Neoadjuvant Chemotherapy Regimen Research Articles

Circulating tumor DNA (ctDNA) to predict response to neoadjuvant chemotherapy (NAC) and prognosis in patients (pts) with early breast cancer (BC).

e12642 Background: pCR to NAC is an important predictor of clinical recurrence. Up to 16% of patients with pCR may experience disease recurrence, 45% of patients with RD do not. Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response EBC patients receiving NAC. We evaluated whether ctDNA status and dynamics can predict the tumor response to NAC and the risk of recurrence in patients with EBC. Methods: We conducted an observational, retrospective, single-center study to investigate whether ctDNA can predict tumor response to NAC and prognosis in BC patients. 74 pts received standard of care NAC;g 4 patients were treated in the adjuvant setting. Blood samples were collected at diagnosis from 44 pts (baseline) and longitudinally during treatment from 34 patients. Tumor response and progression outcomes were reported. A clinically validated, tumor-informed ctDNA assay (Signatera). ctDNA status and dynamics were correlated with pathologic and radiologic outcomes. Results: 29 TNBC pts were ctDNA+ at baseline, 6 were ctDNA- Of the 29 pts, early ctDNA clearance by week 6 of NAC was observed in 10 pts, weeks 7-16 in 9 pts, clearance post-surgery in 1, 3 pts remained ctDNA+ after surgery, serial ctDNA testing is underway for the remaining 6 pts. All TNBC patients who had radiological complete response (CR) had early clearance of ctDNA . All pts with persistent ctDNA positivity levels after completion of NAC had radiological partial response (PR). Of the 9 TNBC pts with undetectable baseline ctDNA, 33% achieved CR on MRI and 43% achieved pathologic CR. Of the 19 TNBC pts with ctDNA clearance in response to NAC, 89% (17/19) remained ctDNA- and with no evidence of disease (NED) (length of follow up). 1 pt initially cleared their ctDNA on NAC, turned ctDNA+ 4 weeks prior to radiological recurrence. 1 pt with ctDNA clearance on NAC remained ctDNA post-surgery but experienced recurrence. All (n=3) TNBC pts with persistent ctDNA-positivity levels after curative treatment (NAC and surgery) had disease recurrence. The remaining 6 pts ctDNA are ongoing NAC. Of the 6 pts with undetectable baseline ctDNA, 6/6 continued to be ctDNA- regardless of their disease status. At diagnosis, 8/9 ER+ ps were ctDNA+. 3/8 (38%) ER+ pts with positive baseline ctDNA had early clearance of ctDNA after NAC. All 3 had residual disease on pathology. 2/8 (25%) remained ctDNA+ after surgery and neither achieved radiologic CR or pCR. The remaining 3 pts are ongoing NAC. Conclusions: In early TNBC, ctDNA monitoring can be used to predict tumor response to NAC and tailor therapeutic regimens. ctDNA persistence can predict early recurrence and helps identify patients in which treatment escalation or enrollment on clinical trials is necessary. In ER positive breast cancer, and despite the small number of patients, ctDNA clearance does not predict response to NAC.

Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy.

e12608 Background: Rates of pathological complete response (pCR) are much lower in patients with hormone receptor–positive (HR+) /HER2-negative (HER2-) breast cancer than in those with HER2-positive and triple-negative breast cancer (TNBC). The majority of HR+/HER2- breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2- breast cancer after neoadjuvant chemotherapy. Methods: We analyzed HR+/HER2- breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3-5 and positive lymph node ratio of ≤10%, was used as a pathological evaluation indicator. MPR evaluates the extent of residual invasive carcinoma in both the breast and axillary lymph nodes following neoadjuvant therapy. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. Results: From January 2010 to December 2020, 386 patients were included in the final analysis. The median age was 46 years. 244 patients (63.2%) were premenopausal, with 271 (70.2%) patients diagnosed with stage III disease. The predominant neoadjuvant chemotherapy regimen was anthracycline combined taxane (79.3%). 28 patients (7.3%) achieved pCR and 118 patients (30.6%) achieved MPR. The median duration of follow-up was 54.4 months. Multivariate analysis showed that PR expression, Clinical stage, Miller–Payne grades and Positive lymph node ratio were independent prognostic factors for EFS (all P values <0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.26–0.76; P = 0.008), with 5-year EFS of 87% vs. 68% in the non-MPR group. In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95% CI, 0.51–9.84; P = 0.28). Conclusions: MPR was a novel pathologic end point for prognostic evaluation in HR+/HER2- breast cancer after neoadjuvant chemotherapy. Compared to pCR, MPR may hold greater applicability in the prognosis evaluation.

Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

Predictive biomarkers for pathological complete response in early-stage triple negative breast cancer following neoadjuvant chemotherapy.

598 Background: Identifying predictive biomarkers for early-stage triple negative breast cancer (TNBC) is essential for tailoring neoadjuvant chemotherapy (NACT) strategies effectively. Methods: We investigated potential clinical and pathological biomarkers in early-stage TNBC patients who underwent NACT regimens with anthracyclines and taxanes at a single cancer center. Medical records were scrutinized for clinical and laboratory data, with categorical variables analyzed using Fisher’s exact test. Logistic regression assessed factors associated with pathological complete response (pCR). Sensitivity and specificity of the biomarkers were explored using receiver operating characteristics (ROC) curve analyses. Results: Among 110 TNBC patients receiving anthracycline- and taxane-based NACT with complete pathology data, the median age was 48 years, 60% had stage III tumors, and 30.9% achieved pCR. Stromal tumor infiltrating lymphocytes (TILs) > 10% were observed in 54.5%, 32.7% had TILs ≥30%, and 90.9% had Ki67 ≥ 50%. Univariate analysis showed no association between pCR and TILs >10% (p=0.5), Ki67 ≥ 50% (p=0.4), anatomic stage (p=0.06), eosinophil-to-lymphocyte ratio (p=0.3), platelet-to-lymphocyte ratio (p=0.08), age (p=0.5), grade (p=0.6), or HER2 status (p=0.6). Neutrophil-to-lymphocyte ratio (NLR) was significantly associated with pCR in both univariate (OR 3.92; 95% CI 1.67 - 9.57; p=0.002) and multivariable analyses (Table). No association was observed between NLR ≤ 1.76 and TILs, anatomic stage, or Ki67. The optimal NLR cutoff using ROC curve was 1.76, yielding 60.6% sensitivity and 71.8% specificity for pCR. NLR cutoffs of ≤ 1.43 had specificities higher than 85%. Although TILs value was not associated with pCR in the regression model, high TILs value (≥50%) yielded a specificity of 89.4% for pCR. Conclusions: NLR emerged as a significant and independent predictor of pCR in early-stage TNBC. Prospective studies should explore this readily available biomarker in assessing neoadjuvant strategy responses. Moreover, high specificities for pCR were observed with NLR ≤ 1.43 and TILs ≥ 50%, representing cutoff values that could be explored for treatment de-escalation. [Table: see text]

Radiologic Occult Metastases in Pancreatic Cancer: Analysis of Risk Factors and Survival Outcomes in the Age of Contemporary Neoadjuvant Multi-agent Chemotherapy.

