Abstract
Background.
Surgical axillary staging demonstrating positive nodal disease before neoadjuvant chemotherapy (NAC) necessitates axillary lymph node dissection (ALND) post-NAC. Despite evidence supporting post-NAC surgical staging, we hypothesized that there is persistent use of pre-NAC staging and that it is associated with aggressive clinicopathologic features and a higher rate of subsequent ALND.
Patients and Methods.
Stage I–III breast cancer patients who underwent lymph node staging surgery and received NAC between 2013 and 2017 in the National Cancer Database were included. Sequence of staging surgery and chemotherapy administration was determined. Multivariable regression was used to assess characteristics associated with pre-NAC staging. Rate of ALND was compared between those who had pre- and post-NAC surgical axillary staging.
Results.
In total, 120,538 met inclusion; 68% received NAC first and 32% had pre-NAC staging. Pre-NAC staging surgery was associated with younger age (age < 30 versus 40–49 years, HR 1.1) and decreased with older age (ages 70–79/80+ versus 40–49 years, HR 0.86 and 0.73). Advancing clinical T stage, lobular subtype, higher grade, and HR+/HER2− subtype were also associated with pre-NAC surgical staging. Women who underwent pre-NAC surgical staging were more likely to undergo ALND.
Conclusions.
Over 30% of women underwent surgical axillary staging prior to NAC, resulting in higher rates of ALND in this cohort. While certain features suggestive of aggressive behavior (grade and T stage) were associated with pre-NAC surgical axillary staging, women with more aggressive tumor subtypes (triple negative/HER2+) were less likely to undergo pre-NAC surgical axillary staging. Pre-NAC surgical axillary staging should be performed only in rare circumstances to avoid unnecessary ALND.
Axillary lymph node status remains one of the most significant prognostic indicators for patients with breast cancer.1 Until the introduction of sentinel lymph node biopsy (SLNBx) in the 1990s, axillary lymph node dissection (ALND) was the standard practice for axillary staging.2 SLNBx is a less invasive technique with lower complication rates, including reduced sensory loss, lymphedema, seroma formation, mobility restriction, infection, and psychological morbidity3–5 and has been proven both accurate and safe from an oncologic perspective for staging women with clinically node negative breast cancer who undergo surgery first.6–9Neoadjuvant chemotherapy has been increasingly employed to facilitate breast conservation, downstage the axilla, and assess response to therapy. Three prospective studies (SENTINA, ACOSOG Z1071, and SN FNAC) have demonstrated the feasibility of sentinel lymph node biopsy in select patients after neoadjuvant chemotherapy (clinically node negative or those who convert from clinical stage N1 to N0 during therapy).10–14 Both SLNBx and targeted axillary dissection are acceptable methods of axillary staging post-neoadjuvant chemotherapy.15 The results of these studies were incorporated into National Comprehensive Cancer Network guidelines in 201616 and have presumably resulted in a significant reduction in the use of ALND and therefore its associated cost and morbidity.
Even with the potential benefits of axillary staging after neoadjuvant chemotherapy (NAC), at present there are no clear guidelines on timing of axillary staging in relation to NAC. Pre-NAC SLNBx has been performed in the past to facilitate medical decision-making and in the context of clinical trials; however, there are now only rare reasons for its use. Despite the surgical implications of pre-NAC surgical axillary staging (committing node positive patients to ALND) and level 1 evidence supporting the use of post-NAC SLNBx, we hypothesized that there is persistent use of surgical axillary staging pre-NAC and that its use is associated with aggressive clinicopathologic features and a higher prevalence of subsequent ALND.
PATIENTS AND METHODS
Study Design and Patient Population
This was a retrospective cohort study using data from the National Cancer Database (NCDB), a joint database project of the Commission on Cancer (CoC) and the American College of Surgeons, which captures incident cancer cases from participating sites. Established in 1989, this nationwide, facility-based registry captures approximately 70% of newly diagnosed cancer cases each year in a de-identified fashion. Given the de-identified nature of the data, the University of North Carolina Institutional Review Board deemed this study exempt (IRB# 20-1493).
