Node-positive Breast Cancer Research Articles

Abstract P2-10-02: Impact of neoadjuvant treatment on the accuracy of breast MRI and calliper in premenopausal ER-positive, HER2-negative, and node-positive breast cancer patients: Prospective phase III clinical trial

Abstract Background: Improved understanding of factors affecting the accuracy of breast MRI after NST can lead to more tailored use of MRI in deciding surgical extent after NST. Purpose: To investigate whether the accuracy of magnetic resonance imaging (MRI) and caliper predicting residual tumor extent is affected by neoadjuvant treatment in estrogen receptor (ER) positive and HER2-negative, lymph node-positive, premenopausal breast cancer breast cancer. Materials and Methods: We analyzed the imaging and clinicopathologic data of 123 patients in phase 3, randomized clinical trial (NCT01622361), which compared neoadjuvant chemotherapy (NCT) with neoadjuvant endocrine therapy (NET) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), lymph node (LN)-positive, premenopausal breast cancer patients. In this study, we compared the largest size of MRI and Caliper after neoadjuvant treatment with one of pathology. Results: In patient with discrepancy in predicting response to NST, the measurement (MRI or caliper) that predict as non-response (SD or PD) was more accurate in both of NCT and NET group (ICC, Intraclass correlation coefficient, MRI; 0.84, 95% CI 0.616-0.942, Caliper;0.75, 95% CI 0.303-0.931). The accuracy of MRI was better in NCT group than in NET group (ICC 0.86; 95% CI 0.626-0.956 for NCT, 0.47; 95%CI 0.133-0.708 for NET). The mean absolute discrepancies (largest size by MRI or caliper -largest size in pathology) for the MRI and Caliper were, respectively, -0.78cm and -1.04cm in NCT group and -0.44cm and -1.32cm in NET group (p > 0.05). The proportion of discrepancy >1cm or >0.5cm were not significantly difference between NCT and NET groups among MRI and Caliper. Conclusion: In ER-positive, HER2-negative, lymph node-positive breast cancer, both MRI and caliper tend to overestimate residual tumor size than pathology in NET group compare to NCT group. When MRI and caliper show discrepancy in predicting response to NST, the measurement (MRI or caliper) that predict as non-response (SD or PD) was more accurate in both of NCT and NET group. These factors should be considered for deciding the evaluation method of response and surgical decision after NST and surgical decision in this subgroup. REGISTRATION: ClinicalTrials.gov identifier: NCT01622361 Citation Format: Sungchan Gwark, Sei Hyun Ahn, Jong Won Lee, Byung Ho Son, Beom Seok Ko, Jisun Kim, Il-Yong Chung, Sae Byul Lee, Jin-Hee Ahn, Kyung Hae Jung, Sung-Bae Kim, Hee Jin Lee, Gyungyub Gong, Hee Jeong Kim. Impact of neoadjuvant treatment on the accuracy of breast MRI and calliper in premenopausal ER-positive, HER2-negative, and node-positive breast cancer patients: Prospective phase III clinical trial [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 P2-10-02.

Abstract OT3-32-01: OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Abstract Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) tumor are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR_PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Results: The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion: OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib. Funding: OPTIMA is funded by the UK NIHR HTA Programme (10/34/501) and in Norway by KLINBEFORSK and the Norwegian Cancer Society. Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the Department of Health. Trial Inquiries: OPTIMA@warwick.ac.uk Patient characteristics Citation Format: Robert Stein, Andreas Makris, Iain Macpherson, Luke Hughes-Davies, Andrea Marshall, Georgina Dotchin, David A. Cameron, Belinda E. Kiely, Caroline Wilson, Anne Armstrong, Helena M. Earl, Christopher J. Poole, Janice Tsang, Bjørn Naume, Daniel Rea, Hege Ohnstad, Peter S. Hall, Stuart A. McIntosh, Bethany Shinkins, Christopher McCabe, Adrienne Morgan, John MS Bartlett, Janet A. Dunn. OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early 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 OT3-32-01.

Abstract PD9-09: Molecular differences between younger versus older estrogen receptor positive/human epidermal growth factor receptor-2 negative breast cancers

Abstract Background: The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients < 50 years with node-positive breast cancer and Recurrence Score (RS) 0-25, and with node-negative disease and RS 16-25, respectively. Neither trial showed benefit in older women with RS < 26. It is unclear what explains the interaction between age and adjuvant chemotherapy benefit. Methods: We analyzed transcriptomic and genomic data from n=4,507 ER+/HER2- breast cancers to compare differences in estrogen receptor (ER), proliferation, and immune-related gene expressions, and somatic mutation patterns and mutation burden between younger (< 50 years of age) and older (>55 years) patients. We restricted our analysis to patients in the lower 80% range of in silico RS distribution to mimic the RxPONDER and TAILORx populations. Results: Five data sets were analyzed independently to assess consistency of results (TCGA n=530; microarray cohort A n=865; Cohort B n=609, METABRIC n=867, SCAN-B n=1636). Older patients had significantly higher somatic mutation burden and more frequent copy number gain in ESR1, LATS1, ARID1B, SGK1, and MYB genes (odds ratio [OR] > 8.5, FDR< 0.05), but lower frequency of GATA3 mutations (12% versus 26%, P< 0.0001). Younger patients had higher rate of ESR1 copy number loss (OR: 0.45, FDR: 0.03). There was no difference in proliferation-related gene expression. ESR1 mRNA expression was significantly lower in younger women in all cohorts (P < 0.001). A regression model of ESR1 mRNA expression using age and ER IHC positivity indicated that lower ER expression in younger patients is primarily driven by lower ESR1 mRNA per cancer cell and not by fewer ER positive cells. We also assessed four gene signatures associated with endocrine therapy sensitivity including a 4-gene ERS, a 7-gene ERS-Lum, a 106-gene ERS-Pos signature, and a 59-gene ERS-Neg signature associated with endocrine resistance. In the TCGA and METABRIC cohorts, the ERS, ERS-Lum, and ERS-Pos signatures were all lower (FDR< 0.03) while the ERS-Neg signature was higher (FDR< 0.001) in younger patients. Similarly, in both microarray cohorts, and in the SCAN-B-cohort, the ERS-Pos signature was lower and the ERS-Neg signature was higher in younger patients (FDR< 0.002). Next, we assessed 4 different immune cell signatures that have been associated with response to chemotherapy. In the TCGA, B-cell, T-cell, Mast-cell, and TIS signatures were significantly higher (FDR<.05). In the microarray Cohort-A, B cells and mast cells were significantly higher, and the T cell and TIS signatures showed a trend for higher expression. In Cohort-B, T cells, B cells, TIS, and dendritic cells signatures were significantly higher in younger patients. Significantly higher expression of immune gene signatures in younger patients were also seen in the METABRIC and SCAN-B data sets. The ER-related and immune-related gene signatures showed negative correlation and joint analysis defined three subpopulations in younger women: (i) immune-high/ER-low, (ii) immune-intermediate/ER-intermediate and (iii) immune-low/ER-intermediate, whereas in older women the dominant pattern was immune-low/ER-high. Conclusion: ESR1 mRNA and ER-associated gene expression is lower in ER positive cancers of younger compared to older patients, while immune infiltration is higher. The cytotoxic and endocrine effects of adjuvant chemotherapy could both contribute to the survival benefit seen in younger patients, but the relative contributions of these effects may vary by ER and immune phenotype. We hypothesize that in immune-high/ER-low cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play a more important role. Citation Format: Tao Qing, Thomas Karn, Mariya Rozenblit, Julia Foldi, Michal Marczyk, Naing Lin Shan, Kim Blenman, uwe Holtrich, Kevin Kalinsky, Funda Meric-Bernstam, Lajos Pusztai. Molecular differences between younger versus older estrogen receptor positive/human epidermal growth factor receptor-2 negative breast cancers [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 PD9-09.