Radiologic occult metastatic disease (ROMD) in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo contemporary neoadjuvant chemotherapy (NAC) has not been well studied. This study sought to analyze the incidence, risk factors, and oncologic outcomes for patients who underwent the NAC approach for PDAC. A retrospective review analyzed a prospectively maintained database of patients who had potentially resectable PDAC treated with NAC and were offered pancreatectomy at our institution from 2011 to 2022. Multivariable regression analysis was performed to assess risk factors associated with ROMD. Kaplan-Meier curves with log-rank analyses were generated to estimate time-to-event end points. The study enrolled 366 patients. Upfront and borderline resectable anatomic staging comprised 80% of the cohort, whereas 20% had locally advanced disease. The most common NAC regimen was FOLFIRINOX (n = 274, 75%). For 55 patients (15%) who harbored ROMD, the most common site was liver-only metastases (n = 33, 60%). The independent risk factors for ROMD were increasing CA19-9 levels during NAC (odds ratio [OR], 7.01; confidence interval [CI], 1.97-24.96; p = 0.008), indeterminate liver lesions (OR, 2.19; CI, 1.09-4.39; p = 0.028), and enlarged para-aortic lymph nodes (OR, 6.87; CI, 2.07-22.74; p = 0.002) on preoperative cross-sectional imaging. Receipt of palliative chemotherapy (p < 0.001) and eventual formal pancreatectomy (p = 0.04) were associated with survival benefit in the log-rank analysis. The median overall survival (OS) of the patients with ROMD was nearly 15 months from the initial diagnosis, with radiologic evidence of metastases occurring after a median of 2 months. Radiologic occult metastatic disease remains a clinical challenge associated with poor outcomes for patients who have PDAC treated with multi-agent NAC.

Mitomycin C in the treatment of early triple-negative locally advanced BRCA-associated breast cancer

Rationale. BRCA1 associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. At the same time, carcinomas that develop in carriers of BRCA1 mutations are characterized by extremely high sensitivity to DNA-damaging chemotherapy. Mitomycin C alone or in combination with platinum agents has already demonstrated promising results in the treatment of BRCA-associated ovarian cancer (OC) and metastatic breast cancer. In this article, we present the results of a retrospective study aimed at comparing standard neoadjuvant chemotherapy regimens (NACT) with mitomycin-based regimens for primary locally advanced BRCA1-associated TNBC.The aim of the study is to determine the effectiveness of the combination of mitomycin and platinum compounds during neoadjuvant therapy in patients with primary locally advanced BRCA1 – associated TNBC.Materials and methods. The study included 89 patients diagnosed with primary locally advanced BRCA1-associated TNBC. Patients were divided into three groups depending on the therapy: 1) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel (n = 48) (AC + T), 2) 4 cycles of anthracycline and cyclophosphamide followed by 12 weekly injections of paclitaxel and carboplatin (n = 27) (AC + TCbP), 3) mitomycin C plus platinum followed by 12 weekly injections of paclitaxel (n = 14) (MR + T). Pathological complete response (pCR) rates were compared.Results. The pCR rate in the MP+T group was 10/14 (71%). In patients with BRCA1-associated breast cancer who received AC + T and AC + TCbP regimens as NACT, the pCR rate was 17/48 (35%) and 19/27 (70%), respectively. The difference in pCR rate between mitomycin-containing therapy and the standard AC + T regimen was statistically significant (p = 0.03); the frequency of regressions was comparable to the frequency in the AC + TCbP group. During the 20-month follow-up period, no relapses were observed in the MR + T group. Relapses were more frequent in the AC + T group compared with the AC + TCbP group (16/48 (33%) vs 1/27 (4%), p = 0.003, Fisher’s exact test). The toxicity profile of the mitomycin-containing regimen included hematologic adverse events, the most common of which were anemia and leukopenia. Compared to standard regimens, nausea was significantly less pronounced. No patients reported alopecia with this regimen.Conclusions. The addition of mitomycin C to neoadjuvant therapy for BRCA1-associated TNBC may be a promising treatment option for this category of patients and merits further study.

Abstract PO1-02-09: Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for breast cancer

Abstract Background. Determining the most effective drug therapy regimens is one of the top priorities in the individualization of the treatment of patients with breast cancer (BC). Achievement of pathological complete response (pCR) is important prognostic factor, and used as the surrogate primary end point in many clinical trials. According to the literature, the achievement of pCR after neoadjuvant systemic treatment (NST) in breast cancer varies from 30 to 70%. Patients who do not achieve pCR require post-neoadjuvant treatment, even when reaching minimal size of residual tumors. Initially, primary minimal tumors are characterized by high survival rates, which are proved by international and domestic studies. It is required to clarify the survival rates in the presence of a minimal residual tumor (ypT &amp;lt; 10mm) after neoadjuvant systemic therapy and to compare with primary minimal forms of breast cancer (pT1a-b N0M0), characterized by the most favorable prognosis. Objective. Improvement of the effectiveness of treatment of residual minimal forms (ypT1a-b) of BC after NST. Determination of the correlation between the schemes of NST and the rates of tumor response based on the results of postoperative pathological reports including RCB scale. Methods. The study included 602 patients aged 18–65 years with early and locally advanced I–IIIC stage T1-3N1-3M0 breast cancer,who underwent complex or combined treatment. This study included patients treated at the N.N. Petrov National Medical Research Center of Oncology from 2015 to 2021 Conclusion. After reaching a complete pathomorphological response of the tumor to NST (RCB 0), the 5-year disease-free (DFS) and overall (OS) survival rates (DFS – 78.5%; OS 90.4%) were inferior to the survival rates of patients with primary minimal breast cancer (pT1ab N0M0) [DFS – 86.4%; OS – 98.6%]. Neoadjuvant chemotherapy regimens that allow achieving a pathological complete response in triple-negative and HER2- positive breast cancer have been defined. An assessment of adverse factors that affect the effectiveness of breast conserving treatment and correlate with a deterioration in overall survival was performed. Results. Our data analysis revealed that the survival rates (DFS and OS) of patients with minimal residual tumor after neojuvant systemic therapy were not comparable with those in the group of patients with primary minimal breast cancer. Data analysis revealed the most effective combinations of drugs expressed in the rates of pathomorphological response according to the RCB scale. An assessment of adverse factors that affect the effectiveness of organ-preserving treatment and correlate with a deterioration in overall survival was performed. Citation Format: Roman Pesotsky, Vladimir Semiglazov, Petr Krivorotko, Tengiz Tabagua, Konstantin Zernov, Alexander Emelyanov, Viktoria Mortada, Nikolay Amirov, Daria Ulrikh, Valerii Levchenko, Yana Bondarchuk, Diana Enaldieva, Nestan Bekkeldieva, Konsantin Zirov, Sergey Yerechshenko, Vladislav Evseev, Kirill Rychagov, Sergey Novikov, Maria Kazantseva, Larisa Gigolaeva, Elena Zhiltsova, Denis Nesterov, Olga Ivanova, Tatiana Semiglazova. Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-09.