Adult women (≥ 18 years old) diagnosed with stage I–III breast cancer who underwent lymph node staging surgery (either SLNBx and/or ALND) and received NAC before breast-conserving surgery or mastectomy between 2013 and 2017 were eligible for inclusion. ACOSOG Z1071 and SENTINA were published in 2013, and we deliberately chose 2013 as the start date of our study, even though NCCN guidelines were not updated until 2016. Women were excluded if they had evidence of metastatic disease (cM1) or in situ disease, or did not receive neoadjuvant chemotherapy or have lymph node surgery.
The order of lymph node staging and and NAC was determined using information captured on the number of days between diagnosis and (1) first surgery and (2) first systemic treatment initiation. Women were classified as having pre-NAC axillary staging if first surgery occurred before the initiation of systemic treatment, and were classified as having NAC first if systemic treatment was initiated before their first surgery. Since NCDB does not explicitly capture when lymph node staging and chemotherapy occur, this means we assumed each patient’s first surgery included their lymph node staging and that their first systemic treatment was chemotherapy.
The primary outcome of our analysis was both the prevalence of pre-NAC staging and ALND between women who had staging before and after NAC. Women who were recorded as undergoing SLNBx and ALND (either at same time or at a later date) were coded as undergoing ALND. We also identified patient and tumor characteristics that were associated with receiving axillary staging prior to NAC.
Statistical Analysis
Descriptive statistics were used to characterize pertinent demographics and clinical characteristics, including race/ethnicity, Charlson–Deyo comorbidity score, insurance type, facility type, clinical stage, receptor status, tumor grade, histologic subtype, and presence of lymphovascular invasion, across timing of NAC and axillary staging (NAC first versus axillary staging first). Similar methods were used to assess trends in axillary staging first over time (2013–2017) and the prevalence of ALND across the timing of NAC and axillary staging, receptor status, and nodal status.
Using multivariable, log-binomial regression, we assessed (1) the association between clinical characteristics and the probability of undergoing axillary staging prior to NAC, compared with NAC first and (2) the probability of undergoing sentinel lymph node biopsy compared with axillary lymph node dissection, when surgical axillary staging surgery was performed before systemic therapy. Models were adjusted for age, clinical N stage, clinical T stage, histology, receptor status, and grade.
All analyses were performed using SAS version 9.4 (SAS Inc., Cary, NC).
RESULTS
Overall, 120,538 women were diagnosed with stage I–III breast cancer and had received both an axillary lymph node staging surgery (SLNBx and/or ALND) and NAC. Of these women, 82,226 (68%) women received NAC first and 38,312 (32%) underwent surgical axillary staging prior to NAC.
Clinical and Tumor Characteristics
Demographic and clinical characteristics of the cohort are listed in Table 1. Average ages for the NAC cohort and staging surgery first cohort were 53 (SD:12) and 52 (SD:12) years, respectively. The majority of women were non-Hispanic White (69%), followed by non-Hispanic Black (17%) and Hispanic (8%). The majority of women had private insurance (65%), followed by Medicare (19%). Breast cancer care was most often received at comprehensive community cancer programs (41%) or academic/research programs (36%). The majority (89%) of patients had N0 or N1 disease, with only 11% of the entire cohort having clinical N2 or N3 disease. Women receiving neoadjuvant chemotherapy first had a higher prevalence of clinical N0 disease (53% versus 26%) and triple-negative tumors (29% versus 25%). The axillary surgery first cohort had a higher prevalence of lymphovascular invasion (36% versus 26%) and clinical N1 disease (60% versus 37%), and a slightly higher prevalence of clinical N2/N3 disease (13% versus 10%). No notable differences were observed across race/ethnicity, comorbidity status, insurance status, treatment facility, histologic subtype, HER+ disease, or tumor grade.
