Nodal pCR Research Articles

Prospective Feasibility and Phase 1/2 Trial of Preoperative Proton Beam Therapy With Concurrent Chemotherapy for Resectable Stage IIIA or Superior Sulcus Non-Small Cell Lung Cancer

This is the first prospective clinical trial (NCTXXXX) evaluating proton beam therapy (PBT) with concurrent chemotherapy as part of trimodality management for resectable stage IIIA or superior sulcus non-small cell lung cancer (NSCLC). The starting PBT dose level was 50.4 Gy in 1.8 Gy fractions (feasibility study), followed by sequential dose escalation to determine maximum tolerated dose (MTD) of PBT based on dose-limiting toxicities (DLTs) (phase I/II study). DLTs were defined as 30-day postoperative mortality, grade ≥4 hematologic toxicity requiring >14-day treatment breaks, or any grade ≥3 non-hematologic/esophagitis/pneumonitis toxicities attributable to PBT. Primary outcomes included feasibility, MTD, and pathologic complete response (pCR) rate. Twenty patients underwent neoadjuvant PBT and chemotherapy, of which 19 subsequently underwent surgery. There were 13 patients in the feasibility study (at 50.4 Gy) and 6 in the phase I/II study (at 59.4 Gy). The trial closed early due to slow accrual prior to reaching the MTD. Treatment was deemed feasible. There were no DLTs, including no post-operative deaths within 30 days. Two patients (10%) experienced PBT-related acute grade 3 adverse events (post-operative atrial fibrillation and esophagitis/dysphagia); no grade 4-5 acute non-hematologic adverse events were noted. Overall and nodal pCR rates were 5/19 (26%) and 8/18 (44%), respectively; nodal pCR was 4/13 (31%) at 50.4 Gy versus 4/5 (80%) at 59.4 Gy (p=0.12). Median follow-up was 8.5 years. Median and 5-year progression-free survival were 1.8 years and 25%, and median and 5-year overall survival were 3.6 years and 40%, respectively. Eleven patients experienced disease failure, most with a distant component (10 of 11). Concurrent PBT and chemotherapy is feasible as part of trimodality management with favorable oncologic outcomes and low toxicity rates.

Abstract P6-01-22: Age, Ki-67, Nodal pCR and overall survival following Neoadjuvant Chemotherapy for Node Positive ER+/Her2- Breast Cancer

Abstract Background: The role of chemotherapy in node positive (N+) luminal breast cancer (BC) is often debated, given low total pathologic complete response (pCR) rates following neoadjuvant chemotherapy (NAC) and discrepancy in adjuvant chemotherapy benefit. A prior single institution study of cN+ luminal BC showed that pts age < 50 and tumor Ki-67 ≥ 20% had high nodal pCR (> 35%). This study’s goals were 1) to validate Ki-67 and age in relation to nodal pCR and 2) evaluate the prognostic impact of nodal pCR on overall survival (OS). Methods: We queried the National Cancer Database 2010-2019 for pts with cN+ ER+/HER2- BC treated with NAC and surgery. Breast pCR was defined as ypT0/ypTis and nodal pCR as ypN0/ypN0i+. Ki-67 was available in 2018 & 2019 only and was used to evaluate Ki-67 and nodal pCR. 2010-2018 data were used to evaluate nodal pCR and OS. OS was analyzed using multivariable Cox proportional hazards regression. Results: In 2018-2019, 4,801 pts were identified and 2,473 (51.5%) had Ki-67 available. Nodal pCR was 23.7% and was higher in pts < 50 years old (28.1% vs 21.1%) and in those with Ki67 ≥ 20% (28.4% vs 12.7%), both p < 0.001. Pts < 50 with Ki67 ≥ 20% had the highest nodal pCR at 31.7%, followed by age ≥ 50 with Ki67 ≥ 20% at 26.3%. With Ki67 < 20%, nodal pCR was 15.4% (in age < 50) and 11.3% (in age ≥ 50). From 2010-2018, we identified 20,084 cN+ ER+/HER2- BC pts treated with NAC. Total pCR was 7.4%, 14.3% had nodal pCR only, 3.8% had breast pCR only, and 74.5% had residual disease in breast and nodes. OS at 5 years was 79.1% and varied by NAC response: 90.8% with total pCR, 83.8% with nodal pCR only, 80.7% with breast pCR only, and 76.9% with residual disease in breast and nodes. Specifically nodal pCR (with or without breast pCR) was seen in 22.0% and was associated with 5-year OS rate of 86.4% compared to 77.1% without nodal pCR, p < 0.001. On multivariable analysis adjusted for other clinical and treatment factors, nodal pCR was associated with better OS (adjusted HR 0.56, 95% CI: 0.50-0.61, p < 0.001) in all ages combined and within both the age < 50 and age ≥ 50 subgroups (see Table). In a subgroup of pts approximating RxPonder entry criteria (defined as cT1-3, N1, Grade I or II, ER+/PR+), results were consistent with the overall cohort: nodal pCR varied by both age (17.5% in age < 50 and 13.6% in age ≥ 50, p < 0.001) and by Ki67 ≥ 20% vs < 20% (16.8% vs 7.9%, p < 0.001) and nodal pCR remained prognostic for OS with adjusted HR 0.63 (95% CI: 0.50-0.81, p < 0.001). Conclusion: In cN+ ER+/HER2- BC treated with NAC, nodal pCR is more common in pts< 50 and those with high Ki-67 and is highly prognostic for OS. These data strongly suggest that NAC chemotherapy benefit should not be evaluated using total pCR rates in isolation, but for N+ pts to also consider nodal response. Given that nodal pCR is highly prognostic for OS, future neoadjuvant strategies should consider nodal pCR as a potential intermediate biomarker for long term survival. Multivariable analysis of factors associated with overall survival, including the adjusted effect of nodal pCR Citation Format: Dan Moldoveanu, Matthew P. Goetz, Tanya L. Hoskin, Courtney N. Day, Judy C. Boughey. Age, Ki-67, Nodal pCR and overall survival following Neoadjuvant Chemotherapy for Node Positive ER+/Her2- Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-22.