Abstract P2-02-03: Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-analysis

Abstract Background: Adjuvant regional nodal irradiation together with whole breast or chest wall irradiation is considered standard of care in most node positive early breast cancer. Existing data on adding internal mammary irradiation (IMNI) to the regional nodal fields are inconsistent. The objective of this study was to conduct a meta-analysis to explore the efficacy and safety of adding IMNI to adjuvant radiotherapy in early-stage, high risk breast cancer. Methods: A search of PubMed and EMBASE identified randomized trials that investigated the addition of IMNI to standard adjuvant radiation in early-stage breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for overall survival (OS), breast cancer specific survival (BCSS), disease-free survival (DFS) and distant-metastasis free survival (DMFS). The odds ratios (ORs) for regional and loco-regional recurrence, non-breast cancer mortality, secondary non-breast cancer, contralateral breast cancer and cardiovascular morbidity and mortality were also extracted. These data where pooled in a meta-analysis using RevMan 5.4. Results: Analysis included 5 trials comprising 10,994 patients. Compared to the control group, IMNI was associated with a small, but statistically significant improvement in OS (HR=0.91, 95% 0.85-0.97, p=0.004), BCSS (HR=0.84, 95%0.77-0.92, p< 0.001), DFS (HR=0.89, 95% CI 0.82-0.98, p= 0.01) and DMFS (HR=0.89, 95% 0.81-0.98, p=0.02). IMNI was also associated with reduced odds for regional (OR=0.58, 95% 0.44-0.75, p< 0.001) and loco-regional recurrence (OR=0.85, 95% CI 0.72-1.00, p=0.04). Subgroup analyses for OS by tumor location (medial/central vs. lateral) and by nodal burden showed similar benefit is all subgroups. The odds for cardiotoxicity were higher, but did not reach statistical significance (OR=1.23, 95% 0.99-1.53, p=0.07). There was no association with cardiovascular mortality (OR=1.00, 95% 0.69-1.46, p=1.00). There were also comparable odds for non-breast cancer mortality (OR=1.05, 95% 0.79-1.41, p=0.74), secondary cancer (OR=0.95, 95% 0.82-1.10, p=0.51) and contra-lateral breast cancer (OR=1.07, 95% 0.77-1.51, p=0.68). Conclusions: Compared to the control group the addition of IMNI in high-risk patients is associated with a statistically significant improvement in survival, albeit with a magnitude of questionable clinical meaningfulness. Non-significant association with increased cardiovascular toxicity requires further study in longer-term studies. Citation Format: Yasmin Korzets, Dina Levitas, Ahuva Grubstein, Ben W Corn, Eitan Amir, Hadar Goldvaser. Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-analysis [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 P2-02-03.

Abstract P6-01-11: A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved

Abstract Introduction: For a test to be of value, it needs to demonstrate that it is changing clinical decisions, improving clinical confidence and of economic benefit. This trial looked at the use of Oncotype DX Breast Recurrence Score ® (RS) assay against these criteria in 680 women with hormone receptor positive (HR+), HER2 negative early breast cancer with 1 to 3 lymph nodes positive (LN+) in the UK National Health Service (NHS) (5 teaching and 9 district general hospitals) between 2017 and 2022. Methods: Patients with LN+ early breast cancer who were willing and fit to receive chemotherapy (CT) were consented to join the trial. At the initial oncologists’ appointment, physicians were asked to state their preference for or against CT and their level of confidence in their decision on a scale of 1 to 5. Following receipt of the RS result physicians were asked to make a final decision for or against CT and similarly record their level of confidence. Descriptive analyses were used to characterize (1) patient and tumour characteristics, (2) change in treatment recommendations post-RS testing (by RS result and nodal status), and (3) change in physicians’ level of confidence post-RS testing (by RS result and nodal status). Average cost for chemotherapy and RS test price were used to estimate overall cost savings. Results: A total of 680 patients were recruited. 16 patients were excluded (5 failed samples, 5 withdrew consent, 3 HER2 positives, 2 with advanced disease, and 1 specimen delayed in transit), leaving 664 assessable patients. The median age was 58 years and 77.1% of women were post-menopausal. Most patients had a RS of 0-17 (n=400, 60.2%); while 206 (31%) had a RS of 18-30 and 58 (8.7%) had a RS of 31-100. Using post-RxPONDER cutoffs, 566 (85.2%) had an RS of 0-25; 98 (14.8%) had an RS of 26-100. Decision impact results: The decision impact results broken down by RS result and nodal status are detailed in Table 1. Of the 662 patients with complete decision impact data, in 359 (54.2%) the recommendation by the physician changed from CT+ hormone therapy (HT) to HT alone. In 286 (43.2%) cases the decision was unchanged and in 17 (2.6%) the recommendation changed from HT alone to CT+HT. Overall 342 (51.7%) cases were spared chemotherapy. Decision conflict results: The change in the physicians’ level of confidence by RS result and nodal status are detailed in Table 2. Of the 660 cases with complete decision conflict data, physicians reported an increase in confidence in their recommendations after receiving the RS in 363 (55.0%), confidence was unchanged in 219 (33.2%) and decreased confidence in 78 (11.8%) cases. Economic analysis: Using the estimates of Burdanov et al, the average costs of a course of chemotherapy in the UK is £6,000 to £7,000. An estimate of the overall cost saving of 342 courses is £2,064,00 to £2,408,000 and the overall cost of 664 RS assays at the list price of about £2580 (although an undisclosed discount applies to the NHS) is £1,713,120. This suggests that the use of RS assay represents a significant saving to the NHS. Conclusion: The use of Oncotype DX assay in node positive early breast cancer leads to about half of women being spared chemotherapy, a significant improvement in clinical confidence for oncologists and an economic saving to the health care system. Table 1 Pre- vs Post-Oncotype DX Treatment Recommendation by Physician According to Recurrence Score and Nodal Status Table 2 Change in Physicians’ Level of Confidence Post-Oncotype DX Testing According to Recurrence Score and Nodal Status Citation Format: Simon D. Holt, Priyadharshini Sai-Giridhar, Mark Verrill, Laura Pettit, Anna Rigg, Tamas Hickish, Caroline D. Archer, Anshu Wadhawan, Marianne Dillon, Jo Dent, Mark R. Nathan, Ludger Barthelmes, Shazza rehman, Paige Innis, Saira Khawaja. A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved [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 P6-01-11.