TABLE 1.
Demographic and clinical characteristics for women with stage I–III breast cancer who received neoadjuvant chemotherapy and axillary lymph node staging surgery in the National Cancer Database
| Treatment order | |||
|---|---|---|---|
| Overall | NAC first | Axillary staging first | |
| 120,538 | 82,226 | 38,312 | |
| Demographics, n (%) | |||
| Age category (years) | |||
| 18–29 | 2444 (2.0) | 1550 (1.9) | 894 (2.3) |
| 30–39 | 15,059 (12.5) | 9892 (12.0) | 5167 (13.5) |
| 40–49 | 29,604 (24.6) | 19,775 (24.1) | 9829 (25.7) |
| 50–59 | 35,830 (29.73) | 24,475 (29.8) | 11,355 (29.6) |
| 60–69 | 26,767 (22.2) | 18,668 (22.7) | 8099 (21.1) |
| 70–79 | 9430 (7.8) | 6806 (8.3) | 2624 (6.9) |
| 80+ | 1404 (1.2) | 1060 (1.3) | 344 (0.9) |
| Race/ethnicity | |||
| Non-Hispanic White | 82,862 (69.2) | 56,093 (68.7) | 26,769 (70.3) |
| Non-Hispanic Black | 20,361 (17.0) | 13,795 (16.9) | 6566 (17.3) |
| Hispanic | 9734 (8.1) | 7035 (8.6) | 2699 (7.1) |
| Non-Hispanic othera | 6766 (5.7) | 4743 (5.8) | 2023 (5.3) |
| Missing | 815 | 560 | 255 |
| Charlson/Deyo Comorbidity Score | |||
| 0 | 104,616 (86.8) | 71,358 (86.8) | 33,258 (86.8) |
| 1 | 12,637 (10.5) | 8618 (10.5) | 4019 (10.5) |
| 2 | 2345 (1.9) | 1608 (2.0) | 737 (1.9) |
| ≥ 3 | 940 (0.8) | 642 (0.8) | 298 (0.8) |
| Insurance status | |||
| Not insured | 3707 (3.1) | 2697 (3.3) | 1010 (2.7) |
| Private | 77,095 (64.7) | 51,594 (63.6) | 25,501 (67.1) |
| Medicaid | 13,491 (11.3) | 9309 (11.5) | 4182 (11) |
| Medicare | 23,123 (19.4) | 16,349 (20.2) | 6774 (17.8) |
| Other government | 1687 (1.4) | 1149 (1.4) | 538 (1.4) |
| Missing | 1435 | 1128 | 307 |
| Facility type, n (%) | |||
| Community cancer program | 8065 (7.8) | 5904 (8.3) | 2161 (6.7) |
| Comprehensive community cancer program | 42,148 (40.9) | 29,576 (41.8) | 12,572 (39.0) |
| Academic/research program | 36,596 (35.5) | 24,575 (34.7) | 12,021 (37.3) |
| Integrated Network Cancer Program | 16,226 (15.8) | 10,729 (15.2) | 5497 (17.0) |
| Missingb | 17,503 | 11,442 | 6061 |
| Clinical characteristics, n (%) | |||
| Clinical N stage | |||
| Missing | 517 (0.4) | 386 0.5) | 131 (0.3) |
| N0 | 53,431 (44.3) | 43,351 (52.7) | 10,080 (26.3) |
| N1 | 53,201 (44.1) | 30,050 (36.6) | 23,151 (60.4) |
| N2 | 7789 (6.5) | 4988 (6.1) | 2801 (7.3) |
