High-risk Early-stage Breast Cancer Research Articles

Cost-effectiveness of Pembrolizumab in Combination with Chemotherapy as Neoadjuvant Treatment and Continued as a Single Agent Adjuvant Treatment for High-Risk Early-Stage Triple-Negative Breast Cancer in Hong Kong.

The phaseIII randomized KEYNOTE-522 trial demonstrated that pembrolizumab in combination with chemotherapy as neoadjuvant treatment followed by adjuvant pembrolizumab (pembrolizumab + chemotherapy) provided significant improvements in event-free survival (EFS) and overall survival (OS) for patients with high-risk early-stage triple-negative breast cancer (eTNBC). The objective was to assess the cost-effectiveness of pembrolizumab + chemotherapy compared to neoadjuvant chemotherapy alone (chemotherapy) in patients with high-risk eTNBC from a Hong Kong third-party payer perspective. A multistate transition model with four health states (event-free), locoregional recurrence, distant metastases, and death) was developed to assess the lifetime medical costs and health outcomes (3% annual discount), along with incremental cost-effectiveness ratios (ICERs) using efficacy and safety data from the KEYNOTE-522 trial. The health state utilities were derived from KEYNOTE-522 Euro-QoL-five-dimension five-level questionnaire (EQ-5D-5L) data. Costs were expressed in 2022 Hong Kong dollars (HKD).Scenario and sensitivity analyses were performed to assess the robustness of results. Over a 32-year time horizon, base case results showed that pembrolizumab + chemotherapy was associated with a 3.42year longer EFS and expected gains of 3.05 lifeyears (LYs) and 2.45 quality-adjusted lifeyears (QALYs) compared to chemotherapy. The resultant ICERs were HKD135,200 per QALY gained and HKD108,463 per LY gained, which were lower than the World Health Organization (WHO) cost-effectiveness threshold of three times gross domestic product (GDP) per capita for Hong Kong of HKD1,171,308 per QALY. The one-way sensitivity analyses (OWSA) and probabilistic sensitivity analysis (PSA) showed the results were robust across various inputs and alternative scenarios. On the basis of the analysis conducted for a 56-year-old cohort with high-risk eTNBC and assumptions in the model, pembrolizumab + chemotherapy represents a cost-effective proposition (as the ICER is approximately 35% of the GDP per capita in Hong Kong) for patients with high-risk eTNBC in Hong Kong.

RAGE inhibition to decrease cancer therapy related cardiotoxicity in women with early breast cancer (RAGE).

TPS619 Background: Anthracyclines are commonly used to treat high risk early-stage breast cancer (BC). Anthracycline-induced myocardial toxicity is a rare but morbid complication in BC survivors. The mechanism is not completely elucidated but may involve the generation of reactive oxygen species and other inflammatory mediators. RAGE, the receptor for advanced glycation end-products, signaling is upregulated in inflammatory conditions and has been linked to the development and progression of cardiovascular disease and cancer. In experimental models, blocking RAGE protects against cardiac damage and reduces the development of metastases. TTP488 is an orally bioavailable small molecule inhibitor of RAGE. This project is designed to characterize the role of TTP488 to decrease therapy related cardiac toxicity, and it will provide preliminary data about the safety, tolerability, and pharmacokinetics (PK) of common BC (neo)adjuvant chemotherapy agents in the presence of TTP488. Methods: Eligible patients have stage I-III breast cancer and are planned to receive chemotherapy. Enrolled patients will be assigned to 1 of 4 cohorts based on the chemotherapy regimen assigned for the last 2 doses of planned therapy. In Cohort 1, 6 patients will receive dose dense paclitaxel (ddT). In Cohort 2, 6 patients will receive docetaxel and cyclophosphamide (TC). In Cohort 3, 6 patients will receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). In Cohort 4, 6 patients will receive dose dense doxorubicin and cyclophosphamide (ddAC). All chemotherapy is dosed per standard institutional operational practice. For each patient, the first dose of chemotherapy is given in the absence of study drug to serve as the control for the safety and PK assessments. On day -7, prior to the 2nd dose of chemotherapy, TTP 488, 60mg daily for 6 days followed by 20mg daily, is administered and then subjects receive the 2nd dose of chemotherapy. With each cycle, hs-troponin and B-type natriuretic peptide (BNP) are collected prior to chemotherapy administration, and at 4hrs(hs-troponin only) and 24hrs after chemotherapy administration. With each cycle, PK sampling occurs prior to and immediately after chemotherapy (0hr), 1hr, 4hr, and 24hrs after chemotherapy. Primary objectives are to evaluate the change in high sensitivity troponin level before and during treatment with TTP488 and to evaluate the safety and tolerability of TTP488 when administered with chemotherapy. The secondary objective is to characterize the PK and bioavailability of chemotherapy agents with TTP488. Descriptive statistics for the change in troponin level and safety will be summarized. As of 2/1/24, 4 patients have been enrolled, with 4 undergoing screening. At the completion of this trial, we plan a randomized trial to evaluate the role of TTP488 to decrease cardiotoxicity, cancer related cognitive decline and disease recurrence. Clinical trial information: NCT05256745 .