Oncologic outcomes in breast cancer patients with metastatic nodes and pathological nodal response following neoadjuvant chemotherapy without axillary dissection: a literature review.

With promising nodal pathological complete response (pCR) after neoadjuvant chemotherapy, the role of axillary lymph node dissection (ALND) was questioned. While there is much data on the accuracy of axillary staging after neoadjuvant chemotherapy to predict nodal pCR, limited data on the oncological safety of omitting ALND exists. We aim to review the oncological safety of omitting ALND in patients with initially metastatic nodes achieving nodal pCR, based on axillary staging, following neoadjuvant chemotherapy. A PubMed search of relevant articles from 1st January 2013 to 15th September 2022 was performed. Studies with duplication of patients, ALND only, no oncological details, initially N0 patients only and patients without nodal pCR were excluded. Fifteen studies with 1,515 eligible patients (range, 29-242 patients) were analysed. There was heterogeneity of patients among the included studies and patients had varying TN staging, making selection criteria for omission of ALND inconclusive. Sentinel lymph node biopsy (SLNB) was the most studied mode of axillary staging in 1,416 (93.5%) patients, though 35.7% had <3 SLN harvested. On average median follow-up of 52.8 months (range, 9-110 months), axillary recurrence ranged from 0% to 3.4%. There was limited data on survival outcomes. In node positive breast cancer patients who achieved nodal pCR after neoadjuvant chemotherapy, the axillary recurrence rate was low without ALND. However, survival data was limited. The selection criteria and ideal axillary staging technique for patients, who are suitable for axillary preservation, are unclear. More prospective studies with longer follow-up, providing survival data, are needed.

Abstract OT1-07-01: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 36 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (&amp;lt; 10% positive cells in IHC) and PgR-negative (&amp;lt; 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2023 -Primary outcome analysis: Q1/2027 Current accrual: In June 2022, 150 patients were recruited in Germany and Italy. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy) Citation Format: Toralf Reimer, Thorsten Kuehn, Angrit Stachs, Anke Kleine-Tebbe, Nikola Bangemann, Andrea Stefek, Carolin Hammerle, Jörg Heil, Antje Nixdorf, Gabriele Bonatz, Agnieszka Nolte, Isabel T. Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Davide Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-07-01.

Low neutrophil-to-lymphocyte ratio and pan-immune-inflammation-value predict nodal pathologic complete response in 1274 breast cancer patients treated with neoadjuvant chemotherapy: a multicenter analysis.

Systemic inflammatory markers draw great interest as potential blood-based prognostic factors in several oncological settings. The aim of this study is to evaluate whether neutrophil-to-lymphocyte ratio (NLR) and pan-immune-inflammation value (PIV) predict nodal pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in node-positive (cN+) breast cancer (BC) patients. Clinically, cN+ BC patients undergoing NAC followed by breast and axillary surgery were enrolled in a multicentric study from 11 Breast Units. Pretreatment blood counts were collected for the analysis and used to calculate NLR and PIV. Logistic regression analyses were performed to evaluate independent predictors of nodal pCR. A total of 1274 cN+ BC patients were included. Nodal pCR was achieved in 586 (46%) patients. At multivariate analysis, low NLR [odds ratio (OR) = 0.71; 95% CI, 0.51-0.98; p = 0.04] and low PIV (OR = 0.63; 95% CI, 0.44-0.90; p = 0.01) were independently predictive of increased likelihood of nodal pCR. A sub-analysis on cN1 patients (n = 1075) confirmed the statistical significance of these variables. PIV was significantly associated with axillary pCR in estrogen receptor (ER)-/human epidermal growth factor receptor 2 (HER2)+ (OR = 0.31; 95% CI, 0.12-0.83; p = 0.02) and ER-/HER2- (OR = 0.41; 95% CI, 0.17-0.97; p = 0.04) BC patients. This study found that low NLR and PIV levels predict axillary pCR in patients with BC undergoing NAC. Eudract number NCT05798806.

Internal mammary lymph nodal response to neoadjuvant chemotherapy on imaging and breast cancer prognosis.