| N3 | 5600 (4.7) | 3451 (4.2) | 2149 (5.6) |
| Clinical T stage | |||
| Missing | 802 (0.7) | 426 (0.5) | 376 (1.0) |
| T1 | 25,145 (20.9) | 16,154 (19.7) | 8991 (23.5) |
| T2 | 61,957 (51.4) | 42,966 (52.3) | 18,991 (49.6) |
| T3 | 21,011 (17.4) | 14,252 (17.3) | 6759 (17.6) |
| T4 | 11,623 (9.6) | 8428 (10.3) | 3195 (8.3) |
| Histology | |||
| Ductal | 101,705 (84.4) | 69,709 (84.8) | 31,996 (83.5) |
| Lobular | 13,284 (11.0) | 8621 (10.5) | 4663 (12.2) |
| Other | 5549 (4.6) | 3896 (4.7) | 1653 (4.3) |
| Receptor status | |||
| HER2+/HR+ | 28,512 (24.4) | 19,877 (25.0) | 8635 (23.2) |
| HER2+/HR− | 14,469 (12.4) | 9938 (12.5) | 4531 (12.2) |
| HER2−/HR+ | 41,661 (35.7) | 26,838 (33.7) | 14,823 (39.9) |
| Triple negative | 32,104 (27.5) | 22,905 (28.8) | 9199 (24.7) |
| Missing | 3792 | 2668 | 1124 |
| Grade | |||
| 1 | 5330 (4.7) | 3816 (5.0) | 1514 (4.2) |
| 2 | 38,490 (34.2) | 26,038 (34.0) | 12,452 (34.6) |
| 3 | 68,575 (60.9) | 46,586 (60.8) | 21,989 (61.0) |
| 4 | 279 (0.3) | 204 (0.3) | 75 (0.2) |
| Missing | 7864 | 5582 | 2282 |
| Lympovascular invasion | |||
| Yes | 25,756 (29.2) | 15,801 (26.2) | 9955 (35.9) |
| No | 62,329 (70.8) | 44,537 (73.8) | 17,792 (64.1) |
| Missing | 32,453 | 21,888 | 10,565 |
LN lymph node, NAC neoadjuvant chemotherapy
Other race includes those who self-identified as not White, not Black, and not Hispanic.
Facility type and location are not reported for patients < 40 years old.
Probability of Lymph Node Staging before Neoadjuvant Chemotherapy
On multivariable regression, surgical axillary staging prior to NAC was associated with younger age [risk ratio [RR] 1.16, 95% CI 1.09, 1.23 for age < 30 years] and was less likely among older women (RR 0.88, 95% CI 0.85, 0.92 for ages 70–79 years and RR 0.76, 95% CI 0.68, 0.85 for 80+ years), compared with women aged 40–49 years. Increased clinical nodal stage was associated with increased relative risk of having surgical axillary staging surgery first, (N1: RR 2.19, 95% CI 2.14, 2.24; N2: RR 1.87, 95% CI 1.79, 1.95; and N3: RR 2.04, 95% CI 1.95, 2.14). Additionally, advancing clinical T stage, lobular histologic subtype, higher tumor grade, and hormone receptor positive HR+ /HER2− subtype were associated with increased relative risk of undergoing surgical axillary staging prior to NAC (Table 2).
TABLE 2.