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.

Assessing the preventive effect of immediate lymphatic reconstruction on the upper extremity lymphedema.

An immediate lymphatic reconstruction (ILR) combining axillary reverse lymphatic mapping (ARLM) and lymphovenous anastomosis (LVA) has been gradually in the spotlight as a novel surgical technique to prevent lymphedema. In this study, we investigate the preventive effect of ILR for the risk of upper extremity lymphedema. We will compare the incidence of postoperative lymphedema between the ILR treatment group and the no-try or failure group during the same period with analysis of the effects of different variables. In this retrospective cohort study, we analyzed 213 patients who had undergone mastectomy for node-positive unilateral breast cancer in our institution between November 1, 2019 and February 28, 2021. To assess the effect of preventive ILR, we divided the patients into a treatment group (n=30) and a control group (n=183). Univariate and multivariate Cox proportional hazards regression models were used to evaluate the association between ILR and lymphedema occurrence. Of the 30 patients who were attempted, we successfully performed ILRs in 26 patients (86.7%). During a mean follow-up of 14 months, one patient (3.8%) was confirmed to have upper extremity lymphedema in the treatment group, whereas 14 out of 183 patients (7.7%) were diagnosed in the control group. In multivariate analysis, ILR success showed a borderline significant decrease in risk of lymphedema [hazard ratio (HR) =0.174; 95% confidence interval (CI): 0.022-1.374; P=0.097]. Our results suggested that ILR may be a promising surgical treatment to prevent postoperative lymphedema. There is a need for larger studies with longer follow-up to confirm the findings obtained in our study.

Abstract OT3-15-01: TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer

Abstract Background: The introduction of immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy regimens has been shown to significantly improve outcomes in patients with triple negative breast cancer and is being investigated for high-risk hormone receptor-positive (HR+)/human epidermal growth factor-2 negative (HER2-) breast cancer. Preclinical evidence suggests radiation therapy (RT) can stimulate intra-tumoral T cell infiltration and enhance the expression and immune detection of tumor-specific neoantigens. This phase II pilot randomized study (NCT04443348) aims to evaluate the safety and efficacy of two different doses of preoperative primary tumor RT boost when combined with neoadjuvant pembrolizumab, then followed by standard neoadjuvant chemotherapy. Dual co-primary endpoints include determining the pathologic complete response (pCR) rate in the non-irradiated and pathologically confirmed metastatic axillary lymph node(s) in each treatment arm and quantifying tumor-infiltrating T lymphocytes in on-treatment (C1D14) tumor biopsies. We hypothesize that high-dose RT will increase the proportion of tumors with high T cell infiltration (i.e., top quartile) from 25% to 55%. Secondary endpoints include measuring residual cancer burden, evaluating tolerability of the regimen, and assessing quality of life. Exploratory endpoints include evaluation of treatment-associated changes in the tumor immune microenvironment, circulating immune cell analyses, and circulating tumor DNA kinetics. Methods: The study plans to enroll 128 participants with either triple negative (n=80) or high-risk HR=/HER2- (n=48) breast cancer who will be randomized to receive no, low (9 Gy), or high (24 Gy) dose of preoperative RT boost, after which 24 participants of either breast cancer subtype will be enrolled to an exploratory high dose proton therapy boost cohort. The eligibility criteria include patients who have biopsy-proven, axillary lymph node-positive breast cancer that is either triple negative (defined as ER< 10%, PR< 10%, and HER2-negative) or high-risk HR+/HER2- (grade III or having a high-risk genomic assay score). Study treatment is given in 6-week cycles, with 400 mg Pembrolizumab given on day 1 of each cycle. For those participants randomized to receive a preoperative RT boost, treatment is delivered in 3 fractions (3 × 3 Gy or 3 × 8 Gy) over consecutive business days, where one of the fractions is given on the same day as C1D1 Pembrolizumab. Standard neoadjuvant chemotherapy begins on C1D15 with paclitaxel (plus carboplatin for triple negative) administered weekly for 12 weeks, and then starting on C3D15, dose-dense doxorubicin/cyclophosphamide is administered every 2 weeks for 8 weeks. Following neoadjuvant treatment, participants will receive standard breast surgery (including removal of the pathologically confirmed metastatic lymph node) followed by adjuvant pembrolizumab, radiation therapy, and standard-of-care systemic therapy as clinically indicated. Tissue samples from the primary tumor and biopsy-proven lymph node are taken at baseline, C1D14, and at the time of surgery. There are eleven blood collection timepoints throughout the neoadjuvant and adjuvant settings. Participants will be followed for 2 years after surgery to assess safety and durability of responses. Results: This study has accrued 12 participants to date, including 10 with triple negative breast cancer and 2 with high-risk HR+/HER2- breast cancer. Formal results for this study are forthcoming, as the trial is actively accruing at 6 institutions, with plans to open at 3 more within the year. For persons with a specific interest in this trial, please contact Joseph Connolly, Multi-Center Coordinator, at jconnolly28@mgh.harvard.edu. Citation Format: Joseph J. Connolly, Laura M. Spring, Alphonse G. Taghian, Michele Gadd, Laura Warren, Ana C. Garrido-Castro, Tari King, Elizabeth A. Mittendorf, Jose P. Leone, Dana L. Casey, Lisa Carey, Tiffany A. Traina, Yara Abdou, Atif Khan, George Plitas, Jean Wright, Cesar Augusto Santa-Maria, Lisa Jacobs, Rachel Blitzblau, E Shelley Hwang, Carey Anders, Ian Krop, Antonio C. Wolff, Alastair M. Thompson, Elyssa Denault, Gaorav Gupta, Alice Ho. TBCRC-053: P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative 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 OT3-15-01.