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is an important prognostic indicator in breast cancer. Internal mammary lymph node involvement is not currently included in pCR determination, as sampling at the time of surgery is not routinely performed. Pre and post neoadjuvant chemotherapy MRI or PET/CT imaging response of the internal mammary lymph node chain was utilized as a surrogate to pCR and imaging data was correlated with patient outcomes. Internal mammary lymph node response to NAC was associated with disease free survival over the course of this study, regardless of whether axillary nodal pCR was achieved. Internal mammary lymph nodal response to NAC is an important prognostic indicator. Potential use of internal mammary lymph node resolution as an imaging data input for AI models that predict pCR post-NAC may improve accuracy and other metrics in pCR prediction.

Do non-classic invasive lobular carcinomas derive a benefit from neoadjuvant chemotherapy?

Invasive lobular breast cancers (ILCs) respond poorly to neoadjuvant chemotherapy (NAC). The degree of benefit of NAC among non-classic ILC (NC-ILC) variants compared with classic ILCs (C-ILCs) is unknown. Consecutive patients with Stage I-III ILC treated from 2003 to 2019 with NAC and surgery were identified, and grouped as C-ILC or NC-ILC as per the original surgical pathology report, with pathologist (A.G.) review performed if original categorization was unclear. A subset of similarly treated invasive ductal cancers (IDCs) was identified for comparison. Clinicopathologic characteristics and pathologic complete response (pCR) rates were evaluated. Of 145 patients with ILC, 101 (70%) were C-ILC and 44 (30%) were NC-ILC (IDC cohort: 1157 patients). ILC patients were older, more often cT3/T4 and cN2/N3, and less often high-grade compared to IDC patients. Those with NC-ILC were less often ER+/HER2- (55% versus 93%), and more often HER2 + (25% versus 7%) and TN (21% versus 0%, all p < 0.001). Breast pCR was more common among NC-ILC, but most frequent in IDC. Nodal pCR rates were also lowest among C-ILC patients, but similar among NC-ILC and IDC patients. On multivariable analysis, C-ILC (OR 0.09) and LVI (OR 0.51) were predictive of lack of breast pCR; non-ER+/HER2- subtypes and breast pCR were predictive of nodal pCR. When our analysis was repeated with patients stratified by receptor subtype, histology was not independently predictive of either breast or nodal pCR. NC-ILC patients were significantly more likely to achieve breast and nodal pCR compared with C-ILC patients, but when stratified by subtype, histology was not independently predictive of breast or nodal pCR.

Nodal Pathologic Complete Response Rates in Luminal Breast Cancer Vary by Genomic Risk.

Although an advantage of neoadjuvant chemotherapy (NAC) is eradication of axillary disease, nodal pCR rates are much lower for ER+/HER2- breast cancer than other subtypes. We sought to evaluate the association of genomic risk with nodal pCR in ER+/HER2- disease. Patients with ER+/HER2- clinically-node-positive (cT0-cT4d/cN1-cN3/cM0) breast cancer treated with NAC and surgery 2010-2018 in the National Cancer Database were identified. Low genomic risk was classified as Oncotype Dx Recurrence Score (RS) 0-25, or Mammaprint 70-gene or RS coded as "Low." High genomic risk included RS >25, or 70-gene or RS coded as "High." Nodal pCR was compared between patients with high versus low genomic risk by using chi-square tests and multivariable logistic regression. Of 15,698 patients, genomic risk was available for 692 of 15,698 (4.4%). High genomic risk was similar between patients aged <50 years versus 50+ (50.8% vs. 57.3%, p = 0.10). Nodal pCR was higher in high genomic risk (25.0%) than low genomic risk (10.4%, p < 0.001). This difference was observed both for patients aged <50 years (29.9% vs. 9.8%) and aged ≥50 years (22.7% vs. 10.8%). On multivariable analysis adjusted for potential confounding variables, including age, grade, and PR status, genomic risk was independently associated with decreased odds of residual nodal disease (odds ratio 0.49, p = 0.002). For patients with node-positive ER+/HER2- breast cancer treated with NAC, nodal pCR was highest in patients aged <50 years with high genomic risk tumors. In contrast, nodal pCR rates were low in patients with low genomic risk tumors, regardless of age. This information may help when counseling patients regarding axillary management.

Ultrasound-guided radar reflector localization of axillary lymph nodes facilitates targeted axillary dissection

PurposeThis study evaluated feasibility and patient outcomes for targeted axillary lymph node (LN) dissection (TAD) with SAVI SCOUT® ultrasound-guided radar reflector localization (RRL). MethodsIn this IRB-approved retrospective study, 800 consecutive patients who underwent ultrasound-guided RRL between November 2017 and June 2020 were reviewed. Of these patients, those with axillary LN RRL were included in this study. Reports in the electronic medical record were reviewed to determine RRL placement, retrieval, and surgical outcomes. ResultsA total of 147 patients met inclusion criteria. Of these, axillary RRL was performed for biopsy-proven metastatic disease in 134 and inconclusive or benign biopsy in 13. RRL was successful in 146/151 lymph nodes (97%). Two patients had placement >10 mm from target and 3 had no post-placement signal. In all 5, the targets were successfully retrieved at surgery. Specimen radiographs were performed in 135 cases and confirmed the intended target in all 135 (100%). In 109 patients who underwent TAD + sentinel lymph node biopsy (SLNB), the RRL LN and the SLN(s) were different in 18 (17%). In 3 of these, the RRL LN was the only malignant LN (3%). In the 105 patients who underwent neoadjuvant chemotherapy, 43% (45/105) achieved nodal pCR and 85% (89/105) had <3 metastatic lymph nodes at surgery. ConclusionUltrasound-guided RRL of axillary LNs is a feasible approach to facilitate TAD with high placement and retrieval success rates. This enables TAD as an alternative to complete axillary LN dissection (cALND), sparing some patients with low nodal tumor burden from cALND.