Abstract PO5-17-08: Real world outcomes of neoadjuvant chemotherapy in ER-positive/PR-positive, HER2-negative breast cancer

Abstract Background: Neoadjuvant chemotherapy is utilized to downstage locally-advanced estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+), HER2-negative breast cancer despite modest pathological complete response (pCR) rates. The two most commonly utilized regimens include docetaxel plus cyclophosphamide (TC) or dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (ddAC-T). Given few head-to-head comparisons of neoadjuvant TC with ddAC-T in this population, we performed a real world data analysis. Methods: 148 patients with ER+/PR+, HER2-negative breast cancer were included in the analysis. The patients were divided into two groups based on the neoadjuvant chemotherapy regimen used (TC vs ddAC-T) and the clinical responses to chemotherapy were categorized as complete, partial, no response/stable, or progressive disease. We examined the differences or associations in demographics, clinical characteristics, overall survival (OS), and invasive disease-free survival (IDFS) between TC and ddAC-T neoadjuvant chemotherapy. pCR was defined as the absence of invasive carcinoma in breast and lymph nodes (ypT0/ypTis and ypN0). Partial response was defined as a decrease in either or both T and/or N stage, compared to pre-treatment evaluation; no response was defined as no change in either T or N categories; and progressive disease was defined as an increase in either the T or N staging at time of pathologic evaluation. Results: The median age of participants was 55 years (range 28-78 years). 67% had clinical stage II disease, while 26% had stage III. 130 participants received neoadjuvant ddAC-T while 18 participants received TC. The ddAC-T group had 7% patients who achieved a pCR and 37% with a partial response, compared to the TC group with 0% of patients with a pCR and 33% with a partial response. The TC group had a higher rate of progressive disease, compared to the ddAC-T group (67% versus 20%). On univariate analysis, the choice of neoadjuvant chemotherapy was not predictive of pathologic response (p = 0.3864). As expected, premenopausal status was associated with a higher likelihood of a pathologic response with an odds ratio of 2.917 (95% CI: 1.465-5.809). On multivariate analysis, chemotherapy regimen was not predictive of pathologic response (p = 0.6047), after controlling the effects of age and menopausal status. No significant difference was noted in OS or IDFS at 24 and 48 months between the ddAC-T and TC groups. On multivariate analysis, controlling for BMI, ER, PR, race, and ECOG performance status, the choice of chemotherapy was not predictive of IDFS. Non-white participants appeared to have inferior IDFS (HR = 2.956, 95% CI: 1.208, 7.238, p-value = 0.0177). Conclusion: In this single-center retrospective analysis, we show real world outcomes of the use of neoadjuvant chemotherapy regimens among patients with ER+/PR+, HER2-negative breast cancer. Both ddAC-T and TC had low pCR rates, 5.98% and 0%, respectively. However, there was no statistical difference between IDFS or OS when comparing the two chemotherapy regimens. More data are needed to optimize neoadjuvant treatment in this patient population and to determine whether anthracyclines can be avoided. Table. Pathologic responses The results (summarized by odds ratio (OR) and its 95% CI) from logistic regression on the pathological responses (complete and partial). Citation Format: Matthew Kurian, Marcus Trybula, Kanchi Patell, Gregory Guzik, Seunghee Margevicius, Pingfu Fu, Alberto Montero, James Martin. Real world outcomes of neoadjuvant chemotherapy in ER-positive/PR-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-08.

Abstract PO5-15-04: MammaPrint index predicts neoadjuvant chemosensitivity in patients with HR+HER2- early-stage breast cancer in the real-world evidence FLEX study

Abstract Background: Neoadjuvant chemotherapy (NCT) yields low pathologic complete response (pCR, ypT0/is ypN0) rates in hormone receptor positive (HR+), HER2- early-stage breast cancer (ESBC). Genomic signatures may predict chemosensitivity and treatment benefit better than receptor status based clinical subtyping. The 70-gene expression signature, MammaPrint (MP), classifies patients with ESBC as having a High or Low Risk of distant recurrence. In the NBRST and ISPY2 trials, further stratification of MammaPrint High Risk into High 1 (H1) or High 2 (H2) showed significantly higher pCR rates to NCT or targeted agents in MP H2 cancers compared to MP H1 tumors. We evaluated MammaPrint H1 and H2 status as a biomarker for neoadjuvant chemosensitivity in patients with HR+HER2- ESBC enrolled in the real-world evidence FLEX study. Methods: FLEX (NCT03053193) is an ongoing prospective, observational trial that has currently enrolled 12,328 patients with ESBC who were tested with MammaPrint as standard of care, with or without molecular subtyping signature, BluePrint (BP), and consented to clinically annotated full genome data collection (data locked Feb. 2023). Patients with HR+HER2-, MP High Risk tumors who received NCT (majority received AC-T) and had pCR data available were included in this analysis (n = 214). Patients were stratified into MP H1 (index 0.000 to -0.569) and H2 (index -0.570 to -1.000) groups. BP classified MP High Risk tumors into Luminal B-, HER2-, or Basal-Type. Differences in clinical characteristics and pCR rates between H1 and H2 tumors was assessed by Chi-Squared test and two-sided proportional z-test, respectively. The association between MP H1 and H2, BP subtype, and pCR was assessed using logistic regression and was adjusted for age, race, grade, T stage, N stage, and NCT regimen. Results: MammaPrint classified 142 (66%) cancers as H1 and 72 (34%) as H2 tumors. Age, menopausal status, race, tumor stage, and lymph node status were comparable between both groups. Although most H2 tumors (78%) were Grade 3, only 59% of all Grade 3 tumors were H2. Nearly all (98%) H1 tumors were Luminal B whereas for H2 tumors, 51% were Luminal B and 49% were Basal by BP classification. pCR rate was significantly higher in H2 tumors (29.2%) compared to H1 tumors (6.3%, p &amp;lt; 0.01) (Table). Basal-Type, H2 tumors (n=35) exhibited the highest pCR rate of 37.1%. Among BP Luminal B tumors, those with MP H2 tumors had a significantly higher pCR rate (21.6%) vs. MP H1 tumors (5.8%, p = 0.003). Multivariate analysis revealed MP H2 (OR=4.91, p=0.003) and BP Basal-Type (OR=3.54, p=0.03) were significantly associated with likelihood of pCR, whereas clinical variables were not associated with pCR. Conclusion: These data demonstrate MammaPrint and BluePrint utility to predict the likelihood of achieving pCR after NCT in HR+HER2- ESBC. Although both MP High Risk groups exhibit chemosensitivity, High 2 tumors have higher chemosensitivity than High 1 tumors. MP High 2 status can be utilized to identify ER+ patients who are the most likely to experience pathologic downstaging and pCR after NCT. Also, patients with High 2 tumors treated with PD-L1 or PARP inhibitors in the ISPY2 trial exhibited significantly higher pCR rates than those observed for High 2 tumors treated with NCT alone. These data suggest that for patients with MP High 2 tumors, neoadjuvant use of chemotherapy is appropriate and these patients may further benefit from the addition of targeted agents to standard NCT. Table: Distribution of pCR rates among MammaPrint H1 and H2 and BluePrint molecular subgroups Data presented as # of patients with pCR/(total # patients in subgroup) and as percentage Citation Format: Joyce O'Shaughnessy, Lajos Pusztai, Cathy Graham, Pat Whitworth, Peter Beitsch, Cynthia Osborne, Rakhshanda Rahman, Andrea Menicucci, William Audeh, FLEX Investigators' Group. MammaPrint index predicts neoadjuvant chemosensitivity in patients with HR+HER2- early-stage breast cancer in the real-world evidence FLEX study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-04.