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 P4-07-36: Chest-Wall and Nodal Irradiation in Non-Metastatic, Node Positive Breast Cancer Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy and Surgery, in A Retrospective Cohort of Women Aged 45 Years and Younger

Abstract Purpose/Objective(s): Several randomized clinical trials and non-randomized studies have consistently shown that achievement of pathologic complete response (pCR) in the breast with negative axillary nodes is associated with excellent long-term outcomes. NSABP B-511 is a phase III trial aimed to determine if chest wall and regional nodal irradiation (CWRNI) post-op reduces invasive breast cancer recurrence-free interval in patients (pts) with positive axillary lymph nodes (LN) who achieve pCR after neoadjuvant chemotherapy (NAC). However, physicians might be biased towards avoiding enrollment of young patients (≤ 45 years) in this trial. Which in turn, could give way to this population becoming under-represented at the time of determining the standard of care. Our primary objective is to determine if the omission of CWRNI is associated with an increased risk of recurrence in a young patient population. Materials/Methods: Data were obtained from two institutions in South Florida. Patients aged ≤ 45 years, with non-metastatic invasive breast cancer, and positive clinical (LN) involvement, diagnosed between 2010 to 2017 and treated with NAC were identified through retrospective chart review. Disease recurrence including local and distant recurrence data were collected. The Kaplan-Meier survival function was used for plotting patients treated with CWRNI vs no CWRNI and the log-rank test was used to evaluate the recurrence-free survival according to groups. We reported recurrence probabilities at 5 years. Additionally, we also estimated hazard ratios (HRs) of patients treated with CWRNI vs no CWRNI using Cox proportional hazards regression analysis. Results: A total of 154 patients were identified. Median age was 39 years (24-45). Patients were 57% ER+, 33% HER2+, 29% triple negative and 59.1% were stage 3, with only 1 male patient in the cohort. PCR was achieved in 22.1% (34/154) of pts, and CWRNI frequency in these patients was 81.3%. Overall, 79.9% of pts received post-op CWRNI. Recurrence frequency in patients with a pCR who received CWRNI was 4/26 vs 2/6 in pts that did not receive CWRNI. The Kaplan-Meier survival curves indicated an overall probability of recurrence at 5 years of 31.9% (95%CI 3.8% – 51.8%) in patients that did not receive CWRNI vs 27.49% (95%CI 18.42% – 35.56%) in patients that received CWRNI (log rank p=0.55) however, statistical significance was not met. Cox regression indicated that omission of CWRNI was not associated with an increased risk of recurrence (HR 1.3, 95%CI 0.54 – 3.11, p=0.55). In patients that had a pCR after NAC, omission of CWRNI was not associated with an increased risk of recurrence (HR 2.004, 95%CI 0.36 – 10.9, p=0.42). However, the sample size for these analyses was too small to achieve significance. Conclusion: This data highlights the tendency of giving CWRNI to younger patients with clinically node-positive disease at diagnosis regardless of response to NAC. Overall, absolute recurrence in this cohort was very low. Although an absolute number of recurrences favored CWRNI in the setting of pCR, this was not statically significant given the small sample size. Citation Format: Danielle Cerbon, Alex Sanchez-Covarrubias, Brianna Conte, Cristiane Takita, Lora Freedman, Jessica Meshman, Stuart Samuels, Caroline Shermoen, Neha Goel, Ruben Carmona, Lora Wang. Chest-Wall and Nodal Irradiation in Non-Metastatic, Node Positive Breast Cancer Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy and Surgery, in A Retrospective Cohort of Women Aged 45 Years and Younger. [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 P4-07-36.

Abstract P1-01-02: The impact of adjuvant chemotherapy on overall survival in hormone and node positive breast cancer patients with an Oncotype Dx score of 25 or less. A NCDB analysis

Abstract Background: The RxPONDER trial showed that in premenopausal breast cancer (BC) subjects who were hormone receptor positive (HR+), N1 lymph node status and had an OncotypeDx (RS) score ≤ 25, the use of adjuvant chemotherapy (AC) along with endocrine therapy (ET) had better disease free and distant relapse free survival than ET alone. Using a large national database, we wanted to see if adding AC improved overall survival in a similar cohort of node positive BC patients. Methods: The 2004-2018 National Cancer Database was used to include female BC patients aged 18-50 years. Inclusion criteria were N1-N3 lymph node status, M0 patients with any T stage, RS ≤ 25, HR+ and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients with and without AC use. Results: 8628 women were included of which only 3519 (40.8%) received AC (AC+). 5109 (59.2%) did not receive AC (AC-). AC+ had the following age distribution: (18-40 years: 23.73%, 41-50 years: 76.27%), while AC- had the following: (18-40 years: 15.15%, 41-50 years: 84.85%). RS score distribution are as follows: AC+(0-11: 17.56%, 12-25: 82.44%), AC-(0-11: 35.49%, 12-25: 64.51%). Most of the cohort received ET (AC+: 94.74%, AC-: 93.25%) and majority were N1 (AC+: 92.61%, AC-: 98.9%). Factors associated with AC use includes caucasian race [african american vs caucasian: 0.777(0.647,0.934), p=0.0072], higher stage [II vs I: 1.825(1.598,2.084), p=&amp;lt; 0.0001, III vs I: 3.199(1.593,6.426), p=0.0011] and higher grade [G3 vs G1: 2.261(1.886,2.711), G2 vs G1: 1.467(1.301,1.655), p&amp;lt; 0.0001], radiation (RT) use [1.758(1.544,2.002), p&amp;lt; 0.0001], younger age [40-50 vs 18-40: 0.684(0.542,0.863), p=0.0013], higher RS [12-25 vs 0-11: 2.325(2.065,2.618), p&amp;lt; 0.0001], mastectomy [vs partial surgery: 1.668(1.469,1.894), p&amp;lt; 0.0001] and N2N3 nodal stage [N2N3 vs N1: 2.688(1.423,5.079), p=0.0023]. KM curves showed that AC+ had better survival at 10 years (93% vs 91%) (Table 1). Hazard Ratio (HR) comparison between the 2 groups favored AC+ [0.602(0.482,0.751), p&amp;lt; 0.0001] (Table). Subgroup analysis for overall mortality benefits from AC+, using MV adjusted HR showed favorable results in caucasian race [0.512(0.348,0.752)], both age groups of 18-40 years [0.429(0.217,0.847) and 40-50 years [0.585(0.394,0.869)], both poorly differentiated [0.404(0.186,0.874)] and well-differentiated [0.386(0.165, 0.903] grades and RS 12-25 [0.549(0.379,0.795)]. RS 0-11 did not reach significance [0.555(0.216,1.423]. Discussion: Based on our analysis, AC use was noted in 40.8% of young, lymph node and HR+ BC patients with an RS score of 0-25. This group of patients had an overall survival advantage of around 40% with AC use, further supporting the findings of the RxPONDER trial. This benefit is of particular significance in patients with a RS of 12-25. The survival advantage was present in all patients less than 50 years, regardless of the age subgroup used in our analysis. Possible mechanisms leading to these outcomes include direct cytotoxic effects and menopausal induction with AC use. Limitations of our study include the use of non-population-based data and the possibility of cofounding despite the use of PS matching. Moving forward, AC use along with hormone therapy may become standard practice in young HR + BC patients with lymph node involvement, regardless of the RS score. Table 1 Survival difference between AC+ and AC-. KM-Kaplan-Meier, AC-Adjuvant Chemotherapy, HR-Hazard Ratio, MV-Multivariate, PS-propensity score. Citation Format: Prashanth Ashok Kumar, Dongliang Wang, Danning Huang, Abirami Sivapiragasam. The impact of adjuvant chemotherapy on overall survival in hormone and node positive breast cancer patients with an Oncotype Dx score of 25 or less. A NCDB analysis [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 P1-01-02.

