 173 (14%) and 16 (13%), respectively, having a recurrence score >25 warranting chemotherapy.

Conclusions:

While few cN0 postmenopausal women with HR+/HER2− tumors had nodal pathology that warranted ALND, receipt of nodal irradiation or indicated need for chemotherapy, in 13%, SLNB would have an impact on consideration for PBI. Among patients eligible for PBI, findings from SLNB may help refine selection among postmenopausal women with this tumor profile.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging among clinically node-negative (cN0) breast cancer patients. Nodal pathology is prognostic and informs the need for additional therapy, including axillary lymph node dissection (ALND), extent of radiation therapy, and adjuvant chemotherapy, although the extent of this influence continues to evolve. In current practice, among cN0 patients undergoing breast-conserving surgery (BCS) and radiation therapy, an ALND is only indicated when 3 or more positive sentinel lymph nodes (SLNs) are identified per the ACOSOG [American College of Surgeons Oncology Group] Z0011 trial.¹ Furthermore, radiotherapeutic considerations, including use of partial breast irradiation (PBI) or need for regional nodal irradiation (RNI) are heavily influenced by nodal pathology. American Society for Radiation Oncology (ASTRO) guidelines outline populations considered suitable for PBI, including those with node-negative disease in addition to other lower-risk tumor features.² While the criteria for RNI are less clearly delineated, nodal irradiation is considered for all node-positive patients, and the decision is further refined by the extent of nodal positivity and other concomitant risk factors. While the presence of any nodal metastases has previously been considered an indication for adjuvant chemotherapy, the RxPONDER trial assessed the role of chemotherapy in women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) node-positive breast cancer and low genomic risk. The trial found no benefit to chemotherapy among postmenopausal women with 1-3 positive nodes and an Oncotype DX (Exact Sciences, Redwood City, CA) recurrence score (RS) ≤ 25.³

As each discipline of breast oncology becomes increasingly guided by tumor biology rather than anatomic staging, the influence of SLNB results on adjuvant therapy selection may be waning, thus calling in to question the role of surgical axillary staging, particularly in the population of postmenopausal patients with early-stage, HR+/HER2− breast cancer. Here we sought to evaluate the effect of SLNB results on adjuvant therapy decision making, including need for ALND, eligibility for PBI, receipt of RNI, and appropriateness for adjuvant chemotherapy in postmenopausal women with clinically node-negative, HR+/HER2− breast cancer.

METHODS

Study Population

Following institutional review board approval at Memorial Sloan Kettering Cancer Center (MSK)(New York, NY, USA), postmenopausal women with cT1-2N0, HR+/HER2− breast cancer treated with lumpectomy and SLNB from 2012-2018 were retrospectively identified from an institutional database. Age ≥ 50 years was used as a surrogate for postmenopausal status. Clinicopathologic characteristics were collected. Patients with missing treatment details and those who underwent neoadjuvant systemic therapy were excluded. Patients at MSK did not undergo routine axillary ultrasound and were staged as cN0 by physical exam. Indications for ALND, PBI, RNI, and adjuvant chemotherapy were assessed using pre- and post-SLNB nodal information.

Adjuvant Therapy Considerations

Adjuvant therapy considerations are outlined in Fig. 1. ALND was considered appropriate for women with ≥ 3 positive SLNs per ACOSOG Z0011.¹ Eligibility for PBI was determined by ASTRO consensus guidelines.² While the criteria for RNI are less clearly delineated, at MSK, patients are considered for RNI with any pN2-3 disease, and in select cases with pN1 disease and additional high-risk features, such as young age, presence of lymphovascular invasion, high grade, medial/central location of the primary, extracapsular extension, or high Oncotype DX RS. Adjuvant chemotherapy was defined as appropriate for women with pN2-3 disease or those with pN0-1 disease and an Oncotype DX RS > 25 (Fig. 1).

FIG. 1.

Adjuvant therapy assumptions.

ALND axillary lymph node dissection, ACOSOG American College of Surgeons Oncology Group, SLN sentinel lymph node, PBI partial breast irradiation, ASTRO American Society for Radiation Oncology, DCIS ductal carcinoma in situ, LVI lymphovascular invasion, RNI regional nodal irradiation

Statistical Analysis

Factors associated with the use of ALND, change in PBI eligibility and use of RNI were assessed using the Wilcoxon rank-sum test for continuous variables, and Fisher’s exact test or the Chi-squared test for categorical variables. All p-values were two sided and adjusted for multiple hypothesis testing using the Benjamini Hochberg procedure. All statistical analysis was performed using R 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Patient Population

A total of 1786 postmenopausal women were identified with cT1-2N0, HR+/HER2− breast cancer treated with lumpectomy and SLNB. The median age of the study population was 62 years (range 50-85). On final pathology, 84% of tumors were pT1 and 16% pT2-3. Among this cohort of cN0 patients, 85% remained pN0 following SLNB, while 14% (n = 244) were pN1 and 1% (n = 17) had pN2-3 disease.