Abstract PO5-01-02: A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III

Abstract Background In 2018 the TRAIN-2 clinical trial demonstrated that in stage II–III HER2-positive breast cancer, the use of a neoadjuvant non-anthracycline chemotherapy regimen of 9 cycles of TCHP [paclitaxel and carboplatin (AUC 6 mg/mL/min) with trastuzumab and pertuzumab resulted in lower toxicity and comparable pathological complete responses to an anthracycline based regimen. A pathological complete response was recorded in 141 (67%) of 212 patients in the anthracycline group and in 140 (68%) of 206 in the non-anthracycline group. Our primary aim was to identify rates of pathological complete response and rates of toxicity with a less intensive regimen of 6 cycles of TCHP where carboplatin was dose adjusted to AUC5. Methods In this single center cohort study, we reviewed patients with stage II-III Her2-positive breast cancer who received a modified chemotherapy regimen of 6 cycles of neoadjuvant paclitaxel (80 mg/m2 days 1 and 8) and reduced dose of carboplatin (AUC= 5 mg/mL/min) with trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks from 2021- June 2023. Clinicopathologic data, the number and length of treatment delays, treatment related toxicities of all grades, and pCR rate were extracted from the electronic medical record. Results 32 patients were included in the analysis. The median age of the cohort was 51 years (30-65). No patient had a BRCA mutation. 20 (62.5%) had T1-2 disease and 12 (37.5%) had T3-4 disease. 14(43.75%) patients had N0 disease and 20 (62.5%) had N1-3 disease. ECOG Performance status was 0, 1 and 2 in 26 patients (81.25%), 4 (12.5%) patients and 2(6.25%) patients respectively. At the time of analysis, 2 patients (6.25%) were continuing active treatment, while 30 (93.75%) had completed planned neoadjuvant therapy and underwent surgery. Of patients who completed planned neoadjuvant therapy, 6 patients (18.75%) had 1 or more hospitalisations due to toxicity. 10 patients (31.25%) required dose reductions and 3(9.38%) had early treatment discontinuation. Rates of adverse events will be presented. pCR rate was 60 % (N=18/30). 19 (63%) of 30 patients underwent mastectomy and 11 (36.7%) underwent breast-conserving surgery. Updated analysis will be included at time of presentation. Conclusion In this single-center retrospective study of patients receiving a modified version of TCHP we found a 60% pCR rate. The rate of dose reductions and treatment discontinuations appears favorable with use of this modified regimen. This was in a heterogeneous population of patients treated in routine clinical practice where there was a high rate of patients with locally advanced disease. Limitations of our study include immaturity of data and small sample size; however, these data warrant further exploration through longer-term follow-up and multi-center validation. Citation Format: Carolyn Moloney, Maggie Louise O'Connor, Caroline O'Leary, Aislinn Reilly, Simon Barry, David O'Reilly, Philip Bredin, Hadia Paryani, David Solaligue, Bryan Hennessy, Megan Greally, Patrick G. Morris. A retrospective review of pathological complete response and toxicity rates to a modified version of TCHP (Paclitaxel, Trastuzumab, Pertuzumab, Carboplatin) for HER2 positive breast cancer stage II and III [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-02.

Abstract LBO1-03: Randomized Phase II Study of Neoadjuvant Nivolumab (N) 2 week lead-in followed by 12 weeks of concurrent N+carboplatin plus paclitaxel (CbP) vs concurrent N+CbP in Triple Negative Breast Cancer (TNBC): (BCT1902/IBCSG 61-20 Neo-N)

Abstract Background: A previous clinical study suggested that a priming dose of programmed cell death ligand 1 (PD-L1) inhibitor monotherapy 2 weeks prior to addition of chemotherapy could be more efficacious than starting all agents concurrently. Furthermore, the addition of checkpoint therapy may allow shorter chemotherapy duration in selected patients. The aim of this study was to investigate the strategies of lead-in Nivolumab (N) monotherapy and starting concurrent N with 12 weeks of carboplatin and paclitaxel in TNBC. Methods: In this multicenter Phase II study, eligible patients with stage I (cT1c)-II TNBC were randomized to receive either Arm A (lead-in): N 240 mg monotherapy, followed 2 weeks later by N 360mg + carboplatin (AUC 5) every 21 days x 4 cycles + weekly paclitaxel (80 mg/m2) for 12 weeks; or Arm B (concurrent): same agents initiated concurrently given over 12 weeks, followed 2 weeks later by N 240mg monotherapy, prior to surgery. The primary endpoint was pathological complete response (pCR ypT0/Tis ypN0). Secondary endpoints are residual cancer burden (RCB), safety, response according to baseline stromal tumor infiltrating lymphocytes (sTILs) quantity and PD-L1 expression and event-free survival (EFS). sTIL high was defined as ≥30% and PD-L1 positive as ≥1% (SP142 assay). A non-comparative Simon two-stage design was used to test the null hypothesis, in each Arm separately, of a pCR rate ≤40% vs an alternative pCR rate of ≥60% with 90% Confidence Intervals (CI). No adjuvant N was given, and adjuvant chemotherapy was at the discretion of the investigator in case of non-pCR. Results: 110 patients were randomized from July 2020 to April 2022; 108 patients who initiated treatment were analyzed. Baseline characteristics: median age was 49yrs (IQR 43-60yrs), 16.7% had node-positive disease, 34.3/64.8% had stage I/II disease, 33.3% were sTIL high and 47.2% were PD-L1 positive. For Arms A and B respectively, pCR rates were 50.9% (90% CI:39.0-63.2) and 54.5% (90% CI:42.7-66.2) with an overall pCR rate of 52.8% (90% CI:44.4-61.0). The RCB 0+1 rates were overall 68.5% (90% CI: 60.4-75.9); with 64.2% (90% CI: 52.0-75.1) and 72.7% (90% CI: 61.2-82.4) for Arms A and B respectively. Overall, in the sTIL high vs low subgroups, pCR was 66.7% (CI: 51.7-79.5) vs 45.7% (CI: 35.5-56.2%), and in the PD-L1 positive vs negative subgroups, pCR was 70.6% (CI: 58.4-80.9) vs 33.3% (CI: 21.8-46.6) respectively. pCR was 48.6% in stage I and 54.9% in stage II. Treatment-related adverse events were similar in both arms, with grade 3-4 adverse events in 64.8% patients. Early discontinuation of N occurred in 17 patients (15.7%). Immune related endocrine dysfunction (any grade) was observed in 22 patients (20.4%). Conclusion: The pCR rates exceeding 50% support that 12 weeks of a neoadjuvant non-anthracycline chemotherapy regimen with nivolumab is efficacious for Stage I/II TNBC with either concurrent or lead-in N. This study did not support the hypothesis that lead-in N was associated with a pCR advantage. The regimen was well tolerated, with no new safety signals. Patients with immune enriched tumors, identified by high sTILs or PD-L1 positivity, had very high pCR rates, identifying a subpopulation for whom a 12 week anthracycline-free chemotherapy regimen with N may be appropriate. EFS results are still maturing. Citation Format: Sherene Loi, Samuel Niman, Nicholas Zdenkowski, Prudence Francis, Sally Baron Hay, William Fox, Kevin Punie, Alexander M Menzies, Rebecca Angus, Carlie Mavin, Lauren Rennie, Isobel Stoodley, Bruce Mann, Marion JJ Kuper-Hommel, Meredith Regan. Randomized Phase II Study of Neoadjuvant Nivolumab (N) 2 week lead-in followed by 12 weeks of concurrent N+carboplatin plus paclitaxel (CbP) vs concurrent N+CbP in Triple Negative Breast Cancer (TNBC): (BCT1902/IBCSG 61-20 Neo-N) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-03.