Abstract CC1-1-1: To clip or not to clip (Part 1)

Abstract Clinically node positive breast cancer patients often recieve neoadjuvant chemotherapy which can eradicate nodal disease. While sentinel node dissection alone has been shown to predict treatment response with a false negative rate of 12-14%, it is possible to increase the accuracy by performing targeted axillary dissection (TAD). To perform TAD, a clip is placed in a node if biopsy confirms disease. The procedure then involves selectively localizing and removing the clipped node in addition to the sentinel nodes. Multiple studies have show that this approach has a false negative rate of &amp;lt;5%. These studies also show that the clipped node is not retrieved as a sentinel node in &amp;gt; 20% of cases. This means that evaluating the sentinel nodes alone would miss evaluating the node with confirmed disease in a significant proportion of patients. This session will focus on the question of whether there is benefit to placing clips in nodes and ensuring removal after neoadjuvant chemotherapy. Citation Format: Abigail Caudle. To clip or not to clip (Part 1) [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 CC1-1-1.

Abstract P2-11-11: Computer analysis of nuclear morphology with Multiple Instance Learning Predicts Overall Survival for Node Positive Breast Cancer Patients from SWOG S8814: A Blinded Validation Study

Abstract Background: Adjuvant chemotherapy is a common treatment for breast cancer patients with aggressive tumors, but imposes severe side effects. Although lymph node involvement is associated with higher likelihood of mortality, a subset of LN+ patients can survive without relapse, even without adjuvant chemotherapy. SWOG-8814 (S8814) was a randomized clinical trial of hormone receptor positive, LN+ post-menopausal women (pathologic stage T1-3N1-2) to compare patient outcome between endocrine therapy alone (tamoxifen), chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil) followed by 5 years of tamoxifen, and chemotherapy with concurrent tamoxifen. In this work, we evaluated the ability of a machine learning approach called multiple instance learning (MIL) to predict long-term overall (OS) and disease-free survival (DFS) in patients from the S8814 clinical trial via analysis of digitized H&amp;E tissue slides. Methods: The training set (St, n=121) consisted of digitized H&amp;E Whole Slide Images (WSIs) of ER+ LN+ patients from ECOG-2197 - a clinical trial to compare patient outcome under chemotherapy with doxorubicin/docetaxel vs. doxorubicin/cyclophosphamide. For each WSI, the nuclei of ten tumor patches (2000 × 2000 pixels) were automatically segmented by a pretrained machine learning algorithm called Convolutional Neural Networks (CNN). The results of the CNN’s segmentations were used to obtain ten corresponding feature vectors of 3963 features relating to nuclear morphology and spatial arrangement. Five top discriminative features (Haralick texture, Delaunay triangulation, orientation entropy, perimeter kurtosis, architecture) were identified by reliefF-MI feature filtering and forward selection on St. A Normalized Set Kernel Support Vector Machine classifier was trained on St to construct a MIL binary classifier (M+), which generates a continuous survival score to predict which patients would have &amp;gt;10-years of DFS and OS. The score cutoff thatmaximized F1 score on St was used to generate binary predictions of patient outcome. Blinded validation of the risk scores on S8814 was performed by SWOG. Results: M+ was significantly prognostic of OS in univariate analysis (HR=0.72, p=0.020, 95% CI= 0.55 – 0.95) on S8814. M+ stratifications remained statistically significant after multivariable analysis controlling for treatment, number of positive lymph nodes, and tumor size (HR = 0.71, p=0.017, 95% CI=0.54-0.94). M+ predictions did not achieve statistical significance for DFS in univariate analysis (HR=0.81, p=0.081, 95% CI 0.64-1.03) nor multivariable analysis (HR=0.81, p=0.080, 95% CI 0.63-1.03). M+ was not predictive of chemotherapy benefit for OS (p=0.88) and DFS (p=0.65). There was no correlation of the generated continuous score with Recurrence Score (r=-0.05), previously shown to be a predictive factor for chemotherapy benefit. Conclusion: Our findings demonstrate that nuclear morphology provides insight into overall survival in ER+ LN+ breast cancer patients. Future work will involve combining the MIL based morphologic predictor with other clinicopathologic factors to improve DFS risk stratification. Funding: Funding NIH/NCI grants U10CA180888, U10CA180819, U24CA196175; and in part by Genomic Health, INC. (now Exact Sciences Corp.) Citation Format: Daniel Shao, William E. Barlow, Haojia Li, Cheng Lu, Kathy S. Albain, James Rae, Daniel F. Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi, Lajos Pusztai. Computer analysis of nuclear morphology with Multiple Instance Learning Predicts Overall Survival for Node Positive Breast Cancer Patients from SWOG S8814: A Blinded Validation Study [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 P2-11-11.

Abstract PD15-11: PD15-11 Axillary dissection to determine nodal burden to inform systemic therapy recommendations in patients with clinically node-positive breast cancer: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101)

