The Schrödinger's Cat Paradox: Can MAMMI PET with 68Ga-FAPI Determine Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Omitting Surgery?

‘Small’ randomised neo-adjuvant chemotherapy trials in breast cancer reporting on pathological response: more harm than good?

Purpose: To evaluate the value of early FDG-PET (18F-Fluorodeoxyglucose-Positron Emission Tomography) metabolic criteria for prediction of pathologic complete response in axilla (pCRAx) after neoadjuvant chemotherapy (NAC) in breast cancer. Methods: Inclusion criteria were all T-stage breast cancers, non-metastatic, with initial lymph node involvement estimated by PET +/- lymph node biopsy, treated with NAC followed by surgery with axillary lymph node dissection (ALND), managed at the George-François Leclerc Cancer Center in Dijon, France, between 2009 and 2019. A PET was performed before and after the first course of chemotherapy (PET1 and PET2). pCRAx was defined as the absence of invasive cells in the nodes at the time of ALND (i.e. ypN0). The Sataloff classification was used as reference on each pathological report. Patients with a Sataloff NA classification (i.e. evidence of therapeutic effect, and no residual disease) and, if axillary involvement was proven at diagnosis, NB (i.e. no metastasis, no therapeutic effect) were considered as pCRAx. The PET metabolic criteria studied in the axilla were: - SUVmax (Standard Uptake Value) on PET1 and PET2 = fixation in the axillary voxel with the highest activity (kBq/mL)/(injected dose (kBq)/weight (g)) - ΔSUVmax (%) = metabolic response after the first course of NAC = 100 x (SUVmax1 - SUVmax2)/(SUVmax1). Univariate and multivariate analysis were performed to identify factors (clinical, pathologic, metabolic) that may be associated with pCRAx. Relationships between baseline TEP uptake and prognostic parameters were assessed using Receiver Operating Characteristic (ROC) curves. Results: Among 188 patients included, the rate of pathologically proven node involvement was 63.3% (n=119). The pCRAx rate was 45.7% (n=86/188) but varied according to tumor subtypes: 14.5% (n=9/62) of HR(Hormone Receptor)+/HER2-negative, 47.7% (n=21/44) of HR+/HER2-positive, 61.4% (n=27/44) of triple-negative (TN) and 76.3% (n=29/38) of HR-/HER2-positive. Factors significantly associated with pCRAx were by univariate analysis: HER2-positive (HR+ and HR-) and TN subtypes (p< 0.001), SBR (Scarff-Bloom-Richardson) grade (p=0.01), breast pCR (ypT0/is) (p< 0.001), SUVmax2 (p=0.01) and ΔSUVmax (p< 0.001). By multivariate analysis, it persisted the HR-/HER2-positive (p=0.02) and TN (p=0.02) subtypes and breast pCR (p< 0.001). In global population, a decrease in ΔSUVmax of 63% was the optimal threshold to predict pCRAx (Area Under the Curve AUC = 0.73) with a sensitivity (Se) of 51% and specificity (Sp) of 83%. ΔSUVmax remains the best performing parameter in TN (AUC = 0.72; Se at 52%; Sp at 88%). In HR-/HER2-positive patients, SUVmax2 appeared to be a better predictor of pCRAx than ΔSUVmax. A SUVmax2 value of 1.99 was the optimal threshold for predicting pCRAx (AUC = 0.72), yielding a Se of 66% and a Sp of 78%. None of the PET criteria predicted axillary response with sufficient accuracy for HR+ subtypes. Conclusion: PET alone does not appear to be sufficient to predict pCRAx. It seems necessary to use other parameters, whether clinical, biological or imaging, to discriminate responders from non-responders to NAC in order to adapt the subsequent surgical management. Citation Format: ELOISE MICHEL, FRANCOISE BELTJENS, ALEXANDRE COCHET, JEAN LOUIS ALBERINI, CHARLES COUTANT, CLEMENTINE JANKOWSKI. Utility of 18F-FDG PET/CT for the prediction of pathologic complete response in axilla to neoadjuvant chemotherapy in 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 P5-01-11.