(A) Adjusted association between clinical characteristics and probability of undergoing axillary lymph node staging surgery first, compared with NAC first, among women with stage I–III breast cancer diagnosed between 2013 and 2017
| RR (95% CI)a | p Value | |
|---|---|---|
| Age category, years | ||
| 18–29 | 1.16 (1.09–1.23) | <0.0001 |
| 30–49 | 1.03 (1.00–1.06) | 0.06 |
| 40–49 | 1.00 (reference) | – |
| 50–59 | 0.97 (0.95–1.00) | 0.05 |
| 60–69 | 0.93 (0.91–0.96) | <0.0001 |
| 70–79 | 0.88 (0.85–0.92) | <0.0001 |
| 80+ | 0.76 (0.68–0.85) | <0.0001 |
| Clinical N stage | ||
| N0 | 1.00 (referent) | – |
| N1 | 2.19 (2.14–2.24) | <0.0001 |
| N2 | 1.87 (1.79–1.95) | <0.0001 |
| N3 | 2.04 (1.95–2.14) | <0.0001 |
| Clinical T stage | ||
| T1 | 1.00 (reference) | – |
| T2 | 0.80 (0.79–0.82) | <0.0001 |
| T3 | 0.73 (0.71–0.76) | <0.0001 |
| T4 | 0.59 (0.57–0.62) | <0.0001 |
| Histology | ||
| Ductal | 1.00 (reference) | – |
| Lobular | 1.15 (1.12–1.18) | <0.0001 |
| Other | 1.03 (0.98–1.09) | 0.24 |
| Receptor status | ||
| HER2+/HR+ | 0.92 (0.90–0.95) | <0.0001 |
| HER2+/HR− | 0.91 (0.88–0.94) | <0.0001 |
| HER2−/HR+ | 1.00 (reference) | – |
| Triple negative | 0.89 (0.86–0.91) | <0.0001 |
| Grade | ||
| 1 | 1.00 (reference) | – |
| 2 | 1.10 (1.04–1.15) | <0.001 |
| 3 | 1.15 (1.09–1.21) | <0.0001 |
| 4 | 1.08 (0.85–1.37) | 0.55 |
RR risk ratio, CI confidence interval
Multivariable, log-binomial regression was used to estimate the independent association between patient demographics, cancer characteristics, and undergoing axillary lymph node staging before neoadjuvant chemotherapy (compared with NAC first); model was adjusted for age, clinical N stage, clinical T stage, histology, receptor status, and grade.
Of all patients in our study population who received surgical axillary staging first, 58.2% had SLNBx while 41.8% had ALND. When stratified by nodal status, 85.1% and 14.9% of patients with N0 disease underwent SLNBx and ALND prior to systemic therapy, respectively, compared with 48.5% and 51.5% of patients with N1–3 disease. Subanalysis was conducted to evaluate factors associated with patients undergoing sentinel lymph node biopsy, versus axillary lymph node dissection, when surgical axillary staging surgery was performed before receipt of NAC. On multivariable regression, patients were less likely to undergo SLNBx (versus ALND) if they were older (age 50+ years), or had cN1 disease or greater, clinical T stage 3 or 4, or “other” histology (Table 3). Patients were more likely to receive SLNBx for their lymph node staging surgery if they had HER2+ or triple-negative disease, (HER2+/HR+ subtype: RR 1.05, 95% CI 1.04, 1.06; HER2+/HR− subtype: RR 1.04, 95% CI 1.02, 1.05; triple-negative subtype: RR 1.03, 95% CI 1.02, 1.04). When lymph node staging surgery was performed first, patients were less likely to have sentinel lymph node biopsy as their staging procedure (RR 0.9844, 95% CI 0.98, 0.99).
TABLE 3.