Personalized circulating tumor DNA for minimal residual disease and dynamic assessment in patients undergoing neoadjuvant chemotherapy for breast cancer: Preliminary analysis from MSK-LINC.

3049 Background: Identification of minimal residual disease (MRD) with circulating tumor DNA (ctDNA) in pts with early-stage breast cancer holds promise to identify risk of relapse. MSK-LINC is prospective ctDNA plasma analysis of breast cancer pts. This pilot study evaluated the utility of serial ctDNA assessment as a biomarker for monitoring MRD and recurrence prediction in clinical stage II-III breast cancer pts undergoing neoadjuvant chemotherapy (NAC). Methods: 30 pts who underwent NAC across all subtypes were identified from MSK-LINC. The ctDNA analysis was performed at baseline, on-NAC, post-NAC/pre-surgery, within 8 weeks post-surgery, and during follow-up. Personalized ctDNA RaDaR assays were designed using whole exome sequencing data of paired primary tumor and germline samples from each pt. ctDNA levels were quantified as an estimated variant allele fraction (eVAF). Results: ctDNA panels were successfully designed for 29/30 pts (16 Stage II, 13 Stage III), including 6 HR+/HER2-, 12 HER2+, and 11 TNBC, with a median follow up of 4.2 years. The bespoke ctDNA assays targeted a median of 48 variants (21-51), with a median of 43 variants (11-48) passing quality control. A total of 175 plasma samples were analyzed, including 24 baseline and 24 post-surgery. A 100% ctDNA detection rate was observed at baseline in the 24 pts for whom a baseline sample was available (median eVAF 0.33%, range 0.0083% - 8.91%). Pathologic complete response (pCR) was achieved in 11 pts who remained disease free; and of the 18 pts without a pCR, 5 recurred. All patients with a pCR were ctDNA negative post treatment. In 3/5 patients who recurred, MRD detection was achieved, including one patient with persistent ctDNA positivity throughout all timepoints. For the other two pts, ctDNA was first detected in follow-up plasma collected at 4.4 and 9.8 months prior to clinical recurrence. Conclusions: This study demonstrates the potential of ctDNA as a dynamic biomarker for monitoring disease burden in pts with high-risk early-stage breast cancer, highlighting its remarkable sensitivity at baseline and its capability for MRD detection preceding clinical recurrence. These findings suggest the need for further research to fully understand the relationship between ctDNA dynamics during and after NACT with prediction of breast cancer outcomes. ctDNA detection rates in plasma samples across collection timepoints. [Table: see text]

Frequency of dose reductions of abemaciclib in metastatic and early-stage hormone positive, HER2 negative breast cancer.

e13099 Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p<0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p<0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p<0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.

CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer.