Abstract Introduction: Chemotherapy is recommended for patients with luminal breast cancer and more than three positive nodes. In addition, recent landmark trials raised the question if the exact number of positive nodes is required to indicate genomic testing. In the neoadjuvant setting, response-driven therapy is increasingly used and may be influenced by surgical staging of the axilla. The present study addressed the role of axillary lymph node dissection (ALND) as decision aid for systemic therapy in a contemporary cohort of patients with clinically node-positive breast cancer in the adjuvant and neoadjuvant setting. Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614). The first 500 patients with clinically node-positive breast cancer who were randomized after tailored axillary surgery (TAS) to undergo ALND or axillary radiotherapy (ART) without ALND in the context of extended regional irradiation were included from August 2018 to June 2022. Clinically node-positive breast cancer was defined by confirmed nodal disease at the time of initial diagnosis; in case of neoadjuvant therapy, the finding of residual nodal disease was mandatory for randomization. TAS consisted of removal of palpably suspicious findings and the sentinel nodes with the option of image guidance. In the ART arm, the total number of positive nodes was not known. We analyzed the impact of ALND on rate and type of systemic therapy. Results: A total of 500 patients with a median age of 57 years (IQR: 48-69 years) were included at 44 breast centers from six European countries. Subtype was hormone receptor (HR) positive (+) and human epidermal growth factor receptor 2 (HER2) negative (-) in 393 (80.0%), HR+/HER2+ in 52 (10.6%), HR-/HER2+ in 5 (1.0%) and HR-/HER2- in 34 (6.9%) patients. Of 343 patients (68.6%) who were treated in the adjuvant setting, 297 had HR+/HER2- disease. Of these 297 patients, 145 (48.8%) underwent ART without ALND and 152 (51.2%) underwent ALND after TAS. In the ART arm, the median number of lymph nodes removed was five (IQR 4-8), three (IQR 1-4) of which were positive and in the ALND arm, the number was 19 (IQR 14-26), four (IQR 2-9) of which were positive (p &amp;lt; 0.001). The use of ALND had no significant impact on the rate of patients with HR+/HER2- disease undergoing adjuvant chemotherapy (51.0% in the ART and 57.9% in the ALND arm, p=0.2), and there were no significant differences in type of systemic therapy with the exception of tamoxifen, which was 18.4% with ALND versus 9.0% without (p=0.018). A total of 143 patients (28.6%) underwent neoadjuvant chemotherapy, 13 had neoadjuvant antihormonal treatment and one had neoadjuvant double HER2-blockade without chemotherapy. Of the 143 patients who received neoadjuvant chemotherapy, 71 (49.7%) underwent ART without ALND and 72 (50.3%) underwent ALND. In the ART arm, the median number of lymph nodes removed was four (IQR 3-6), one (IQR 1-3) of which was positive and in the ALND arm, the number was 16 (IQR 12-19), two (IQR 1-5) of which were positive (p &amp;lt; 0.001). The use of ALND in patients after neoadjuvant treatment had no significant impact on the rate of adjuvant systemic therapy (71.8% in the ART and 65.3% in the ALND arm, p=0.4), with no significant differences in type of chemotherapy (e.g., capecitabine: 11.3% vs 12.5%, p=0.8; T-DM1: 11.3% vs. 11.1%, p&amp;gt;0.9) or antihormonal therapy (e.g., aromatase inhibitors: 49.3% vs. 41.7%, p=0.4; tamoxifen: 11.3% vs. 5.6%, p=0.2). Discussion: This study showed that although ALND significantly increased the number of positive nodes removed in the adjuvant and neoadjuvant setting, it had no relevant impact on rate and type of adjuvant systemic therapy. Citation Format: Walter P. Weber, Zoltan Matrai, Stefanie Hayoz, Christoph Tausch, Guido Henke, Daniel R. Zwahlen, Günther Gruber, Frank Zimmermann, Thomas Ruhstaller, Simone Muenst, Markus Ackerknecht, Sherko Küemmel, Vesna Bjelic-Radisic, Viktor Smanykó, Conny Vrieling, Rok Satler, Inna Meyer, Charles Becciolini, Susanne Bucher, Colin Simonson, Peter M. Fehr, Natalie Gabriel, Robert Maráz, Dimitri Sarlos, Konstantin J. Dedes, Cornelia Leo, Gilles Berclaz, Hisham Fansa, Christopher Hager, Klaus Reisenberger, Ákos Sávolt, Christian F. Singer, Roland Reitsamer, Jelena Winkler, Giang Thanh Lam Lam, Mathias K. Fehr, Tatiana Naydina, Magdalena Kohlik, Karine Clerc, Valerijus Ostapenko, Florian Fitzal, Martin Heidinger, Nadia Maggi, Alexandra Schulz, Pagona Markellou, Loïc Lelièvre, Daniel Egle, Jörg Heil, Michael Knauer, Christian Kurzeder. PD15-11 Axillary dissection to determine nodal burden to inform systemic therapy recommendations in patients with clinically node-positive breast cancer: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101) [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 PD15-11.

Abstract P2-14-08: Trends in neoadjuvant systemic therapy rates in Europe: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101)

Abstract Introduction: Even though randomized controlled trials could not show a significant survival benefit for the use of neoadjuvant systemic therapy (NST), it is increasingly recommended for patients with clinically node-positive breast cancer due to its implications on prognosis, locoregional downstaging and response-driven adjuvant systemic therapy. The aim of this study was to assess the need for international standardization of treatment recommendations by evaluating clinical practice heterogeneity in use of NST for patients with clinically node-positive breast cancer in Europe. Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) after randomization of the first 500 patients with clinically node-positive breast cancer who underwent axillary lymph node dissection (ALND) or axillary radiation (ART) without ALND after tailored axillary surgery (TAS) in the context of extended regional nodal irradiation. Clinically node-positive breast cancer was defined by confirmed nodal disease at the time of initial diagnosis; in case of neoadjuvant therapy, residual nodal disease was mandatory. Investigators were encouraged to enroll all eligible patients consecutively. However, TAXIS is unique inasmuch as its pragmatic design allows both the neoadjuvant and adjuvant setting according to the preferences of the treating physicians and institutions and thus provides an excellent opportunity to study patterns and trends in use of NST in patients with clinically positive nodes in Europe. Results: A total of 500 patients with a median age of 57 years (IQR: 48-69 years) were included at 44 breast centers in 6 European countries from August 2018 to June 2022. Subtype was hormone receptor (HR) positive (+) and human epidermal growth factor receptor 2 (HER2) negative (-) in 393 (80.0%), HR+/HER2+ in 52 (10.6%), HR-/HER2+ in 5 (1.0%) and HR-/HER2- in 34 (6.9%) patients. The rate of patients undergoing NST was 31.4% with a significant upward trend over time during the study period (from 20.0% in 2018 to 38.1% in 2022; p=0.044). The use of NST varied significantly by country (p=&amp;lt; 0.001) and by site (p=0.015). For patients with clinical AJCC tumor stage II and III, the rates of patients undergoing NST in Switzerland were 26.5% (18 of 68) and 35.9% (92 of 256), in Germany 22.2% (2 of 9) and 30.4% (7 of 23), in Austria 50% (7 of 14) and 60% (9 of 15) and in Hungary 0% (0 of 15) and 20.7% (18 of 87), respectively (p=0.019 and 0.004). Large differences by country were found for ER+/HER2- breast cancer, ranging from 13.1% (11 of 84) in Hungary to 47.8% (11 of 23) in Austria (p=0.007). Within Switzerland, which was the country with most included patients (328 of 500) and participating sites (n=25), the rate of patients undergoing NST for ER+/HER2- breast cancer varied considerably by site, ranging from 10% (2 of 20) to 50% (11 of 22). Discussion: This study revealed substantial heterogeneity in clinical practice in Europe, indicating the need for development of and adherence to consistent guidelines to standardize the international use of NST. Citation Format: Walter P. Weber, Zoltan Matrai, Stefanie Hayoz, Guido Henke, Daniel R. Zwahlen, Günther Gruber, Frank Zimmermann, Thomas Ruhstaller, Simone Muenst, Markus Ackerknecht, Christian Kurzeder, Sherko Küemmel, Vesna Bjelic-Radisic, Viktor Smanykó, Conny Vrieling, Rok Satler, Inna Meyer, Charles Becciolini, Susanne Bucher, Colin Simonson, Peter M. Fehr, Natalie Gabriel, Robert Maráz, Dimitri Sarlos, Konstantin J. Dedes, Cornelia Leo, Gilles Berclaz, Hisham Fansa, Christopher Hager, Klaus Reisenberger, Ákos Sávolt, Christian F. Singer, Roland Reitsamer, Jelena Winkler, Giang Thanh Lam Lam, Mathias K. Fehr, Tatiana Naydina, Magdalena Kohlik, Karine Clerc, Valerijus Ostapenko, Florian Fitzal, Martin Heidinger, Nadia Maggi, Alexandra Schulz, Pagona Markellou, Loïc Lelièvre, Daniel Egle, Jörg Heil, Michael Knauer, Christoph Tausch. Trends in neoadjuvant systemic therapy rates in Europe: Pre-planned substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101) [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 P2-14-08.