Adjusted association between clinical characteristics and probability of undergoing sentinel lymph node biopsy first, compared with axillary lymph node dissection, among women with stage I–III breast cancer diagnosed between 2013 and 2017 who received axillary staging surgery prior to chemotherapy
| RR (95% CI)a | p Value | |
|---|---|---|
| Age category, years | ||
| 18–29 | 1.00 (0.97–1.02) | 0.8725 |
| 30–49 | 0.99 (0.98–1.01) | 0.3442 |
| 40–49 | 1.00 (reference) | – |
| 50–59 | 0.99 (0.98–1.00) | 0.0035 |
| 60–69 | 0.99 (0.98–1.00) | 0.0091 |
| 70–79 | 0.98 (0.97–1.00) | 0.0490 |
| 80+ | 0.86 (0.82–0.91) | <0.0001 |
| Clinical N stage | ||
| N0 | 1.00 (reference) | – |
| N1 | 0.61 (0.61–0.62) | <0.0001 |
| N2 | 0.43 (0.41–0.45) | <0.0001 |
| N3 | 0.41 (0.39–0.43) | <0.0001 |
| Clinical T stage | ||
| T1 | 1.00 (reference) | – |
| T2 | 1.00 (1.00–1.01) | 0.4063 |
| T3 | 0.91 (0.89–0.92) | <0.0001 |
| T4 | 0.56 (0.54–0.58) | <0.0001 |
| Histology | ||
| Ductal | 1.00 (reference) | – |
| Lobular | 0.99 (0.98–1.00) | 0.1274 |
| Other | 0.96 (0.93–0.98) | 0.0001 |
| Receptor status | ||
| HER2+/HR+ | 1.05 (1.04–1.06) | <0.0001 |
| HER2+/HR− | 1.04 (1.02–1.05) | <0.0001 |
| HER2−/HR+ | 1.00 (reference) | – |
| Triple negative | 1.03 (1.02–1.04) | <0.0001 |
| Grade | ||
| 1 | 1.00 (reference) | – |
| 2 | 1.00 (0.98–1.01) | 0.7451 |
| 3 | 1.00 (0.99–1.02) | 0.6577 |
| 4 | 0.96 (0.86–1.06) | 0.4141 |
| Timing | ||
| Chemo first | 1.00 (reference) | – |
| LN surgery First | 0.9844 (0.98–0.99) | 0.0005 |
RR risk ratio, CI confidence interval
Multivariable, log-binomial regression was used to estimate the independent association between patient demographics, cancer characteristics, and undergoing sentinel lymph node biopsy as the patient’s first surgical axillary staging procedure (compared with axillary lymph node dissection); model was adjusted for age, clinical N stage, clinical T stage, histology, receptor status, and grade.
Prevalence of Axillary Lymph Node Dissection
Women who underwent surgical axillary staging prior to NAC were more likely to undergo ALND as their final axillary procedure: 72.1% versus 63.2% of HR+/HER2− patients; 62.3% versus 46.5% of HR+/HER2+ patients; 63.6% versus 49.3%. of HR−/HER2+ patients; 60.1% versus 47.2% of triple-negative patients. Women with clinical N0/1 disease who had axillary staging first had higher rates of subsequent ALND (61.1% versus 47.8%) than those who received chemotherapy first (Fig. 1a). The difference was less prominent in cases with clinical N2/3 disease; women who received axillary staging procedures first were slightly more likely to have ALND as their final axillary procedure (86.7% versus 85.1%). This trend held true across all tumor receptor subtypes in both clinical N0/1 patients (Fig. 1b) and clinical N2/3 patients (Fig. 1c).
FIG. 1.
Prevalence of ALND, among women who underwent axillary staging first and those who underwent neoadjuvant therapy first, stratified by a clinical nodal status, b receptor status in clinical N0/N1 patients, and c by receptor status in clinical N2/N3 patients. Patients who underwent SLNBx followed by ALND were classified as ALND
Use of Pre-NAC Axillary Staging Surgery over Time
The overall prevalence of pre-NAC axillary staging for our study cohort was 31.8%. The prevalence of surgical axillary staging procedures before receipt of neoadjuvant chemotherapy remained steady from 2013 to 2017 (Cochran–Armitage trend test p = 0.1302), even though guidelines changed in 2016 (2013: 32.2%, 2014: 30.8%, 2015: 31.8%, 2016: 31.9%, and 2017: 32.2%, Fig. 2).
FIG. 2.
Trends in the proportion of women with stage I–III breast cancer who underwent axillary lymph node staging surgery before receipt of neoadjuvant chemotherapy between 2013 and 2017 in National Cancer Database
DISCUSSION
In a national cohort of women with stage I–III breast cancer diagnosed between 2013 and 2017 and who underwent NAC, we observed that over 30% underwent surgical axillary staging prior to initiation of NAC, resulting in a significantly higher prevalence of ALND in this group. While certain features suggestive of aggressive behavior (grade and T stage) were associated with use of pre-NAC surgical axillary staging, women with more aggressive tumor subtypes (e.g., triple-negative disease, HER2+ receptor status) were less likely to undergo pre-NAC surgical axillary staging. As expected, women who underwent axillary staging before NAC were more likely to receive ALND, given level 1 evidence that repeat SLNB after NAC is not accurate. To our knowledge, this is the first study to date that looks specifically at prevalence of axillary surgery in relation to timing of NAC by breast cancer subtype.