Neoadjuvant Chemotherapy for Breast Cancer In the Elderly: Are We Accomplishing Our Treatment Goals?

Rates of downstaging and tolerability to NAC in women age ≥70 years with operable breast cancer have not been well studied. We sought to compare downstaging rates and NAC completion between women age 50-69 years and age ≥70 years. Consecutively treated women age ≥50 years with cT1-3N0-1 breast cancer receiving NAC followed by surgery from November 2013 to April 2020 were studied. Rates of downstaging from breast-conserving surgery (BCS)-ineligible to BCS-eligible and avoidance of axillary dissection (ALND) in cN1 patients were compared between patients age 50-69 and ≥70 years. NAC regimens and rates of completion also were assessed. Overall, 651 women, age ≥50 years, with 668 cT1-3N0-1 breast cancers that were treated with NAC, were identified; 75 (11.1%) were age ≥70 years. Patients age ≥70 years were less likely to have lobular cancers (5% vs. 10%, p=0.03), receive an anthracycline-based regimen (69% vs. 93%, p<0.001), and complete their entire prescribed regimen (57% vs. 78%, p<0.001). Of 312 BCS-ineligible patients eligible for downstaging, conversion rates to BCS-eligibility were similar between age groups (72% [≥70] vs. 74% [50-69], p>0.9). Women age ≥70 years who converted to BCS-eligible post-NAC were more likely to undergo BCS than younger patients (93% vs. 74%, p=0.04). Of 390 cN1 patients, 162 (42%) achieved a nodal pCR; ALND avoidance was similar between age groups (43% [≥70] vs. 42% [50-69], p>0.9). While patients age ≥70 years received less anthracycline-based NAC and were less likely to complete their prescribed regimen, they experienced high rates of breast and axillary downstaging, similar to younger patients, suggesting that well-selected elderly patients can safely receive NAC with substantial clinical benefit.

The impact of neoadjuvant treatment (NAT) on surgery in early breast cancer (EBC): A real-world data study.

e12609 Background: NAT is being used with increasing frequency in the multimodal treatment of EBC. Oncologically, NAT provides an opportunity to assess response to early systemic therapy and tailor adjuvant treatment. The surgical objective of NAT is down staging the tumor, which may lead to improved chances of breast conservation surgery; potentially decreasing surgical morbidity. Down staging of axillary disease may also lead to minimizing the need for complete axillary lymph node dissection (ALND) and its associated surgical morbidity. We aimed to describe the potential impact of NAT on surgical de-escalation in the primary breast tumor and axilla in patients (pts) with HER2-positive, node-positive EBC treated in the community setting. Methods: We conducted a retrospective cohort study using a nationwide US electronic health record-derived de-identified database (Flatiron Health). Pts were diagnosed from Jan 1, 2011 to Sep 30, 2021, had reported clinical staging cN≥1, underwent primary breast surgery (index date), and had records indicating initiation of systemic treatment before surgery. Early clinical benefit includes, post-NAT: a) nodal pathologic complete response (pCR; pN=0); b) pCR (absence of residual invasive disease in the breast and axillary lymph nodes at NAT completion, subsequently confirmed at primary surgery); c) down staging (lowered T or N stage). Surgical operations recorded at index date were ALND and sentinel node excision (SNE), mastectomy (MT), and lumpectomy (LT). Results: 174 pts were included. At diagnosis, median age was 55 years, 162 pts (93%) presented with invasive ductal carcinoma, and &lt;5 had bilateral BC. 124 pts (71%) were treated with dual HER2 blockade. As for early clinical benefit, nodal pCR was achieved in 106 pts (61%), pCR in 90 (52%), and down staging in 137 (79%). Types of surgical procedure for the axilla were SNE only for 62 pts (36%), ALND only for 84 (48%), and SNE and ALND for 26 (15%). Surgical procedures for the breast were MT for 118 pts (68%), of which 59 were bilateral, and LT for 55 (32%). Compared with not achieving nodal pCR, achieving nodal pCR was associated with increased odds of SNE only (odds ratio [OR] 2.59 [95% confidence interval (CI) 1.28, 5.53]), decreased odds of ALND (OR 0.47 [95% CI 0.23, 0.93]), increased odds of LT (OR 2.05 [95% CI 1.00, 4.39]), and decreased odds of MT (OR 0.47 [95% CI 0.22, 0.96]). Conclusions: In a real-world population of pts with HER2-positive EBC, NAT use was associated with early clinical benefit, potentially leading to less invasive primary surgery of the breast and axilla. The high use of MT and bilateral MT despite a high pCR rate demonstrates the multiple factors at play behind surgical and pt decision making. These data illustrate how NAT use can benefit pts by de-escalating surgical treatment options. Limitations include the modest sample size and lack of association between early and long-term clinical benefit.