Adjuvant Therapy Pre- and Post-SLNB

While no patients would be considered appropriate for ALND if presumed to be pN0, post-SLNB, 20 women (1%) in our cohort had 3 or more positive SLNs, thus qualifying for ALND (Table 1, Fig. 2a). Larger tumor size was associated with an increased likelihood of requiring ALND (p < 0.001)(Table 2). Regarding radiation therapy, no node-negative patients in this cohort would be considered appropriate for RNI, while overall, 58 (3%) received RNI based on final nodal pathology (Table 1, Fig. 2a). Higher pT stage, grade, and mixed or ductal tumor histology were all associated with receipt of RNI (p < 0.05)(Table 3). Based on PBI appropriateness criteria, prior to SLNB, 96% of women would be considered eligible for PBI; however, following incorporation of SLNB results, 83% remained PBI eligible, disqualifying 13% (Table 1, Fig. 2b). Change in PBI eligibility post-SLNB was associated with younger age, larger tumor size, and higher grade, (p < 0.05)(Table 3). When assuming pN0 status, use of chemotherapy would be determined by genomic profiling. Among 1401 patients in our cohort with an Oncotype DX RS, 189 (11%) had an RS > 25, suggestive of benefit from chemotherapy. When adding SLNB results to this decision, a total of 206 (12%) had an indication for chemotherapy based on an RS > 25 or pN2-3 disease (Table 1). Notably, no patients with pN2-3 disease had Oncotype DX testing performed. Among 772 women with tumors ≤ 1 cm, none had pN2-3 disease, 1 (0.1%) had 3 positive SLNs warranting an ALND, and 3 (0.4%) received RNI. Of this cohort, 769 were deemed eligible for PBI pre-SLNB and 716 (93%) remained PBI eligible with the addition of SLNB results.

TABLE 1.

Adjuvant therapy assumptions pre-sentinel lymph node biopsy (assumes pN0) and post- sentinel lymph node biopsy based on actual pN stage

*Excludes pN0-1 patients with no Oncotype DX Recurrence Score available

SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, RNI regional nodal irradiation, PBI partial breast irradiation

	Pre-SLNB (assume pN0) (n = 1786)	Post-SLNB based on pN status	% change
ALND appropriate	0	20 (1%)	1%
RNI Received	0	58 (3%)	3%
PBI Eligible	1705 (96%)	1478 (83%)	13%
Chemotherapy appropriate based on RxPONDER*	189 with Oncotype DX Recurrence Score > 25 (11%)	206 with Oncotype DX Recurrence Score > 25 or pN2-3 (12%)	1%

FIG. 2.

Appropriateness of adjuvant therapy by pN status. (a) axillary lymph node dissection and regional nodal irradiation by pN status; (b) partial breast irradiation eligibility by pN status; (c) chemotherapy appropriateness by pN status.

HR hormone receptor, HER2 human epidermal growth factor receptor 2, ALND axillary lymph node dissection, SLNB sentinel lymph node biopsy, RNI regional nodal irradiation, SLN sentinel lymph node, PBI partial breast irradiation

TABLE 2.

Factors associated with change in axillary surgery post-sentinel lymph node biopsy

*1401 patients had an Oncotype DX score available

SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma

Characteristic	SLNB only (n = 1766)	ALND appropriate post-SLNB (n = 20)	p-value
Median age at surgery, years	62	58	0.3
Tumor size			< 0.001
< 5 mm	240 (100%)	0 (0%)
6-10 mm	531 (99.8%)	1 (0.2%)
11-20 mm	714 (99%)	8 (1%)
21-30 mm	214 (97%)	7 (3%)
31-50 mm	62 (94%)	4 (6%)
> 50 mm	5 (100%)	0 (0%)
Tumor differentiation			0.3
Well	380 (99.7%)	1 (0.3%)
Moderately	1084 (99%)	15 (1%)
Poorly	302 (99%)	4 (1%)
Histology			0.2
IDC	1407 (99%)	14 (1%)
ILC	227 (99%)	3 (1%)
Mixed	95 (99%)	1 (1%)
Other	37 (95%)	2 (5%)
Oncotype DX Recurrence Score*			> 0.9
≤ 25	1179 (99.7)	3 (0.3%)
> 25	219 (100%)	0 (0%)

TABLE 3.