There is substantial evidence that, when possible, SLNBx should be used instead of ALND, to avoid complications, decreased quality of life, and higher healthcare costs.17–19 For example, the ALMANAC trial demonstrated substantial arm swelling and numbness in women treated with ALND in comparison with SLNBx alone.7,19 A large, prospective study by Gregorwitsch et al. evaluating breast cancer patient-reported outcomes demonstrated that axillary surgery was associated with impaired physical functioning and arm morbidity for up to 18 months after surgery. Patient-reported symptoms were significantly less in those treated with only SLNBx.18 Due to this severe patient morbidity, research has focused on validating the safety and feasibility of de-escalating ALND, with multiple studies showng the feasibility of omission of ALND for small-volume disease,20 omission of axillary surgery in certain subsets of patients,21–23 and, most relevant to this study, using NAC to avoid ALND.10,24
Neoadjuvant chemotherapy can effectively downstage the axilla, allowing many clinically node-positive patients to acheive pathologic complete response (pCR).25,26 And while the rate of post-NAC pathologic complete response in axillary nodes varies between 20% and 40%, the addition of other receptor-targeted therapies, such as the HER2-targeted therapy, have yielded pCR rates as high as 40–74%.26 Nonetheless, when axillary staging surgery is performed pre-NAC, the opportunity to perform SLNBx at time of definitive surgery is lost, and these women are committed to the morbidity of ALND. Given the significant number of patients able to achieve a clinically negative axilla after NAC, many studies examining pCR after primary chemotherapy have thus advocated for use of SLNBx over ALND in this patient population.27–30 Similar to this investigation, other analyses have corroborated the reduction in ALND with use of post-NAC SLNBx. In a prospective study of women with clinical stage II/III biopsy-proven nodal disease treated with NAC, almost 70% of these women were clinically node negative after receipt of chemotherapy, and almost half of these women were able to avoid ALND.24 Similarly, a smaller retrospective study of women with clinical evidence of axillary metastasis found most were clinically downstaged to N0 after neoadjuvant chemotherapy, resulting in omission of ALND.31
There may be particular cancer subtypes or practice factors influencing decisions on timing of axillary staging procedures in relation to NAC and the use of ALND. Prior to analysis, we speculated that patients with more aggressive cancer subtypes, including those with HER2+ and triple-negative disease, may experience higher use of pre-NAC surgical staging. In contrast to our initial hypothesis, our analysis found these women were actually less likely to receive axillary staging surgery before receipt of neoadjuvant chemotherapy. Multiple studies, including ACOSOG Z1071 and ISPY1, have demonstrated that triple-negative and HER2+ disease patients have higher pathologic complete response rates in both node-positive and node-negative cohorts,32–36 and this knowledge potentially helped clinicians in choosing NAC first, particularly for N0/N1 patients. It is unclear what factors are driving decisions for pre-NAC axillary staging in women with high tumor grade and high T stages. There are likely other unmeasurable influences, such as surgeon training and institutional based practices, affecting pre-NAC axillary staging real-world use. A recent observational study found that, even after adjustment for patient and tumor factors, women treated at low-volume institutions were more likely to receive ALND33 and that de-implementation of completion axillary lymph node dissection in Z0011-eligible patients was dependent on unknown institutional factors.37 Outcomes focusing on use of SLNBx have similarly demonstrated that women treated at facilities where physicians specialize in breast oncology, who accordingly have a higher volume of breast cases and have physicians with membership to breast or surgical oncology professional societies, are more likely to have SLNBx instead of ALND, when appropriate.38,39 We hypothesize that similar factors may explain the prevalence of pre-NAC surgical staging observed in our study cohort.