Neoadjuvant Chemotherapy and Nodal Response Rates in Luminal Breast Cancer: Effects of Age and Tumor Ki67.

Neoadjuvant chemotherapy (NAC) is standard for most triple-negative and human epidermal growth factor receptor 2 (HER2)+ breast cancers, and frequently downstages node-positive (cN+) disease, permitting omission of axillary dissection. In estrogen receptor (ER)+/HER2- disease, response rates are lower. Whether Ki67 is associated with axillary downstaging in ER+/HER2- diseaseis unknown. With institutional review board approval, we queried our institutional database to identify all patients with primary ER+/HER2- biopsy-proven cN+ breast cancer treated with NAC followed by surgery from January 2012 to December 2021. Nodal pathologic complete response (pCR) rates were evaluated by pretreatment Ki67 and patient age. 315 patients (median age 50years) were included. Nodal pCR rate was 24.8% (78/315) and was higher in patients aged < 50years than ≥ 50years (31.8% versus 17.7%, p = 0.004). Ki67 was available on 236 patients (74.9%). Median Ki67 was 29.0% (range 1-98%) and did not differ by age category (p = 0.23). Patients with nodal pCR had higher Ki67 (median 40.3% versus 25.0%, p < 0.001). Nodal pCR rates were 28.4% (Ki67 ≥ 20%) versus 8.1% (Ki67 < 20%) (p < 0.001). On multivariable analysis, Ki67 and age category were predictive of nodal pCR. Combining these two parameters together, nodal pCR rates in age < 50years were 35.8% when Ki67 ≥ 20% versus 14.3% with Ki67 < 20% (p = 0.02). In contrast, for age ≥ 50years, nodal pCR was 21.0% for Ki67 ≥ 20% versus 2.6% with Ki67 < 20% (p = 0.008). In ER+/HER2- breast cancer, nodal downstaging with NAC is associated with age (< 50years) and Ki67 (≥ 20%). Age and Ki67 should be considered for NAC decision-making and can identify patients with high rates of nodal downstaging (36%) who would benefit from NAC to enable axillary preservation.

Determining the benefit of neoadjuvant chemotherapy in reduction of axillary dissection rates in Z0011 trial cohort with high nodal burden.

In breast cancer patients fulfilling the Z0011 trial criteria, axillary lymph node dissection (ALND) is reserved for patients with a high nodal burden of ≥3 metastatic nodes. In this group of patients, to avoid an ALND, neoadjuvant chemotherapy (NACT) could be given instead to achieve nodal pathological complete response (pCR). However, the benefit of NACT in achieving nodal pCR and avoiding ALND in this group of patients is unknown. We aimed to determine the nodal pCR rate in this group of patients who otherwise would have needed an ALND. cT1-2N0 breast cancer patients, with histologically proven nodal metastasis, who underwent NACT were identified from a prospectively maintained database. The sonographic criteria of ≥3 abnormal nodes, which has been reported as highly predictive of high nodal burden, was then used to identify the high nodal burden group. Nodal pCR was determined based on the ALND following NACT. Twenty-four patients with high nodal burden were identified. Mean age was 55.2 years. 91.7% had invasive ductal carcinoma and 29.2% had grade III cancer. 54.2% achieved nodal pCR which was associated with ypT (P=0.006). Nodal pCR was 75%, 70% and 30% in the triple negative, human epidermal growth factor receptor2 (HER2) positive and ER/PR+HER2- tumors, respectively. In the postulated T1-2 breast cancer patients with high nodal burden, needing an upfront ALND, NACT could result in nodal pCR of 54.2%, with higher pCR in certain subtypes. Hence, to minimize ALND risk, NACT should be offered in this high nodal burden group.

Initial experience with targeted axillary dissection after neoadjuvant therapy in breast cancer patients.

BackgroundTargeted axillary dissection (TAD) combines sentinel node biopsy (SNB) with the removal of the previously marked metastatic node. TAD is a promising concept for axillary restaging in node-positive breast cancer patients with pathological complete response (pCR) to neoadjuvant therapy (NAT). We aimed to evaluate TAD feasibility in this context.MethodsA prospective observational study was conducted in biopsy-confirmed cN1 patients. The removal of the clipped node (CN) was guided by intraoperative ultrasound. SNB used indocyanine green and patent blue V dye. If the CN or sentinel lymph nodes (SLN) had any metastatic foci, or the TAD procedure was unsuccessful, the patient underwent axillary lymph node dissection (ALND).ResultsThirty-seven patients were included. TAD and SNB identification rates were 97.3%. Every retrieved CN was also a SLN. At the individual level, SNB identification rate was 89.2% with indocyanine green and 85.5% with patent blue V dye. The CN identification rate was 81.1%, being higher when the CN was localized on the intraoperative ultrasound (84.4% vs 60.0%). Nodal pCR was achieved by 54.1% of our patients and was more frequent in HER2-positive and triple-negative tumors (p = 0.039). Nineteen patients were spared from ALND.ConclusionTAD with intraoperative ultrasound-guided excision of the CN and SNB with indocyanine green and patent blue V dye is a feasible concept to identify patients without axillary residual disease after NAT, that can be spared from ALND, although the need for marking the biopsied node should be further investigated.