5001 Background: Oncogenic addiction to androgen receptor (AR) signaling drives mCRPC progression, highlighting the unmet need for novel treatment strategies to maximize AR-directed therapy. Preclinical evidence suggests a key role for CDK4/6 in sustained AR signaling, uncontrolled proliferation, and hormonal resistance in prostate cancer. Abemaciclib (ABEMA) is a potent CDK4/6 oral inhibitor that significantly augments the efficacy of endocrine therapy in hormonally driven (ER+) high-risk early-stage and metastatic breast cancer. ABEMA also showed single-agent activity in heavily pretreated mCRPC. Here, we report the primary results of CYCLONE 2, a Phase 3 study of ABEMA plus abiraterone (ABI) in pts with 1L mCRPC. Methods: CYCLONE 2 was a seamless Phase 2/3 adaptive trial with a dose-finding safety lead-in. Randomization to the ABEMA or placebo (PBO) plus ABI and predniso(lo)ne was stratified by prior docetaxel receipt for mHSPC, measurable disease, and radiographic progression at study entry. Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. The study was powered at ~90%, assuming a HR of 0.55 for rPFS, at a cumulative 2-sided alpha level of 0.05. Results: Between Nov 2018 and Jul 2022, 393 pts were randomized. Baseline characteristics were balanced across arms. Primary endpoint of rPFS was not met (HR 0.829; 95% CI, 0.619–1.111; p=0.2123), medians were 21.96 months for the ABEMA plus ABI group vs 20.28 months for the PBO plus ABI group. rPFS by blinded independent central review was consistent with investigator assessment (HR 0.842; 95% CI, 0.611–1.160). OS was a gated secondary endpoint and not inferentially tested (HR 0.927; 95% CI, 0.669–1.285; 38.9% maturity). Other secondary endpoints included time to PSA progression (HR 0.637; 95% CI, 0.474–0.856), time to symptomatic progression (HR 0.768; 95% CI, 0.522–1.131), and time to worst pain progression (HR 0.935; 95% CI 0.665–1.314). The most common grade ≥3 adverse events (AEs) reported in the ABEMA plus ABI group were anemia (13.6% vs 4.3% in the PBO plus ABI group), neutropenia (12.6% vs 0.5%) and ALT increased (8.7% vs 6.5%). Discontinuations of all study treatments due to AEs were 13.1% vs 4.3% in ABEMA plus ABI vs PBO plus ABI groups, while discontinuations of ABEMA or PBO alone due to AEs were 5.8% vs 1.6%, respectively. Conclusions: In patients with mCRPC, adding abemaciclib to abiraterone did not significantly increase rPFS. While no OS detriment was observed, secondary endpoints were not meaningfully improved. Overall, the combination was well tolerated, and safety was consistent with the known profiles of the individual medicines. Clinical trial information: NCT03706365 Clinical trial information: NCT03706365 .

Elucidating the immune active state of HR+HER2- MammaPrint High 2 early breast cancer.

506 Background: The 70-gene signature, MammaPrint (MP), classifies patients (pts) with early-stage breast cancer (EBC) as having an UltraLow, Low, High 1 (H1), or High 2 (H2) risk of distant recurrence. I-SPY 2 showed that pts with MP H2, HR+HER2- tumors have significantly higher response rates to neoadjuvant chemotherapy + immunotherapy relative to pts with MP H1 tumors. Expression-based immune deconvolution provides more detailed information about immune cell function beyond conventional methods enumerating tumor infiltrating lymphocytes. To elucidate the underlying biology that mediates immune therapy response, we performed in silico analysis of full transcriptome data to characterize immune cell frequencies and antigen presentation in HR+HER2-, MP High Risk EBC from pts enrolled in FLEX. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III pts with EBC who received MP testing and consented to full transcriptome and clinical data collection. Women with HR+HER2-, and MP High Risk invasive ductal EBC were included (n = 2916). Tumors were stratified into MP H1 or MP H2. The R-package Limma was used to preprocess gene expression data. The gene signature-based method xCell was used to determine immune cell abundances for each group based on enrichment score. Expression of genes involved in “antigen processing and presentation KEGG pathway”, and immune regulation, were evaluated between groups. Differences in immune cell frequency and gene expression were determined by a t-test with an adjusted p-value < 0.05. Results: MP classified 79% (n=2292) of HR+HER2- EBC as H1 and 21% (n=624) as H2. Pts with H2 EBC were more likely to be ≤ 50 years (32%) compared to pts with H1 tumors (23%). Although low ER staining (1-10%) tumors were more frequent in H2 vs H1 (15% vs 1%), a majority of H2 tumors (75%) had ER staining > 10%. Nearly 30% of H2 tumors were Grade 1 or 2, whereas 22% of H1 tumors were Grade 3. H2 tumors had significantly higher frequency of antigen presenting cells (APCs) including activated dendritic cells and macrophages, CD4+ memory T cells, CD8+ T cells, memory B cells and plasma cells relative to H1 tumors. The genes expressing PD-1 and PDL-1 and genes involved in antigen processing, including B2Mand TAP1/2, and presentation, i.e., major histocompatibility (MHC) class I ( HLA-A, -B, -F) and class II molecules ( HLA-DM, -DQ), were significantly upregulated in H2 vs H1. Conclusions: H2 tumors exhibited a heighted immune active state compared to H1 tumors among HR+HER2- EBC pts. The presence of APCs and increased antigen presentation, which are critical in eliciting T- and B-cell activation may explain the improved response rates to immunotherapy observed in H2 tumors. Selecting pts based on grade or ER% alone may exclude pts likely to benefit from immune therapy. These data support ongoing trials evaluating the response and benefit of adding immunotherapy to standard of care treatment regimens in MP H2 tumors. Clinical trial information: NCT03053193 .