Background: Human epidermal growth factor receptor 2 (HER2) status can undergo alteration following neoadjuvant chemotherapy (NAC) in breast cancer. This study aimed to investigate the alteration of HER2 status after NAC in breast cancer and its impact on clinical outcomes of patients, focusing on HER2-low status. Methods: We retrospectively reviewed 1,063 breast cancer patients who received NAC followed by surgery between 2013 and 2020. Using paired samples of 670 patients with residual disease, HER2 discordance rate between pre- and post-NAC samples, the relationships between HER2 discordance and clinicopathological characteristics, and clinical outcomes of the patients were analyzed. Results: As a whole, HER2-low status before NAC was associated with a lower pathological complete response rate and higher Residual Cancer Burden (RCB) class, compared with HER2-zero and HER2-positive status. However, in subgroup analysis by hormone receptor (HR) status, no statistical differences were found in chemo-responsiveness between HER2-low and HER2-zero breast cancers. Following NAC, the overall HER2 discordance rate was 21.2% (κ = 0.676). The most common type of alteration was zero-to-low (10.8%) conversion, followed by low-to-positive (3.4%) conversion. HER2 discordance was significantly associated with lower HER2 levels and HR positivity before NAC, as well as lymphovascular invasion, higher ypT stage, lymph node metastasis, and higher RCB class in residual disease after NAC. In further analyses, HER2-zero-to-low conversion showed an association with HR positivity and low histologic grade. In multivariate logistic regression analyses, HR positivity and higher RCB class were identified as independent predictive factors for HER2 discordance. In survival analyses, HER2 discordance revealed a worse prognostic impact on disease-free survival of the patients, particularly within HR-positive subgroup, which remained statistically significant on multivariate Cox regression analysis. However, no survival differences were found between patients with HER2-zero-concordant and those with zero-to-low conversion. Conclusion: Given the prognostic implications of HER2 discordance, which primarily involves zero-to-low conversion, and the therapeutic benefits of newly developed antibody-drug conjugates in HER2-low breast cancer, HER2 status should be re-evaluated in surgical resection specimens following NAC, especially in cases showing HR positivity and high RCB class. Citation Format: Hyun-Jung Sung, Hyun Jung Kwon, Hee-Chul Shin, Eun-Kyu Kim, Koung Jin Suh, Se Hyun Kim, Jee Hyun Kim, So Yeon Park. Alteration of HER2 status following neoadjuvant chemotherapy in breast cancer: a clinicopathological analysis focusing on HER2-low status [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-02.

P051. Neo-adjuvant chemotherapy in breast cancer; predictors of pathological complete response

Can FDG-PET/CT predict early response to neoadjuvant chemotherapy in breast cancer?

Background: Neoadjuvant chemotherapy is the standard treatment for patients with locally advanced breast cancer which was recently introduced for operable breast cancer especially to achieve negative margins in breast conservation. Several studies have shown that Pathologic complete response (pCR) after neoadjuvant chemotherapy increases survival rate. The aim of this study therefore, was to evaluate the rate of pathologic complete response and its effective factors in breast cancer research center (BCRC). Methods: During a cross-sectional study, 179 patients with stage I to III breast cancer, who received neoadjuvant chemotherapy in breast cancer research center from 1997 to 2014, were included. Cases with pathologic complete response were defined as no tumor residue in the breast tissue and axillary region. This group of patients was compared with patients who had residual tumor at pathology. Data were analyzed by descriptive and inferential statistics using SPSS 19. Results: The mean age of patients was 45.4 years. Thirty-four patients (19%) were identified in the pathological complete response group (pCR). There was no significant difference between the pCR and non-pCR groups with respect to Age, Menopausal status, Family history of breast cancer, Tumor size, Histological type, Hormone receptors, Her-2neu and Phenotypic subtypes. However, ki67 index was significantly different between the two groups of patients, indicating that in patients with Ki67 of more than 40, pCR was the most observed (P = 0.01). Conclusions: This study showed that among the demographic, clinical, pathological and therapeutic factors, Ki67 can be a predicting factor for pathologic complete response after neoadjuvant chemotherapy.

Background: Early clinical response to neoadjuvant chemotherapy (NACT) in breast cancer correlates with pathological response at surgery. A tailored approach using biomarkers to predict response to NACT has become a research priority. Predictors of response can be divided into pathological and radiological biomarkers. Advances in gene expression profiling and diffusion-weighted MRI techniques are used to predict tumour response, and combinations thereof are the future of predicting response to NACT in early-stage breast cancer. Methods: We searched Medline, CINAHL and Embase databases for studies on NACT. Key words used were NACT, breast cancer, pathological* complete response, primary chemotherapy, radiological*, predictor*, gene expression and biomarkers limited to the English language. Pathological markers such as tumour subtypes, topoisomerase IIα expression, Ki67, apoptosis-related markers and gene expression profiling were included. Results: From 119 articles, 42 studies were reviewed; the majority of studies identified used pathological clinical response as an end point to NACT, whilst others used complete clinical response. Despite extensive studies, results regarding long-term survival following NACT and potential predictors are inconclusive. Conclusion: Future development of a predictive model combining key pathological and radiological biomarkers could provide personalised treatment regimens that improve pathological complete response rates and longer-term outcomes.