Abstract OT1-08-01: AXSANA – EUBREAST3: An international prospective multicenter cohort study to evaluate different surgical methods of axillary staging in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy

Abstract Background The optimal surgical staging procedure of the axilla in patients who convert from a clinically positive (cN+) to a clinically negative node status (ycN0) through neoadjuvant chemotherapy is still controversial. Widely diverse techniques such as full Axillary Lymph Node Dissection (ALND), Targeted Axillary Dissection (TAD), Targeted Lymph Node Biopsy (TLNB) and Sentinel Lymph Node Biopsy (SLNB) alone are given preference in different international guidelines. So far, no comparative data on the oncological outcome or the morbidity of the different procedures are available. Further research is needed to safely de-escalate the extent of axillary surgery in this patient group. Trial design The AXSANA study is an international prospective cohort study including cN+ patients converting to ycN0 status and treated with different axillary staging techniques according to the standard at their treating institution. The study was initiated by the EUBREAST network. The trial includes patients with cT1-4c tumors, who present initially with clinically axillary lymph node involvement metastasis scheduled for neoadjuvant chemotherapy. According to an amendment in 2020 the inclusion of patients with highly suspicious nodes without confirmation using a minimally invasive biopsy is allowed. All patients converting to ycN0 status undergo follow-up for 5 years irrespectively of the ypN status. Primary endpoints: Invasive disease-free survival, axillary recurrence rate and health-related quality of life (HRQoL). HRQoL are evaluated using four standardized questionnaires (EORTC QLQ-C 30, EORTC QLQ-BR23, Lymph-ICF and SOC 13) at baseline and after 1, 3 and 5 years after surgery. Secondary endpoints are the feasibility and performance of different axillary staging techniques (detection rate, number of removed lymph nodes and association with complications, arm morbidity and quality of life, operating time and use of clinical and economic resources); impact of learning curve, and the detailed mapping of surgical and oncological treatment standards in different countries. The impact on different regional treatment strategies (radiotherapy, ALND) in patients with ypN0(i+), ypN1(mi) and ypN1 is assessed. Current status of the study: 2347 patients from 247 study sites and 23 countries were enrolled in the study between June 2020 and June 2022. Among 1804 patients with a defined surgical concept 758 women were scheduled for ALND, 722 for TAD, 232 for SLNB, 16 for TLNB and 19 for other procedures. A target lymph node was marked in 1215 patients, most frequently using clips/coils (982, 82.0%), followed by magnetic seeds (100, 8.4%), carbon ink (99, 8.3%), radar marker (21, 1.8%), radioactive seeds (5, 0.4%), and other techniques (8, 0.7%). Citation Format: Thorsten Kühn. AXSANA – EUBREAST3: An international prospective multicenter cohort study to evaluate different surgical methods of axillary staging in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy [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 OT1-08-01.

Abstract P5-01-05: A Predictive Model for Axillary Pathologic Response after Neoadjuvant Chemotherapy for Clinically Node-Positive Breast Cancer

Abstract Purpose: Neoadjuvant chemotherapy (NAC) has resulted in the eradication of axillary lymph node metastasis in approximately 40% of patients. Sentinel lymph node biopsy (SLNB) could be an alternative surgical procedure for these patients to avoid complications from axillary lymph node dissection (ALND). However, high false-negative rates of SLNB for clinically node-positive patients were reported in previous prospective trials. The aim of the present study was to evaluate clinicopathological factors and imaging characteristics by MRI and ultrasound (US) as predictors of axillary pathologic complete response (ypN0) after NAC, which enables to identify candidates for SLNB in patients with clinically node-positive disease. Patients and methods: We identified 177 patients with clinically node-positive breast cancer who received NAC from May 2009 to May 2021. All patients underwent MRI and US before and after NAC. Patients were judged to be node-positive when they have the cytologically-proven nodal disease by fine-needle aspiration (FNA) or suspicious lymph nodes by diagnostic imaging. Lymph nodes with the cortical thickness (&amp;gt;3.5mm), loss of fatty hilum, or round shape (short-axis/long-axis ratio &amp;gt; 0.5) were defined as suspicious lymph nodes. To develop a predictive model for ypN0, the association between ypN0 status and clinicopathological and imaging characteristics was assessed by multivariate logistic regression analysis. The area under the receiver operating characteristic (ROC) curve was used to evaluate discrimination by the model. The model was further evaluated in the validation cohort with 20 patients who received NAC from March 2021 to December 2021. Results: The median age was 54.0 (range: 22-79) years and the mean tumor size was 3.97 ±2.29cm. Of 177 patients, 90 (50.8%) patients had luminal, 47 (26.6%) had HER2-positive, and 40 (22.6%) had triple-negative disease. Sequential anthracycline and taxane were administered for 157 (88.7%) patients, and 45 (95.7%) patients with HER2-positive-disease received concomitant anti-HER2 agents preoperatively. Overall, 77 (43.5%) patients achieved ypN0. Independent predictors of ypN0 status were clinical stage N1 (odds ratio [OR]: 9.17 vs. cN2-3, p=0.002), absence of lymphadenopathy after NAC (OR: 8.54, p&amp;lt; 0.001), breast complete response (CR) by MRI (OR: 5.96, p&amp;lt; 0.001), HER2 positivity (OR: 3.80, p=0.008), nuclear grade (NG) 3 (OR: 2.77 vs. NG1-2, P=0.020) and hormone receptor negativity (OR: 2.52, p=0.048). In a model using these predictors, the area under the ROC curve was 0.887 (95% confidence interval: 0.839-0.935, p&amp;lt; 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the model were 80.0%, 82.8%, 77.9% and 84.5%, respectively. In the validation cohort, the sensitivity, specificity, positive predictive value and negative predictive value were 66.7%, 90.9%, 85.7% and 76.9%, respectively. Among 84 patients who were predicted ypN0 by the model, SLNB was performed in 42 (50.0%) patients, and the identification rate of SLN was 95.2% (40/42). Overall, ALND was omitted in 38 (45.2%) patients and irradiation to regional lymph nodes was performed in 23 (60.5%) out of 38 patients. After a median follow-up of 53.9 months, 5-year recurrence-free survival was comparable between patients with or without ALND (78.0% vs. 94.4%, p=0.259). Conclusions: Our predictive model based on clinicopathological factors and imaging characteristics by MRI and US could help to identify good candidates for the omission of ALND after NAC in patients with clinically node-positive breast cancer. Citation Format: Akiko Matsumoto, Saki Naruse, Yuka Isono, Yuka Maeda, Ayana Sato, Miki Yamada, Tatsuhiko Ikeda, Hiromitsu Jinno. A Predictive Model for Axillary Pathologic Response after Neoadjuvant Chemotherapy for Clinically Node-Positive 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 P5-01-05.