Factors associated with change in partial breast irradiation eligibility and regional nodal irradiation post-sentinel lymph node biopsy

*p-value was not calculated due to small cell counts

†1401 patients had an Oncotype DX score available

PBI partial breast irradiation, RNI regional nodal irradiation, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma

Characteristic	Remained PBI eligible (n = 1478)	Became PBI ineligible post-SLNB (n = 227)	p-value	No RNI (n = 1728)	RNI (n = 58)	p-value
Median age at surgery	62	61	0.02	62	65	0.3
Tumor size			<0.001			*
< 5 mm	233 (98%)	5 (2%)		240 (100%)	0
6-10 mm	483 (91%)	48 (9%)		529 (99.4%)	3 (0.6%)
11-20 mm	601 (84%)	115 (16%)		693 (96%)	29 (4%)
21-30 mm	161 (73%)	59 (27%)		205 (93%)	16 (7%)
31-50 mm	0	0		56 (85%)	10 (15%)
> 50 mm	0	0		5 (100%)	0
Tumor differentiation			<0.001			<0.001
Well	346 (92%)	29 (8%)		379 (99%)	2 (0.5%)
Moderately	906 (86%)	152 (14%)		1060 (96%)	39 (4%)
Poorly	226 (83%)	46 (17%)		289 (94%)	17 (6%)
Histology			0.7			0.008
IDC	1180 (86%)	187 (14%)		1370 (96%)	51 (4%)
ILC	190 (90%)	21 (10%)		229 (99.6%)	1 (0.4%)
Mixed	72 (81%)	17 (19%)		90 (94%)	6 (6%)
Other	36 (95%)	2 (5%)		39 (100%)	0
Oncotype DX Recurrence Score†			>0.9			0.8
≤ 25	1050 (91%)	99 (9%)		1171 (99%)	11 (1%)
> 25	195 (91%)	19 (9%)		218 (99.5%)	1 (0.5%)

DISCUSSION

In the era of personalized medicine, oncologic interventions must be increasingly evaluated for utility in specific settings. While lymph node status remains prognostic, the impact of SLNB on adjuvant therapy decision making is in evolution. In this large cohort of postmenopausal patients with early-stage, HR+/HER2− breast cancer, we report a very low rate of pN2-3 disease (1%) that would warrant ALND or consideration for chemotherapy based on current practice guidelines, while 3-13% of women would have a potential change in RNI or PBI eligibility, respectively.

Efforts are ongoing to identify populations of patients for which axillary surgery can be minimized or eliminated to decrease postoperative morbidity, including lymphedema and arm dysfunction. ACOSOG Z0011 established the safety of omission of ALND in patients with cT1-2N0 breast cancer treated with lumpectomy and whole-breast radiation therapy,¹ and has become the standard of care for this patient population. Prior studies have reported that the majority of ACOSOG Z0011-eligible patients with a positive SLN are spared ALND.⁴ In this series, where women were defined as cN0 by physical exam alone and managed according to Z0011, only 1% had final pathology that would warrant ALND with > 2 positive SLNs. Recent studies have compared SLNB to no axillary surgery among cN0 women with negative axillary imaging and report similar results. The SOUND⁵ and INSEMA⁶ trials have reported early results and found 0% and 0.3% rates of pN2-3 disease, respectively, coupled with improved quality of life, with decreased postoperative pain and arm morbidity, in the no-axillary-surgery cohorts.

While SLNB results infrequently change axillary surgery recommendations in this patient population, following the RxPONDER results, this is now also true for determination of adjuvant chemotherapy among women with HR+/HER2− breast cancer. In addition to node-negative patients, the RxPONDER trial confirmed that postmenopausal women with 1-3 positive lymph nodes with HR+/HER− breast cancer and an Oncotype DX RS of < 25 do not derive benefit from systemic chemotherapy.³ In the current study, 17 women, or 1%, had pN2-3 disease that would warrant automatic consideration of chemotherapy, suggesting that for nearly all patients, tumor biology rather than anatomic nodal staging is the driver for this adjuvant therapy decision. Although chemotherapy recommendations are unlikely to change with the addition of nodal pathology in this cohort, nodal pathology may continue to influence other systemic therapy decisions among this population. Emerging data on targeted therapy with the CDK4/6 inhibitor abemaciclib in node-positive HR+/HER2− patients remain an important consideration. The monarchE trial reported improved invasive disease-free survival among high-risk patients randomized to abemaciclib with endocrine therapy compared to endocrine therapy alone.⁷ The definition of high-risk in this study was patients with 4 or more positive nodes, or those with 1-3 positive nodes and either tumor size ≥ 5 cm, histologic grade 3 tumor, or Ki-67 ≥ 20% suggesting that in patients with these high-risk tumor features, SLNB results will continue to impact systemic therapy recommendations. In our cohort of nearly 1800 cT1-2N0 patients, 5 women (0.3%) had pT3 tumors and 17% had poorly differentiated tumors. While Ki-67 is not routinely reported at our institution, women with high-grade tumors or elevated Ki-67 known preoperatively would likely benefit from nodal staging to determine eligibility for abemaciclib at this time. Among patients with HER2 overexpressing or triple negative tumors, nodal pathology continues to play an important role in individualizing systemic therapy considerations, such as the addition of immunotherapy for node-positive triple negative breast cancer⁸ and the potential de-escalation of chemotherapy regimens in node-negative HER2+ disease.⁹