Abstract PO2-16-12: Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival

Abstract Introduction: Breast cancer is the most common malignancy among women in Brazil and worldwide. Neoadjuvant chemotherapy (NAC) has been increasingly used for the treatment of breast cancer conditions ranging from locally advanced tumors to early-stage triple-negative and HER-2 positive tumors. Nowadays only 5% of breast cancer patients are enrolled in clinical trials. Real-world data is important to evaluate how clinical trial treatments behave in the real world with all the heterogeneous patient characteristics of those treated differently from the homogeneity of clinical trials. Objectives: To evaluate the rates of pathological complete response (pCR) in patients undergoing neoadjuvant chemotherapy (NAC) for the treatment of breast cancer (BC) To examine the differences in pathological complete response (pCR) rates between HER-2 positive breast cancer patients with and without trastuzumab treatment, and between triple-negative breast cancer (TNBC) patients with and without platinum-based treatment, Additionally, we aim to assess the impact of pCR on overall survival (OS) and disease-free survival (DFS) using real-world data (RWD). Methods: This was a retrospective, multicentric cohort study, that included female patients over 18 years of age, with a diagnosis of non-metastatic breast cancer undergoing NAC. As an exploratory real-world data study, no confirmatory hypothesis was established, so no corrections for multiple comparisons were necessary. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method calculated at five years. Additionally, we conducted a multivariate analysis to identify significant associations with pathologic complete response (pCR) and overall survival (OS). We employed a forest plot to visually represent these associations Results: From 2011 to 2020, 1,891 patients were included in the study, and 421 (22,3%) achieved pCR (ypT0 ypN0) and considering the presence of residual in situ carcinoma (DCIS) the pCR was seen in 467 patients (23,5) without significant difference (p=0,567) . The pCR rate varied between the subtypes: luminal A 17,0%, luminal B 21,3%, luminal HER2 23,0%, TNBC 22,5% and HER2 28,5% (p = 0,057). The type of neoadjuvant chemotherapy (NAC) regimen was correlated with pathological complete response (pCR). Among HER2-positive patients, those who received Trastuzumab had a significantly higher rate of pCR compared to those who did not receive it (p &amp;lt; 0.0001). Similarly, in patients with TNBC, those who underwent treatment with platinum-based regimens also showed higher rates of pCR (p &amp;lt; 0.0001). There were 694 deaths, and the 5-year OS rate was 62.9%. OS was also grouped according to pCR status, and pCR OS rate was 88,3% and non-pCR 58.1% significant difference observed (p &amp;lt; 0.0001). Five-year DFS of pCR was 92.2% and non-pCR 64.3% (p &amp;lt; 0.0001). Conclusion: this real-world data study evaluated the rates of pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The results revealed varying pCR rates among different breast cancer subtypes, with HER2-positive and triple-negative subtypes showing higher rates. The use of Trastuzumab in HER2-positive patients and platinum-based regimens in triple-negative patients correlated with significantly higher pCR rates. Furthermore, achieving pCR was associated with improved overall survival (OS) and disease-free survival (DFS). These findings emphasize the importance of considering individual tumor characteristics and tailoring treatment strategies for breast cancer patients to optimize outcomes. Clinicopathological characteristics of patients AJCC, American Joint Committee on Cancer; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; TNBC triple negative breast cancer. NAC schemas and correlation with pCR. AC-T, doxorubicin + cyclophosphamide – taxane; AC-TPlatinum, doxorubicin + cyclophosphamide – taxane+carboplatin; AC-TH, doxorubicin + cyclophosphamide – taxane+herceptin. Citation Format: Marcelo Antonini, Andre Mattar, Fernanda Grace Bauk Richter, Gabriel Pannain, Andressa Amorim, Marina Diogenes, Odair Ferraro, Luiz Gebrim, Reginaldo Coelho Lopes, Juliana Real. Real world evidence of neoadjuvant chemotherapy for breast cancer treatment in a Brazilian multicenter cohort: correlation of pathological complete response and overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-12.