Abstract P4-07-14: Long-term prognosis of minimal residual disease in breast cancer patients with breast or nodal pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC)

Abstract Background: Achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is known important for predicting survival. However, few studies have reported prognosis of minimal residual disease. In this study, we evaluated the long term survival of the patients with breast or nodal pCR and compare patients with minimal residual disease to the breast and node pCR group. As it is difficult to analyze residual cancer burden and tumor-infiltrating lymphocytes in the retrospective study, we assessed the residual tumor or nodal status according to the pathologic report after surgery based on the AJCC 8th edition staging system. Methods: This study retrospectively reviewed 753 patients who achieved pCR of breast or node after NAC from 2010 to 2017 at Severance Hospital. We divided patients into five groups based on the residual disease; breast and node pCR (ypT0/TisN0), minimal residual disease (ypT1mi/T1aN0, ypT0/TisN0i+/N1+), breast-only pCR (ypT0/TisN1+), node-only pCR with residual tumor size no larger than 20mm (ypT1b/T1cN0), and node-only pCR with residual tumor size larger than 20mm (ypT2+N0). The basic characteristics and the 10-year event free survival (EFS) were evaluated. EFS was defined as time from surgery to last follow-up date without any events. Results: We analyzed the data until May 26, 2021, and 50.2% (n=378) of the patients achieved breast and node pCR. Minimal residual disease, defined as residual tumor size no larger than 5mm and residual nodal size 2mm, included 126 patients (16.7%). Overall, there was significant difference in 10-year EFS among five groups (ypT0/TisN0; 94.7%, ypT1mi/T1aN0, ypT0/TisN0i+/N1+; 93.7%, ypT1b/T1cN0; 86.8%, ypT0/TisN1+; 87.9%, ypT2+N0; 71.9%, p&amp;lt;0.001). As the variables such as age, subtypes, clinical T and N stage, regimen of chemotherapy, response to the chemotherapy and operation type were adjusted, the minimal residual disease group showed no significant difference with the breast and node pCR group (HR 1.410, 95% CI 0.615 - 3.235, p=0.417), yet the other groups showed poorer outcomes (ypT1b/T1cN0; HR 3.183, 95% CI 1.687- 6.004, p&amp;lt;0.001, ypT0/TisN1+; HR 3.186, 95% CI 1.047 - 9.694, p=0.041, ypT2+N0; HR 6.089, 95% CI 3.019- 12.281, p&amp;lt;0.001). Conclusion: Patients with minimal residual tumor 5mm or less, or residual metastatic lymph node with a maximal diameter of 2mm have shown equivalent 10-year EFS compared to the patients who achieved breast or node pCR after NAC. Keywords: Neoadjuvant chemotherapy, Pathologic complete response, Minimal residual disease, Long-term survival, Breast cancer Citation Format: Jieon Go, Jee Hyun Ahn, Jung Min Park, Soon Bo Choi, Jee Ye Kim, Hyung Seok Park, Seung Il Kim, Byeong-Woo Park, Seho Park. Long-term prognosis of minimal residual disease in breast cancer patients with breast or nodal pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-14.

Prognostic Factors in Breast Cancer Patients With Clinical N3b (Ipsilateral Internal Mammary and Axillary) Disease