Automated digital oncologic data review for breast cancer research: AI-enabled mCODE and field-of-interest extraction framework.

e12647 Background: Enhancing outcomes in cancer care and research can be optimally achieved by accelerating data extraction from unstructured electronic health resources. Understanding the association between treatment response markers and long-term outcomes is crucial for refining cancer therapeutic approaches and improving patient prognosis. In this study, we explore the association of oncologic outcomes with pathologic complete response (pCR) in high-risk early-stage breast cancer treated with neoadjuvant chemotherapy (NACT) using automated oncologic data extraction framework. Methods: Patients with primary stage I-III breast cancer who received NACT followed by mastectomy, with or without immediate breast reconstruction from January 2010 to August 2023 were retrospectively analyzed. We extracted pCR results and data on clinical and pathological stage, tumor subtype, grade, and treatment regimens and factors affecting postoperative complications from electronic medical records based on the AI enabled-mCODE (Minimal Common Oncology Data Elements) and fields of interest extraction framework. Employing mixed-effects Cox models, we explored the association between pCR and event-free survival (EFS), distant recurrence free Survival (DRFS) and overall survival (OS). Survival curves of patients were estimated using Kaplan-Meier method. Multivariate analysis was performed to evaluate the predictive factors for pCR. Results: Overall, 2725 patients were analyzed. The median age was 50.6 years. The median follow-up was 67 months. pCR was achieved in 31.0%. Hazard ratio for pCR vs. non-pCR were 0.34 for EFS (95% CI, 0.25-0.45), 0.32 for DRFS (95% CI, 0.23-0.43), 0.21 for OS (95% CI, 0.13-0.34), varying from 0.13 to 0.56 for EFS, 0.12 to 0.48 for DRFS and 0.07 to 0.40 for OS. The presence of pCR remained prognostic for event-free survival in multivariate models adjusted for age, tumor size, and nodal status at baseline. Conclusions: This study confirms that patients achieving pCR after NACT have better long-term survival outcomes that patients who do not. Oncologic data extraction from unstructured electronic medical records using AI-enabled extraction framework can be expected to enhance robust cancer research and generate valuable insights from real-world practice settings for tailored therapeutic decision-making. [Table: see text]

Abstract PO4-03-03: Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage Breast Cancer