Abstract PO3-01-12: Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy

Abstract Background: The evolution of Neoadjuvant chemotherapy(NAC) regimen has enabled the down-staging of locally advanced breast cancer, allowing patients to undergo breast conserving surgery. NAC is known to be effective in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. However, the role of NAC in hormone receptor-positive and HER2-negative (HR+HER2-) breast cancer patients remains unclear. In this study, we aimed to explore the utility of NAC for estrogen receptor-positive and HER2-negative (ER+HER2-) breast cancer patients. Methods: Clinical data were collected from 120 patients who were diagnosed with estrogen receptor (ER)-positive and HER2-negative breast cancer and received neoadjuvant chemotherapy between July, 2017 and April, 2023 at Seoul St Mary’s Hospital (Seoul, Korea). We analyzed the factors that affect clinical response subgroups, including pathologic complete response (pCR), partial response (PR), stable disease(SD), and progressive disease (PD), following neoadjuvant chemotherapy. The median follow-up period was 17 months. &amp;lt; Results: Among 120 patients after NAC, 5.8% achieved pCR, while 67.5% had a partial response. The median age at the time of surgery was 55 years at pCR group, 49 years at PR group, 47 years at SD group, and 49 years at PD group. Although the age of patients achieving pathological complete response was higher, this differences was not statistically significant. Patients achieving pCR had a higher incidence of progesterone receptor (PR) negativity (pCR 71.4% vs PR 30.9%, p=0.011) and higher levels of Ki-67 expression than those who did not achieve pCR (71.7% vs 35.6%, p=0.003). Also, there was no significant difference in Androgen receptor (AR) and HER-2 expression between the groups. Tumor size was also significantly associated with clinical response (p=0.003). However, no differences in clinical response was observed between patients with lymph node metastasis (p=0.221). Our analysis of 107 patients who were clinically N positive before NAC showed that the Ki-67 index level was the only factor found to affect nodal pCR. In addition, in the non-pCR group, patients with a Ki-67 index of less than 20% after neoadjuvant had a significantly better disease-free survival (5yr DFS, 79.8% vs 65.9%, p=0.039) Conclusion: Our analysis revealed that patients with higher levels of Ki-67 and lower level of PR expression were more likely to achieve pCR or PR. Also, decrease in Ki-67 index was confirmed to be an important prognostic factor of ER+ HER2- breast cancer. A combination of clinical and molecular factors, such as tumor size, progesterone receptor expression, and Ki-67 expression, can be used to optimize treatment plans and improve outcomes for the patient population. Citation Format: Jin Ah Lee, Young Joo Lee, Dooreh Kim, Chang Ik Yoon, Woo-Chan Park, Soo Youn Bae. Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-12.

Abstract PO1-28-09: Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis

Abstract Background: Neoadjuvant chemotherapy (NACT) has been more frequently used in breast cancer, but it’s controversial whether NACT or adjuvant chemotherapy (ACT) is more effective in improving survival outcomes for triple-negative breast cancer (TNBC) patients. Recent studies also proposed pathologic complete response (pCR) could not be a robust surrogate for survival outcomes in certain types of breast cancer. To address these questions, a general meta-analysis and a network meta-analysis (NMA) were conducted to compare the survival outcomes of patients with pCR, non-pCR after NACT and ACT. The cut-off pCR rate was also declared to indicate when NACT produces equivalent survival outcomes to ACT (Registration: PROSPERO CRD42022336732). Methods: Databases including PubMed, Embase, Web of science and Cochrane library were searched up to June 2023 to investigate studies comparing NACT and ACT, as well as randomized controlled trials (RCTs) comparing different regimens in NACT or ACT settings in early operable TNBC patients. Heterogeneity was assessed using χ² based Q-test and I², combined with hazard ratios (HRs) with 95% confidence intervals (CI) computed for overall survival (OS), and disease-free survival (DFS, or event-free survival). The NMA with a Bayesian framework was conducted using both random and fixed effect model. The Weighted Least Square method and the Least Absolutely Deviation method were used to determine the cut-off pCR rates of OS and DFS. Results: A total of 35 studies involving 21 RCTs and 34143 TNBC patients were included. The general meta-analysis comprised 14 cohort studies. Eight high-quality cohort studies with propensity score matching and 21 RCTs were included in NMA. The pooled pCR rate for NACT was 42.2% (95% CI 37.8%-46.8%). Overall, the NACT cohort showed significantly worse OS and DFS than ACT cohort (HR=1.67, 95% CI 1.22-2.31; HR=1.37, 95% CI 1.14-1.64). However, patients with pCR after NACT showed improved OS than ACT (HR=0.58, 95% CI 0.50-0.66), while the patients without pCR after NACT had pooper OS than ACT (HR=2.03, 95% CI 1.88-2.19). As for DFS, there was no statistically difference between pCR after NACT and ACT groups (HR=1.04, 95% CI 0.63-1.73), while patients without pCR after NACT had significantly worse DFS than ACT (HR=2.65, 95% CI 1.98-3.55). From the NMA, the OS and DFS were better when combining modern target therapy such as Bevacizumab, PARPi, and PD-1/PD-L1 inhibitor (Figure 1), but not achieving pCR completely negated the benefits of newer drugs. Adding adjuvant capecitabine to patients not achieving pCR seemed to favor the OS. It was predicted that when the pCR rates were 64.7% and 46.9% (Figure 2), respectively, the OS and DFS of patients treated with NACT would be the same as those of patients treated with ACT. Conclusions: Higher pCR rate after NACT was associated with improved OS compared with ACT in TNBC patients. However, failure to achieve pCR after NACT resulted in worse survival outcomes than ACT. NACT had similar survival outcomes with ACT only when the pCR rate was at least 46.9%. The development of effective NACT regimens is beneficial for breast cancer patients. Figure 1. Forest plot of the Hazard Ratio for OS and DFS in TNBC patients pCR: pathological complete response; Bev: Bevacizumab; Pt: platinum; NACT: neoadjuvant chemotherapy; ACT: adjuvant chemotherapy; vel: veliparib; PDi:PD1/PDL1 inhibitor; X: capecitabine Figure 2. The cut-off value of pCR when NACT and ACT have the same Hazard Ratio based on OS and DFS. pCR: pathological complete response; Bev: Bevacizumab; Pt: platinum; NACT: neoadjuvant chemotherapy; ACT: adjuvant chemotherapy Citation Format: Xiaoying Qiao, Shu Wang, Taobo Hu, Baosheng Liang. Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-09.

Abstract PO5-03-05: Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis

Abstract Background: Neoadjuvant chemotherapy (NACT) has been more frequently used in breast cancer, but it’s controversial whether NACT or adjuvant chemotherapy (ACT) is more effective in improving survival outcomes for triple-negative breast cancer (TNBC) patients. Recent studies also proposed pathologic complete response (pCR) could not be a robust surrogate for survival outcomes in certain types of breast cancer. To address these questions, a general meta-analysis and a network meta-analysis (NMA) were conducted to compare the survival outcomes of patients with pCR, non-pCR after NACT and ACT. The cut-off pCR rate was also declared to indicate when NACT produces equivalent survival outcomes to ACT (Registration: PROSPERO CRD42022336732). Methods: Databases including PubMed, Embase, Web of science and Cochrane library were searched up to June 2023 to investigate studies comparing NACT and ACT, as well as randomized controlled trials (RCTs) comparing different regimens in NACT or ACT settingsin early operable TNBC patients. Heterogeneity was assessed using χ² based Q-test and I², combined with hazard ratios (HRs) with 95% confidence intervals (CI) computed for overall survival (OS), and disease-free survival (DFS, or event-free survival). The NMA with a Bayesian framework was conducted using both random and fixed effect model. The Weighted Least Square method and the Least Absolutely Deviation method were used to determine the cut-off pCR rates of OS and DFS. Results: A total of 35 studies involving 21 RCTs and 34143 TNBC patients were included. The general meta-analysis comprised 14 cohort studies. Eight high-quality cohort studies with propensity score matching and 21 RCTs were included in NMA. The pooled pCR rate for NACT was 42.2% (95% CI 37.8%-46.8%). Overall, the NACT cohort showed significantly worse OS and DFS than ACT cohort (HR=1.67, 95% CI 1.22-2.31; HR=1.37, 95% CI 1.14-1.64). However, patients with pCR after NACT showed improved OS than ACT (HR=0.58, 95% CI 0.50-0.66), while the patients without pCR after NACT had pooper OS than ACT (HR=2.03, 95% CI 1.88-2.19). As for DFS, there was no statistically difference between pCR after NACT and ACT groups (HR=1.04, 95% CI 0.63-1.73), while patients without pCR after NACT had significantly worse DFS than ACT (HR=2.65, 95% CI 1.98-3.55). From the NMA, the OS and DFS were better when combining modern target therapy such as Bevacizumab, PARPi, and PD-1/PD-L1 inhibitor, but not achieving pCR completely negated the benefits of newer drugs. Adding adjuvant capecitabine to patients not achieving pCR seemed to favor the OS. It was predicted that when the pCR rates were 64.7% and 44.6%, respectively, the OS and DFS of patients treated with NACT would be the same as those of patients treated with ACT. Conclusions: Higher pCR rate after NACT was associated with improved OS compared with ACT in TNBC patients. However, failure to achieve pCR after NACT resulted in worse survival outcomes than ACT. NACT had similar survival outcomes with ACT only when the pCR rate was at least 44.6%. The development of effective NACT regimens is beneficial for breast cancer patients. Citation Format: Xiaoying Qiao, Taobo Hu, Baosheng Liang, Shu Wang. Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-05.