<h3>Purpose/Objective(s)</h3> Patients with clinical N3b (cN3b) breast cancer often do not undergo surgical resection of gross internal mammary (IM) nodes. Therefore, radiation is important for curative therapy. However, limited data exist to guide treatment recommendations. <h3>Materials/Methods</h3> We retrospectively reviewed 119 patients with non-metastatic cN3b breast cancer treated at our institution between 2014 and 2019 with curative intent. Staging included u/s evaluation of all regional nodal basins. All patients received neoadjuvant chemotherapy (NAC), surgical resection of the breast primary and nodal dissection, followed by adjuvant radiation to the chest wall/breast, infraclavicular (ICV), SCV and IM nodes. Institutional nodal boost guidelines recommend 10 Gy to radiographically resolved N3b nodal basins, and 16 Gy to unresolved N3b nodes, normal tissue constraints permitting. Patient, tumor, and treatment characteristics were collected and analyzed using a saturated multivariable analysis (MVA) model with backwards elimination to identify variables associated with improved overall survival (OS) at <i>P</i> < 0.10. Local (LC), regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were evaluated with Kaplan Meier analysis. <h3>Results</h3> 119 patients were analyzed with a median follow-up of 2.78 years. Median age at diagnosis was 46 years, 56 (47%) were ER+/HER2-, 19 (16%) ER+/HER2+, 13 (11%) ER- /HER2+, and 31 (26%) ER-/HER2-, 86 (74%) had high grade histology, and 68 (57%) had cT3/T4 disease. Mastectomy was performed in 96 (81%) of patients, 36 (30%) had biopsy confirmed IMC involvement, and 8 (7%) had dissection of IM nodes. The median initial radiation dose was 50 Gy (range, 50-55), IMC boost 10 Gy (range, 8-16), and 41 (34%) received cumulative IMC dose > 60 Gy. The 3-year OS, FFDM, RC, and LC were 80%, 71%, 93%, and 94%, respectively. Patients with a nodal pCR of dissected nodes, had improved 3-year OS, 95% vs 71% (<i>P</i> = 0.008). Among patients who had a nodal pCR, nodal boost to > 60 Gy did not significantly improve 3-year OS, 100% vs. 93% (<i>P</i> = 0.40). In patients with less than a nodal pCR, who received IMC > 60 Gy, 3-year OS was numerically improved but was not statistically significant 81% vs. 64% (<i>P</i> = 0.33). In MVA, cumulative IMC dose > 60 Gy, nodal pCR, ER positivity, HER2 positivity, and lower clinical T-stage were independently associated with improved OS (Table 1). <h3>Conclusion</h3> Nodal pathologic response to NAC and cumulative IMC dose > 60 Gy were independently predictive for improved OS in patients with non-metastatic cN3b breast cancer treated with curative intent. Regional nodal control using a boost was excellent even among those with less than nodal pCR.

Outcomes After Multimodality Therapy in Modern Breast Cancer Patients Presenting With Clinical N3c Supraclavicular Node Involvement

<h3>Purpose/Objective(s)</h3> Breast cancer patients with clinical N3c (cN3c) disease at diagnosis have poor outcomes relative to other breast cancer patients. Radiotherapy (RT) has an important role in the management of these patients as the supraclavicular (SCV) nodes are not routinely surgically dissected. However, outcomes and prognostic factors in the era of modern neoadjuvant chemotherapy (NAC) are not well-described. <h3>Materials/Methods</h3> We reviewed breast cancer patients with non-metastatic cN3c disease treated at our institution from 2014-2019 with curative intent NAC, surgery, and adjuvant RT. All patients received nodal RT including the SCV, infraclavicular, and internal mammary nodes. Institutional guidelines recommend a 10 Gy boost to clinically resolved N3 nodal basins and 16 Gy to unresolved N3 nodes. Variables including initial and boost dose, pathologic response, and type of nodal dissection were collected. Local (LC) and regional control (RC), freedom from distant metastases (FFDM), and overall survival (OS) were analyzed with the Kaplan Meier method. A saturated multivariable Cox proportional hazards model of OS with backward elimination identified clinical variables associated with OS at <b>P</b> < 0.10. <h3>Results</h3> A total of 176 consecutive patients were analyzed. The median follow-up time was 2.83 years. The median age was 54 years, 76 (43%) were ER+/HER2-, 20 (11%) ER+/HER2+, 26 (15%) ER-/HER2+, and 54 (31%) ER-/HER2-. 102 (57%) had T3/4 disease, 41 (23%) underwent lumpectomy, 142 (81%) had pathologic confirmation of N3c, and 10 (6%) had a neck dissection. The median initial radiation dose was 50 Gy (range, 44-56.25), SCV boost 10 Gy (range, 6-16), and 156 (89%) received cumulative SCV dose ≥60 Gy. The 3-year OS, FFDM, RC, and LC were 79%, 64%, 93%, and 96%, respectively. For cumulative SCV dose of ≥60 Gy vs. < 60 Gy, the 3-year OS was 81% vs. 61% (<i>P</i> = 0.03). Among patients with a nodal pCR after NAC, the 3-year OS for SCV dose ≥60 Gy vs. < 60 Gy was 93% vs. 53% (<i>P</i> = 0.03). In multivariable analysis, cumulative SCV dose ≥60 Gy, extranodal extension, ER status, HER2 status, number of dissected lymph nodes, and ECOG status were associated with OS (Table 1). <h3>Conclusion</h3> In a large, modern cohort of non-metastatic cN3c breast cancer patients treated with multimodality therapy, cumulative SCV dose ≥60 Gy was found to be associated with improved OS. Although optimal radiation dosing cannot be established from this data, a SCV radiation boost should be considered in cN3c patients treated with curative intent respecting normal tissue constraints.