Biological evidence has revealed antitumor effect of vitamin D, but whether it could predict the response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients remains inconclusive. The aim was to investigate the association between pretreatment vitamin D level and response to NAC and subsequent survival outcomes in BC patients. The authors systematically searched the Medline, Embase, Cochrane Library, and Web of Science databases and clinical trial registries to identify relevant articles from inception to 8 October 2024. Eligible studies investigating the associations between pretreatment plasma vitamin D and response to NAC in BC patients were selected according to the predefined criteria, with the study characteristics extracted by two reviewers. The primary outcome was pathological complete response (pCR), while overall pathological response and event-free survival (EFS) were adopted as secondary outcomes. Summary effect estimates of odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were pooled using a random-effects model. Subgroup and sensitivity analyses were performed based on study characteristics and methodological quality. Six retrospective cohort studies involving 1291 BC patients were included. The authors observed a significant association between pretreatment vitamin D deficiency and 50% increased odds of non-pCR after NAC (OR=1.50, 95% CI: 1.11-2.03, P=0.008) with no heterogeneity (I2=0%). The authors also identified a significant association of vitamin D with the overall pathological response (OR=1.33, 95% CI: 1.01-1.75, P=0.046). A similar association with EFS (HR=1.27, 95% CI: 0.92-1.75, P=0.139) was also noted although the effect estimate was not statistically significant. Sensitivity analyses based on methodological quality showed consistent findings. Pretreatment vitamin D deficiency is associated with an inferior response to NAC in BC patients. Our meta-analysis advocates further prospective studies with large sample sizes before vitamin D supplementation could be administered to improve NAC response and subsequent prognosis of BC patients.

Background Previous studies have suggested that texture analysis is a promising tool in the diagnosis, characterization, and assessment of treatment response in various cancer types. Therefore, application of texture analysis may be helpful for early prediction of pathologic response in breast cancer. Purpose To investigate whether texture analysis of features from MRI is associated with pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer. Materials and Methods This retrospective study included 136 women (mean age, 47.9 years; range, 31-70 years) who underwent NAC and subsequent surgery for breast cancer between January 2012 and August 2017. Patients were monitored with 3.0-T MRI before (pretreatment) and after (midtreatment) three or four cycles of NAC. Texture analysis was performed at pre- and midtreatment T2-weighted MRI, contrast material-enhanced T1-weighted MRI, diffusion-weighted MRI, and apparent diffusion coefficient (ADC) mapping by using commercial software. A random forest method was applied to build a predictive model for classifying those with pCR with use of texture parameters. Diagnostic performance for predicting pCR was assessed and compared with that of six other machine learning classifiers (adaptive boosting, decision tree, k-nearest neighbor, linear support vector machine, naive Bayes, and linear discriminant analysis) by using the Wald test and DeLong method. Results Forty of the 136 patients (29%) achieved pCR after NAC. In the prediction of pCR, the random forest classifier showed the lowest diagnostic performance with pretreatment ADC (area under the receiver operating characteristic curve [AUC], 0.53; 95% confidence interval: 0.44, 0.61) and the highest diagnostic performance with midtreatment contrast-enhanced T1-weighted MRI (AUC, 0.82; 95% confidence interval: 0.74, 0.88) among pre- and midtreatment T2-weighted MRI, contrast-enhanced T1-weighted MRI, diffusion-weighted MRI, and ADC mapping. Conclusion Texture parameters using a random forest method of contrast-enhanced T1-weighted MRI at midtreatment of neoadjuvant chemotherapy were valuable and associated with pathologic complete response in breast cancer. © RSNA, 2019 Online supplemental material is available for this article.

To investigate relationships between several protein biomarkers and clinical responses to neoadjuvant chemotherapy (NAC) in breast cancer. Tumour tissue samples from female patients with locally advanced breast carcinoma (stages IIA to IIIC), treated with NAC regimens (including 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel, epirubicin, cyclophosphamide) were analysed retrospectively. Immunohistochemical analysis was used to test for protein levels of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER)-2, protein 53 (p53) and γ-synuclein. Relationships between protein biomarkers and responses to NAC were analysed by multivariate logistic regression analysis. Data from 154 patients (median age, 51 years; range 27-75 years) were included. Multivariate logistic regression analysis showed that γ-synuclein was an independent predictor of NAC objective response rate, and a statistically significant relationship was observed between NAC regimen, γ-synuclein levels and pathological complete response rate. These study findings suggest that γ-synuclein - in combination with other markers such as ER, PR and HER-2 - may serve as a biomarker for response to NAC in breast cancer and warrants further study.