Abstract PO3-22-07: Predicting Additional Axillary Metastases in Breast Cancer Patients with Positive Targeted Axillary Dissection Lymph Nodes after Neoadjuvant Treatment

Abstract Background: Neoadjuvant chemotherapy (NACT) is increasingly used for axillary downstaging in clinically node-positive breast cancer patients, and a considerable proportion achieves axillary pathological complete response (ax-pCR). After NACT, axillary staging can be done by targeted axillary dissection (TAD). In case of metastases at TAD, axillary lymph node dissection (ALND) is offered regardless of metastases size. This contrasts primary surgery, where small sentinel node metastases (ypN0(i) and ypN1mi) and ≤2 positive sentinel nodes do not confer ALND, although a proportion of patients with small metastases have additional metastatic lymph nodes (LNs) in the axilla. So far, the residual metastatic burden in the axilla when TAD LNs are positive after NACT is unknown. If subgroups of patients with low residual metastatic burden in the axilla (non-TAD LNs) could be identified, these subgroups may be offered de-escalated axillary treatment. Therefore, we investigated the risk of residual metastatic burden in the axilla when the TAD LNs harbored metastases. Methods: We retrospectively retrieved DBCG data on patients staged by TAD after NACT in Denmark between 1.1.2016-31.8.2021. We registered: age, breast biopsy date, type of surgery, type of axillary surgery, count of LNs, sentinel nodes, and marked lymph nodes with and without metastases, including metastasis size, breast tumor histology and receptor subtype, breast tumor size at diagnosis and in the surgical specimen, malignancy grade and type of neoadjuvant treatment. We excluded patients with inflammatory breast cancer, &amp;lt; 4/&amp;gt;8 cycles of NACT, or a non-standard NACT regimen. The primary outcome was risk factors for having high ( &amp;gt;3), low (1-3), or no residual metastatic burden in the axilla when the TAD LNs harbored metastases. We modeled risk factors for both high and low residual metastatic burden in the axilla using multivariable logistic regression and constructed risk models based on the regression coefficients. Results: We identified 1626 patients receiving NACT and TAD in the inclusion period. After excluding ineligible patients and patients who achieved ax-pCR with no subsequent ALND (46%), the study included 383 patients with positive LNs at TAD for further analysis: thereof 188, 127, and 68 with 0, 1-3 and &amp;gt;3 positive non-TAD LNs, respectively. In the adjusted logistic regression analysis, we found that breast pCR (OR= 0.06, 95% CI &amp;lt; .01-0.41, p &amp;lt; .001) and a low proportion of positive TAD LNs (0-66% vs &amp;gt;66%) (OR=0.32, 95% CI 0.17-0.58, p = &amp;lt; .001) were associated with low risk of high residual metastatic burden in the axilla. Patients with one or both low-risk factors present had an 8% (14 of 176 patients) risk of high residual metastatic burden in the axilla. The predictive value of the model for having &amp;lt; 3 non-TAD LN metastases was 92%. When analyzing the 315 patients with ≤3 positive non-TAD LNs, the adjusted logistic regression analysis of 1-3 vs 0 positive non-TAD LNs showed that ypN0(i) in the TAD LN (OR=0.14, 95% CI 0.04-0.53, p = 0.002), small tumor size at diagnosis (20-49 mm vs ≥ 50 mm) (OR = 0.29, 95% CI 0.14-0.60, p = 0.002), breast pCR (OR= 0.38, 95% CI 0.15-0.98, p = 0.04) and low proportion of positive TAD LNs (33-66% vs &amp;gt;66%) (OR= 0.46, 95% CI 0.27-0.77, p = 0.01) were associated with no residual metastases in the axilla. Using these risk factors, 19% (11/58) of the patients in the lowest risk quartile had further metastatic spread to the axilla. Conclusion: Based on an extensive breast cancer registry, we find that breast pCR, low proportion of positive TAD LNs, small metastases, and small tumor size are associated with low risk of residual metastatic LNs in the axilla when the TAD LNs are positive after NACT. With these risk factors, we propose two models to identify patients with low non-TAD residual metastatic burden and patients with a high likelihood of no further metastases. The models can guide breast surgeons in de-escalating axillary treatment in these groups. Citation Format: Frederikke Munck, Maj-Britt Jensen, Ilse Vejborg, Maria Gerlach, Maja Maraldo, Niels Kroman, Tove Tvedskov. Predicting Additional Axillary Metastases in Breast Cancer Patients with Positive Targeted Axillary Dissection Lymph Nodes after Neoadjuvant Treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-22-07.