Development of a novel nomogram-based online tool to predict axillary status after neoadjuvant chemotherapy in cN+ breast cancer: A multicentre study on 1,950 patients

BackgroundType of axillary surgery in breast cancer (BC) patients who convert from cN + to ycN0 after neoadjuvant chemotherapy (NAC) is still debated. The aim of the present study was to develop and validate a preoperative predictive nomogram to select those patients with a low risk of residual axillary disease after NAC, in whom axillary surgery could be minimized. Patients and methods1950 clinically node-positive BC patients from 11 Breast Units, treated by NAC and subsequent surgery, were included from 2005 to 2020. Patients were divided in two groups: those who achieved nodal pCR vs. those with residual nodal disease after NAC. The cohort was divided into training and validation set with a geographic separation criterion. The outcome was to identify independent predictors of axillary pathologic complete response (pCR). ResultsIndependent predictive factors associated to nodal pCR were axillary clinical complete response (cCR) after NAC (OR 3.11, p < 0.0001), ER-/HER2+ (OR 3.26, p < 0.0001) or ER+/HER2+ (OR 2.26, p = 0.0002) or ER-/HER2- (OR 1.89, p = 0.009) BC, breast cCR (OR 2.48, p < 0.0001), Ki67 > 14% (OR 0.52, p = 0.0005), and tumor grading G2 (OR 0.35, p = 0.002) or G3 (OR 0.29, p = 0.0003). The nomogram showed a sensitivity of 71% and a specificity of 73% (AUC 0.77, 95%CI 0.75–0.80). After external validation the accuracy of the nomogram was confirmed. ConclusionThe accuracy makes this freely-available, nomogram-based online tool useful to predict nodal pCR after NAC, translating the concept of tailored axillary surgery also in this setting of patients.

Predictors of Pathologic Response After Total Neoadjuvant Therapy in Patients With Rectal Adenocarcinoma: A National Cancer Database Analysis.

Purpose/objectivesInduction chemotherapy followed by chemoradiation and surgical resection in rectal cancer, known as total neoadjuvant therapy (TNT), is associated with improved pathologic complete response (pCR) rates. The National Cancer Database was utilized to identify factors associated with pCR and survival following treatment with TNT compared to standard neoadjuvant chemoradiation (nCRT).Materials/methodsThe National Cancer Database was queried from 2004 to 2015 for patients with locally advanced, non-metastatic rectal cancer. We identified 16,299 patients receiving neoadjuvant chemotherapy and radiation followed by definitive surgical resection. Patients were stratified by treatment received, either TNT (n=350) or nCRT (n=15,949). Multivariate binomial regression analysis and propensity matching were used to evaluate predictors of pCR. Kaplan-Meier and Cox multivariate analysis of survival were performed.ResultsMedian follow-up was 38 months vs 53 months in the TNT vs nCRT groups, respectively. There were more patients with T4 or node-positive disease in the TNT group. There was a trend towards improved pCR in the TNT group (p=0.053). Patients achieving pCR had improved 5-year overall survival (OS) of 85.1%. The 5-year OS was not improved for TNT (76.2%) over nCRT (69.9%) (p=0.19). Pelvic nodal pCR was significantly higher in the TNT group (72%). When stratified by clinical stage, patients with cT3 (p=0.038) or cN1 (p=0.049) disease had improved OS with TNT.ConclusionsCompared to nCRT, TNT is correlated with higher rates of complete pelvic nodal clearance in patients with locally advanced rectal adenocarcinoma. The use of TNT showed improved survival in patients with cT3 and cN1 disease, indicating a potential benefit for patients with less advanced disease.

Neoadjuvant Endocrine Therapy as an Alternative to Neoadjuvant Chemotherapy Among Hormone Receptor-Positive Breast Cancer Patients: Pathologic and Surgical Outcomes.

BackgroundNeoadjuvant chemotherapy (NCT) is considered more effective in downstaging hormone receptor-positive (HR+) breast cancer than neoadjuvant endocrine therapy (NET), particularly in node-positive disease. This study compared breast and axillary response and survival after NCT and NET in HR+ breast cancer.MethodsBased on American College of Surgeons Oncology Group (ACOSOG) Z1031 criteria, women age 50 years or older with cT2-4 HR+ breast cancer who underwent NET or NCT and surgery were identified in the National Cancer Database 2010–2016. Chi-square and logistic regression analysis determined differences between the NCT and NET groups and therapy response, including downstaging and pathologic complete response (pCR, ypT0/is and ypN0).ResultsOf 19,829 patients, 14,025 (70.7%) received NCT and 5804 (29.3%) received NET. The NET patients were older (mean age, 68.9 vs. 60.3; P < 0.001) and had greater comorbidity (1+ Charlson–Deyo score, 21% vs. 16%; P < 0.001). Therapy achieved T downstaging (any) for 58% of the patients with NCT versus 40.5% of the patients with NET, and in-breast pCR was achieved for 9.3% of the NCT versus 1.3% of the NET patients (P < 0.001). Approximately half of the mastectomy procedures could have been potentially avoided for the patients with in-breast pCR (53.6% of the NCT and 43.8% of the NET patients). For the cN+ patients, N downstaging (any) was 29% for the NCT patients versus 18.3% for the NET patients (P < 0.001), and nodal pCR was achieved for 20.3% of the NCT versus 13.5% of the NET patients (P < 0.001). Among those with nodal pCR, axillary lymph node dissection (ALND) still was performed for 56% of the patients after NCT and 45% of the patients after NET.ConclusionsAlthough the response rates after NCT were higher, NET achieved both T and N downstaging and pCR. Neoadjuvant endocrine therapy can be used to de-escalate surgery for patients who cannot tolerate NCT or when chemotherapy may not be effective based on genomic testing.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-021-10459-3.