Nodal status has remained central to radiotherapy decision making. Here we sought to determine how often nodal staging indicated the need for RNI or altered eligibility for PBI. Based on the results of MA.20, EORTC 22922, and the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis regarding RNI,^10-12 which all report a significant decrease in breast cancer recurrence, and the latter 2 which report improvement in breast cancer survival, we recommend RNI for all patients with pN2-3 disease and in select patients with pN1 disease and a combination of other risk factors. In this cohort, 3% of patients ultimately received RNI given their pathologic nodal status and concomitant clinicopathologic features. Conversely, nodal pathology also influences eligibility for PBI or omission of radiation therapy for low-risk patients. Given the improvement in long-term cosmetic outcomes, and reduced lung and heart radiation doses with PBI compared to whole-breast radiation therapy, consideration of PBI eligibility is clinically impactful.^13-15 Eligibility for PBI is outlined by ASTRO suitability criteria.² Based on review of all patients both pre- and post- SLNB results, 13% of women who were initially considered eligible for PBI were deemed inappropriate for PBI once nodal pathology was taken into consideration; therefore, this remains an important area for investigation and multidisciplinary cooperation. Similarly, whereas some patients are eligible for omission of radiotherapy in the cN0 and pN0 setting (≥ 65 or ≥ 70 years of age with T1N0 HR+ disease), the identification of nodal involvement typically requires adjuvant radiation therapy (REF CALGB 9343 and Prime 2 study). Ongoing trials are assessing the potential for radiation therapy omission in younger low-risk patients via molecular profiling, again suggesting that tumor biology may become increasingly prominent for radiation planning in the future (e.g., ClinicalTrials.gov: PRECISION NCT02653755; IDEA NCT02400190; EXPERT NCT02889874; DEBRA/NRG BR007 NCT04852887).^16-19

Importantly, when individualizing diagnostic and therapeutic procedures to minimize morbidity, we identified a subgroup for whom SLNB had limited effect on adjuvant therapy. Among patients with pT1 tumors, no patients ultimately had pN2-3 disease, and only 1 patient had 3 positive SLNs indicating the need for ALND. Similarly, < 1% received RNI, and only 7% had a change in PBI eligibility. In practice, those with the smallest tumors are least likely to have a change in clinical management while benefiting from avoidance of axillary surgery. The SOUND, INSEMA, and BOOG 2013-8^5,6,20 trials examine the impact of eliminating axillary surgery in T1 (SOUND) or T1 and T2 (INSEMA, BOOG 2013-8) in patients with a normal axillary ultrasound on distant disease-free survival, invasive disease-free survival, and regional recurrence, respectively, and will provide important information on the safety of this approach. Thus, for appropriately selected and suitably motivated patients, SLNB may be avoided while awaiting results of ongoing studies, provided that the risks delineated above are well understood.

Our findings must be interpreted in the context of the study design. Given the retrospective nature of these analyses, bias and confounding may have influenced our results. Furthermore, while recommendations for ALND and adjuvant chemotherapy in early-stage patients are standardized, there remains heterogeneity in practice regarding recommendations and receipt of chemotherapy, RNI, and PBI, which may limit the general applicability of these data.

Conclusions

In postmenopausal women with early-stage, cN0 HR+/HER2− breast cancer, it is uncommon for patients to undergo ALND, adjuvant chemotherapy, or RNI based on SLNB results given the low likelihood of a significant underlying nodal disease burden. Conversely, the identification of any nodal disease on SLNB does affect PBI eligibility. Further study and multidisciplinary collaboration are needed to optimize the role for SLNB in informing adjuvant treatment decisions.

Synopsis:

Here we evaluate adjuvant therapy decision making as a function of sentinel node pathology. We find pN2-3 disease is uncommon, few require ALND or chemotherapy because of SNLB results, but radiation may be impacted among postmenopausal cT1-2N0 breast cancer patients.