Abstract PO5-18-02: A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality

Abstract Background Most patients with high-risk non-metastatic breast cancer are treated with neoadjuvant chemotherapy (NAC), which includes the administration of anthracyclines. The omission of anthracyclines was shown to be associated with excellent outcomes in selected patients. However, the extent to which anthracyclines are omitted among a population of women treated with NAC and its impact on mortality remain unclear. Objective To investigate the extent to which anthracyclines are omitted among a population of patients with invasive breast cancer treated with NAC and to examine the impact of non-anthracycline NAC on risks of breast cancer-specific and all-cause mortality. Methods We performed a retrospective population-based cohort analysis using patient-level health administrative data. The cohort includes women aged ≥18 years with stage I – III invasive breast cancer diagnosed between January 2012 and December 2020, treated with NAC and surgery. Patients were excluded if they received &amp;lt; 50% of the planned chemotherapy regimen, had bilateral breast cancer and/or a previous malignancy. The exposure of interest was anthracycline versus non-anthracycline NAC regimen. The primary and secondary endpoints were breast cancer-specific mortality and overall (all-cause) mortality. Multivariable Cox proportional hazards models adjusted by propensity score, and clinical/pathologic variables including a measure of comorbidity was performed to examine impact of omission of anthracyclines on outcomes. Cumulative incidence curves were generated to calculate the 5-year cumulative incidence of breast cancer and all-cause mortality for the whole cohort and in subset analyses, stratified by stage and receptor subtype. Results The cohort includes 4,180 women. Median follow was 62 months (IQR 44-85) and median age was 51 years (IQR 43-60). Most patients had low co-morbidities (96.0%), Stage II (44.1%) or Stage III (47.7%) disease, underwent mastectomy (72.6%), had axillary node dissection (64.4%) and received post-operative radiotherapy (88.8%). 279 (6.7%) individuals were treated with a non-anthracycline NAC and 3,901 (93.3 %) received an anthracycline NAC. Women who received non-anthracycline NAC were older (median 62 years vs. 50 years; p&amp;lt; 0.001), more likely to have stage I-II disease (77.0% vs. 51.3%; p&amp;lt; 0.001), and more likely to have triple-negative breast cancer (TNBC) (14.0% vs. 24.4%; p&amp;lt; 0.001) than those who received anthracyclines.On propensity adjusted multivariable analysis, factors associated with an increased risk of BC mortality include Stage III (HR 9.3, 95%CI 4.5 - 19.2, p&amp;lt; 0.0001) or stage II at presentation (HR 2.57 95% CI 1.24, 5.34, p=.01) (ref: stage I) or triple negative subtype (HR 3.7 95% CI 3.03, 4.51, p&amp;lt; .0001) (ref: hormone positive/HER2-). There was no significant difference in the relative risks of BC death (HR 0.8, 95% CI 0.5-1.27) or all-cause mortality (HR 0.85, 95% CI 0.60-1.21) for patients selected for treatment without anthracyclines compared to those treated with anthracyclines.Overall, among individuals selected for treatment without or with anthracycline NAC there was no significant difference in the 5-year cumulative incidence of BC (15.4% vs 10.5%, P=.05) or all-cause mortality (16.4% vs 11.9%, P=.07). However, the 5-year cumulative incidence of BC specific death (31.8% vs 16.5%, p=.03) and 5-year cumulative incidence of all-cause death (31.8% vs. 18.2%, p=.06) was higher among 420 women with HER2+ Stage III breast cancer who received non-anthracycline versus anthracycline-based chemotherapy. No difference was observed for other subgroups. Conclusions The omission of anthracyclines in NAC for individuals with stage III HER2+ breast cancer was associated with higher cumulative risks of breast cancer and all-cause mortality but no difference was observed for other subgroups. Further research is warranted to better understand in whom anthracyclines can be safely omitted. Citation Format: Danilo Giffoni M. M. Mata, Rinku Sutradhar, Matthew Castelo, Lena Nguyen, Danielle Rodin, Ezra Hahn, Omolara Fatiregun, Cindy Fong, Sabina Trebinjac, Andrea Eisen, Lawrence Paszat, Katarzyna Jerzak, Eileen Rakovitch. A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-02.

Abstract PO3-15-11: Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy

Abstract Assess soluble sFAS, sFASL, sPD1, and sPD-L1 levels in patients with HER2 or triple-negative (TN) breast cancer submitted to neoadjuvant chemotherapy. A prospective cohort study was performed with TN and HER2+ breast cancer patients between 2015 and 2018. Soluble levels of sFasL, sFas, sPD-L1, and sPD1 were collected before and after neoadjuvant chemotherapy (NAC). NAC regimens included a dense dose of Adriablastin and cyclophosphamide during four cycles, followed by Paclitaxel for 12 weeks. No clinical evidence of tumor in the breast and axillary lymph nodes was defined as a pathological complete response (pCR). Twenty-one women with TN (56,7%) and 16 (43,3%) HER2+ breast cancer were included. Twenty-one women (56.7%) presented complete pathological response (pCR) after neoadjuvant chemotherapy (NAC), defined as the absence of invasive disease in the breast and lymph nodes. High sPD1 and sFas levels in the TN and HER2+ patients compared to the control group (P&amp;lt; 0.05). In paired analysis, statistical differences of sFas and sFasL levels in TN and HER2+ patients before and after NAC (P&amp;lt; 0.05). Low levels of sPDL1 in HER2+ patients with pCR compared to non-pCR (P&amp;lt; 0.05). High sFasL levels in TN patients with pCR compared to the non-pCR group (P&amp;lt; 0.05). Conclusion: soluble sFas, sFas-L, sPD1, and sPD-L1 levels were apoptosis-related markers with potential predictive value of neoadjuvant chemotherapy response in TN and HER2+ breast cancer. Keywords: breast cancer; FAS receptor; Programmed death 1, HER2+, Triple negative Citation Format: Carolina Vasconcelos, Marcelo Salgado, Carlos Eduardo Anunciação, Denise Viana, Leuridan Torres, Nathália Valois Montarroyos de Moraes. Soluble sFas, sFasL, sPD1, and sPD-L1 analyses in the blood peripheral of locally advanced breast cancer women before and after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-11.

Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Utility of Initial Tumor Reduction as a Prognostic Factor in Esophageal Squamous Cell Cancer Patients Undergoing Neoadjuvant Chemotherapy Followed by Surgery : A Retrospective Cohort Study.

While a neoadjuvant chemotherapy regimen using docetaxel, cisplatin, and 5-fluorouracil (NAC-DCF) is considered the standard treatment for locally advanced esophageal cancer (EC) in Japan, a reliable marker for early prediction of treatment efficacy remains unclear. We investigated the utility of the tumor response after a first course of NAC-DCF as a post-surgery survival predictor in patients with EC. We enrolled 150 consecutive patients who underwent NAC-DCF followed by surgery for EC between September 2009 and January 2019. The initial tumor reduction (ITR), defined as the percentage decrease in the shorter diameter of the tumor after the first course of NAC-DCF, was evaluated using computed tomography. We analyzed the relationship between ITR, clinicopathological parameters, and survival. The median ITR was 21.07% (range -11.45 to 50.13%). The optimal cut-off value for ITR for predicting prognosis was 10% (hazard ratio [HR] 3.30, 95% confidence interval [CI] 1.98-5.51), based on univariate logistic regression analyses for recurrence-free survival (RFS). Compared with patients with ITR <10%, patients with ITR ≥10% showed a significantly higher proportion of ypM0 (80.0% vs. 92.5%) and responders in terms of overall clinical response (50.0% vs. 80.8%). Multivariate analysis for RFS revealed that ypN2-3 (HR 2.78, 95% CI 1.67-4.62), non-response in terms of overall clinical response (HR 1.87, 95% CI 1.10-3.18), and ITR <10% (HR 2.48, 95% CI 1.42-4.32) were independent prognostic factors. Tumor response after the first course of NAC-DCF may be a good predictor of survival in patients with EC who underwent NAC-DCF plus surgery.