Abstract PD15-01: PD15-01 AXILLARY NODAL RECURRENCE IS RARE IN PATIENTS WITH NODE-POSITIVE BREAST CANCER UNDERGOING SLNB FOLLOWING NEOADJUVANT CHEMOTHERAPY : EARLY RESULTS OF THE NEOSENTITURK-TRIAL/MF-18-03

Abstract Background: Whether axillary lymph node dissection (ALND) following sentinel lymph node biopsy (SLNB) could be spared in patients with initially clinically positive axilla after neoadjuvant chemotherapy (NAC) is still controversial even though recent studies indicate that axillary recurrence seems to be a rare event. Our aim is to find out whether omitting ALND could be oncologically safe in patients undergoing SLNB after NAC. Material and Methods: Of patients presented with c T1-4N1-3M0 disease, those undergoing SLNB after NAC were included in the prospective multicentre registry trial " MF18-03/BHWG" (ClinicalTrials.gov/NCT04250129). Cases with inflammatory breast cancer, distant metastases, pregnancy, bilateral breast cancer, or other cancers and those without adjuvant nodal radiotherapy were excluded from the study. The end points of the present report are the axillary nodal recurrence (AR) and locoregional recurrence (LRR) rates at a median follow-up more than 2 years, and determine factors associated with AR and LRR . The locoregional recurrences included ipsilateral, and contralateral axillary recurrences, infra-and supraclavicular recurrences, and recurrences in the mammaria interna region. Results: Between January 2018 to January 2021, 2358 patients with cN(+) disease, who became cN0 after NAC, and underwent SLNB, were analyzed. Median age was 47 (range, 21-86). Of those, the majority of patients had cT1-2 (80.5%) and N1 (80.3%) disease. Following NAC, half of the patients (50%) had breast conserving surgery, whereas the remaining half had mastectomy (50%). Of 2358 patients, 908 (38.5%) had ALND following SLN (ypN+, 85%) and 1450 (61.5%) underwent SLNB alone (ypN0, 72%). SLNB was performed by using the blue dye technique-alone in 66.6% of patients and by targeted axillary dissection in 659 patients (27.9%). Of those, 819 (34.8%) were HER2(+) and 373 (15.8%) were triple negative. The pCR rates for the axilla, breast and both for the axilla and breast were 50%, 35% and 28%, respectively. At a median follow-up time of 28 months (range, 12-62), the LRR, AR and isolated AR rates were 0.6% (n=14), 0.25% (n=6) and 0.13% (n=3), respectively. Furthermore, no significant difference could be found in LRR- and AR- rates between SLNB-alone and ALND groups regardless of the definitive nodal pathology (Table 1). Nodal recurrences were seen at a median of 12 months after the surgery. Of 6 cases with AR, 3 had synchronous local recurrences in breast, and 2 of them also had lung metastases in addition to local recurrence. All patients with AR were interestingly found to have HER2(+) or triple negative breast cancer at the initial diagnosis, and had residual invasive cancer in the breast surgical specimen. Logistic regression analyses revealed that patients with AR were significantly more likely to be younger than 45 (RR=7.81 ; 95% CI, 0.91-66.91) and have a cN2-3 (RR=4.1; 95% CI, 0.83-20.38), and non-luminal breast cancer (RR=12.47; 95% CI, 1.45-106.9) at the initial diagnosis (Table 2). Similarly, patients with LRR were more likely to present with cN2-3 disease (RR=3.09; 95% CI, 1.07-8.94) and non-luminal pathology (RR=6.27; 95%CI, 1.96-20.06) . Conclusion: This large prospective registry data also suggest that nodal recurrences can be detected at very low rates within 3 years after surgery in patients with clinically node-positive disease following NAC regardless of the extent of axillary surgery or nodal pathology as long as regional nodal radiation is provided. Since patients with early nodal recurrences have an agressive tumor biology with a potential of systemic recurrences, effective adjuvant systemic therapies should be considered in those with HER2(+) or triple negative residual breast cancer after surgery following adjuvant nodal radiation. Table 1. Local locoregoinal and systemic recurrences in cT1-4N1-3 patients with ypN0/ypN(+) diseases (n =2358) Table 2. Factors associated with axillary and locoregoinal recurrences (AR = axillary recurrences, LRR = locoregoinal recurrences, pCR = pathologic complete response) Citation Format: Neslihan Cabıoğlu, Hasan Karanlik, Mehmet Ali Gulcelik, Abdullah İgci, Mahmut Muslumanoglu, Havva Belma Kocer, Cihan Uras, Gokhan Giray Akgul, Mustafa Tukenmez, Serkan Ilgun, Didem Can Trabulus, Guldeniz Karadeniz Cakmak, Ahmet Dağ, Nilufer Yıldirim, Baha Zengel, Ebru Sen Oran, Kazim Senol, Halil Kara, Selman Emiroglu, M. Umit Ugurlu, Bulent Citgez, Yeliz Emine Ersoy, Atilla Celik, Ece Dilege, Yasemin Bolukbaşı, Niyazi Karaman, Gul Basaran, Aykut Soyder, Ayfer Kamali Polat, Gurhan Sakman, Serdar Ozbas, Ayse Altınok, Leyla Zer, Alper Akcan, Ibrahim Ali Ozemir, Levent Yeniay, N. Zafer Utkan, Lutfi Dogan, Mutlu Dogan, Mehmet Velidedeoglu, Beyza Ozcinar, Fazilet Erozgen, Abut Kebudi, Kemal Atahan, Vafa Valiyeva, Serdar Yormaz, Ali Sevinc, Cumhur Arici, Atilla Soran, Vahit Ozmen. PD15-01 AXILLARY NODAL RECURRENCE IS RARE IN PATIENTS WITH NODE-POSITIVE BREAST CANCER UNDERGOING SLNB FOLLOWING NEOADJUVANT CHEMOTHERAPY : EARLY RESULTS OF THE NEOSENTITURK-TRIAL/MF-18-03 [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 PD15-01.

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.

Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.

ASO Author Reflections: A Perspective on Nonsentinel Axillary Lymph Node Status in Sentinel Lymph Node-Positive Early Breast Cancer After Primary Systemic Therapy and ALND-Predict.

ASO Author Reflections: A Perspective on Nonsentinel Axillary Lymph Node Status in Sentinel Lymph Node-Positive Early Breast Cancer After Primary Systemic Therapy and ALND-Predict.