Despite the feasibility and safety of performing lymph node staging surgery after the receipt of chemotherapy, over one-third of the women in our study cohort had pre-NAC lymph node surgery. The use of this practice has not declined post-publication of ACOSOG Z1071 and SEN-TINA, as evidenced by the steady use of pre-NAC axillary staging observed over 2013–2017. Slow adoption of therapy de-escalation in breast cancer has been previously observed. For example, despite data from randomized control trials supporting omission of radiation therapy in elderly women with early-stage, hormone receptor positive breast cancers undergoing breast conservation surgery, multiple studies analyzing treatment practices before and after data incorporation in National Comprehensice Cancer Network guidelines found that most women were still in receipt of radiotherapy.16,40,41 Similarly, randomized evidence has proven no survival benefit of axillary dissection in elderly women with early-stage breast cancers; yet despite its decreased utlitity, axillary dissection remains a pervasive therapeutic tool for management in this cohort.42,43 Slow disseminiation and implementation of novel clinical practice guidelines is not unique to breast oncology, and remains a challenge across all specialities. Practice- and community-based interventions such as educational outreach visits and practice audits, as opposed to didactic-based methods, have been found to be superior in clinician adoption of guidelines.44 Other variables, such as practice setting, patient factors, and clinician attitudes towards the clinical guideline, have also been found to influence adoption of new guidelines of care.43–46Our analysis is not without limitations. First, while our study occurred after the publication of results showing the benefit of performing axillary staging after NAC (2013), NCCN guidelines were not updated until 2016; however, we saw a consistent use of pre-NAC axillary staging across the entire study period (2013–2017). Second, NCDB is not nationally representative and may overrepresent large, academic hospitals, although it does capture 70% of incident cancer cases each year. Although our data show that the highest proportions of patients receiving lymph node staging surgery first received care at comprehensive community cancer centers and academic research centers, smaller, rural hospitals may be slower to implement new guideline changes, and therefore we may be underestimating the overall use of pre-NAC axillary staging in the USA. Third, because of how NCDB captures treatment information, we had to assume that each patient’s first surgery was their lymph node staging (with or without definitive surgery) and that their first systemic treatment was neoadjuvant chemotherapy. While these are reasonable assumptions in this patient population, it is likely that we misclassified the treatment order of a few women. Similarly, there were several factors that are not captured in NCDB but would have been of interest for our study. For example, we were unable to comment on the nodal status of the initial SLNB of the patients receiving subsequent ALND. An additional study investigating the nodal status after SLNBx in women who received pre-NAC axillary staging may further support that pre-NAC surgical staging procedures result in unnecessary patient morbidity. There are also other unmeasurable factors influencing decisions for pre-NAC lymph node surgery staging, such as patient frailty and patient treatment preferences.
As the field of breast oncology has redefined the roles for therapeutic approaches associated with high patient morbidity, treatment of the axilla should also be re-examined and tailored to reduce unnecessary adverse physical and psychological consequences. This is especially important for women with complete pathologic response after chemotherapy treatment. Pre-NAC axillary staging surgery often leads to unnecessary ALND in women who could otherwise be treated with SLNBx if they forego staging until after receipt of NAC. We encourage clinicians to critically examine the treatment benefit and high potential for patient morbidity associated with pre-NAC staging surgery and consider eradication of unnecessary axillary surgery.
ACKNOWLEDGEMENTS
Paula Strassle is supported by the Division of Intramural Research, National Institute on Minority Health and Health Disparities, National Institutes of Health. The contents and views in this manuscript are those of the authors and should not be construed to represent the views of the National Institutes of Health. Stephanie Downs-Canner is supported by NIH grant 5K12CA120780-12.
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