Performances de l’imagerie par résonance magnétique au cours des chimiothérapies néoadjuvantes du cancer du sein pour prédire la réponse pathologique complète

e12640 Background: The time to surgery after neoadjuvant chemotherapy (NACT) in breast cancer and its impact on survival has not been sufficiently evaluated in low- or middle-income countries. The objective of this study was to analyze the impact on overall survival in a cancer hospital in Guayaquil, Ecuador. Methods: This is a retrospective study carried out at the SOLCA Guayaquil Hospital in Ecuador from January 2009 to December 2011. The inclusion criteria were women ≥18 years old, diagnosed with invasive breast cancer in stages II and III, who were treated with NACT followed by surgery. The data were collected from clinical records; those with incomplete data were excluded, and the variables age, stage, lymphovascular invasion (LVI), and pathological response were included. Survival was grouped into <8 and ≥8 weeks for the comparative analysis. Survival time was calculated from diagnosis by biopsy until death; A p-value of ˂0.05 was taken as significant; The Kaplan-Meier estimate was used for overall survival, then the groups were compared by Log Rank, and the influence of the covariates was estimated in the Cox regression model. The data were analyzed in an SPSS v29 statistical program. Results: 200 patients were identified, 195 of whom had all the information for the analysis. The median time between the end of NACT and surgery was 7.57 weeks (range, 2.43-29.14 weeks). In the < 8 and ≥ 8 weeks group, there were 111 and 84 patients, respectively. The clinical characteristics are described in the Table. The median overall survival in the entire cohort was 8.32 years (CI: 6.68-9.96), and for the < 8 and ≥ 8 weeks groups, it was 10.0 and 6.56 years, respectively, with a Log-Rank of 0.031. The follow-up (median) of the entire cohort was 7.54 years (range 0.63 – 10.99 years). The multivariate Cox regression showed that LVI, HR: 2.35 p<0.001; clinical stage III (II vs III), HR: 2.47 p<0.001; residual disease (pathological complete response vs residual disease), HR: 2.70 p=0.012; age ≤ 50 years (≤ 50 years vs > 50 years), HR: 1.69 p=0.011; were factors that statistically contributed to worse survival, however, the time between the end of NACT and surgery < 8 and ≥ 8 weeks (p = 0.07) had no statistical impact on survival. Nonetheless, a numerical trend towards better survival was noted in the < 8 week group. Conclusions: The delay in time to surgery after NACT had a negative trend in survival, although it was not statistically significant, which may be due to the small sample size. [Table: see text]

The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

11590 Background: Reducing the primary tumor volume and increasing the breast conserving surgery (BCS) rate are the main roles of neoadjuvant chemotherapy (NAT) in breast cancer. The aim of this study was to evaluate the benefit in adding docetaxel to anthracycline neoadjuvant therapy for breast cancer. Methods: Retrospective cohort study comparing the efficacy of NAT for breast cancer in patients subjected to docetaxel (75mg/m2) and epirubicin (60mg/m2) or 5-fluorouracil (600mg/m2), epirubicin (60mg/m2) and cyclophosphamide (600mg/m2) combinations (DE and FEC group, respectively). The mean number of chemotherapy delivered was three (2 to 6) in both groups (p= 0.8). Forty-six patients in the FEC group and 90 patients in the DE group were clinical stage II. Stage III was observed in 95 and in 68 patients in the FEC and the DE groups, respectively. The primary endpoint was the clinical and pathologic response to primary chemotherapy. The BCS rate was compared. Results: In stage II patients, the objective clinical response (OR) rate was 70% in the FEC group and 81% in the DE group, and the complete clinical response was in 11% and 29% in the FEC and DE groups, respectively (p= 0.01). The complete pathologic response (pCR) rate was 2% in the FEC group and 14% in the DE group (p= 0.01). In stage III patients, the objective clinical response rate was 49.5% in the FEC group and 80% in the DE group with complete clinical response rate of 9.5% and 13% in FEC and DE groups, respectively (p= 0.0001). The complete pathologic response (pCR) rate was 3.3% and 7.7% in FEC and DE groups, respectively (p= 0.1). BCS rate was higher in patients treated with DE scheme (67.5% versus 53% in stage II patients; p= 0.002, and 43.5% versus 29.5% in stage III patients; p= 0.0003). Conclusions: The NAT with DE combination is more effective in terms of clinical and pathologic response propitiating higher BCS rate than the FEC combination in stage II and III breast cancer. No significant financial relationships to disclose.

Obesity is an independent prognostic factor of decreased pathological complete response to neoadjuvant chemotherapy in breast cancer patients