Abstract Background: Because of the diagnosis at an earlier stage, and the wider availability of more effective therapies, treatment outcomes of patients with breast cancer are getting much better resulting in an increasing proportion of patients surviving their disease, however, a significant percentage of patients with early-stage disease at initial diagnosis may eventually relapse. Residual tumor cells can remain dormant for many years before causing tumor recurrence. Physical examination and mammography are strongly recommended in surveillance guidelines, but data on routine blood tests or imaging is lacking. The revolution made in recent years, following the approval of novel targeted and immunotherapy agents, may have better outcome if started earlier in the disease course with the lowest tumor burden and in patients with good performance status and adequate organs’ function. Additionally, early detection of oligometastatic disease can give a chance for cure for a subset of these patients. Levels of CA15.3 and CEA are used in decision making in the metastatic setting but their role in surveillance is still controversial. We aim to investigate whether serial measurement of tumor markers, when it correlates with tumor bulk (conditional), can detect early asymptomatic recurrence among subset of patients with high-risk early-stage breast cancer. Methods: Patients with high-risk early-stage breast cancer were invited to participate. High-risk features include any of the following: large tumor size (T3/4), grade-3, node-positive, triple-negative, HER2-positive or hormone receptor (HR)-negative disease. Patients were considered eligible if they have elevated CA15.3 and/or CEA at baseline, that subsequently normalize 6 weeks after surgical resection; upfront or following neoadjuvant chemotherapy. Serial testing of the elevated CA15.3 and/or CEA is done every 2 months thereafter, samples are cryopreserved and will not be processed until disease relapse. As such results will not be used for clinical decisions. The study is still ongoing, we here present an interim analysis evaluating the correlation between certain tumor characteristics and elevated serum marker(s) levels. Results: Since the launch of the study, 367 patients deemed high-risk by the above criteria, accepted to participate. Abnormal baseline CA15.3 and/or CEA was found in 110 (30%); 65 (18%) patients had elevated CA 15.3 while elevated CEA was found in 45 (12%) patients. Abnormal CA 15.3 was found in 27% of cases with T3/4 disease compared with 13% in T1/2 disease (p=0.001), and in 21% of node positive disease versus 7% in node negative disease (p=0.002), in 9% of HR negative disease versus 20% in HR-positive (P=0.038). Tumor grade and HER2 status were not associated with significant difference. Regarding CEA, abnormal levels were detected in 24% of HER2-positive disease compared to 5% of HER2-negative disease (P< 0.0001). Other tumor features were not associated with significant difference. Conclusions: Only a third of patients with high-risk early-stage breast cancer had high level of serum tumor markers at initial diagnosis and thus such markers may correlate with tumor presence. Large tumors (T3/4) and node positive disease were associated with high CA15.3 but not CEA. HER2-stutus and tumor grade had no effect on CA15.3 level, while HER2 positive disease correlated well with high CEA. Citation Format: Sarah Edaily, Baha' Sharaf, Maher Sughayer, Lina Yousef, Hala Abu-Fares, Sarah Abdel-Razeq, Hala Abu-Jaish, Mahmoud Abunasser, Suhaib Khater, Anas Zayed, Osama El Khatib, Rahaf Rahal, Hazem Abdulelah, Maria Shraim, Hikmat Abdel-Razeq. Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage 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 PO4-03-03.

Abstract PO1-27-09: TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS

Abstract Background. Premenopausal women with high risk early stage BC HR+/Her2- present as a complex disease and generally have worse survival outcomes compared to postmenopausal women with the same disease. There are pathological clinical factors and genomic platforms that help us in therapeutic decisions. The use of triptorelin 3.75mg associated with AI promotes favorable results in terms of survival for premenopausal women with high-risk Early stage BC. TEXT/SOFT trial. TRIPTO3 study evaluates the use of Triptorelin 11.25mg vs. Triptorelin 3.75mg in this specific patient population. Methods: We reviewed medical records of premenopausal female patients with high-risk early stage breast cancer who have been treated and received triptorelin 3.75mg and triptorelin 11.25mg as part of their treatment. All patients were treated at a private Oncology Center between 2013 and 2020. The primary objective was disease-free survival. Results: 52 patients were found who met the inclusion criteria. 28(53.8%) patients received triptorelin 11.25mg and 24(46.2%) patients received triptorelin 3.75mg respectively. The median follow-up was 63 months and the disease-free survival for the Triptorelin 11.25mg group was 91.2% and for the Triptorelin 3.75mg group was 86.8% respectively (Hazard Ratio of disease-free survival was 1.2; 95% IC (0.2-7.2). Disease-free survival for both groups regardless of triptorelin dose was 89% at 5 years. The median disease-free survival was not reached in both groups. Conclusions: Our findings show that triptorelin 11.25 mg is similar to the use of triptorelin 3.75 mg in terms of disease-free survival for premenopausal women with high-risk early stage breast cancer. Citation Format: Ronald Limon, Mariano Lopez-Pereyra, Mario Gianella, Neysa Espinoza, Denize Ramirez, Carlos Antelo, Claudia Sitic, Wara Cortez, Oscar Niño De Guzman, Silvia Neciosup, Natalia Valdivieso. TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS [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 PO1-27-09.

Abstract PO1-03-07: Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level

Abstract Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant clinical trials for non-metastatic breast cancer and as a surrogate endpoint for long-term survival outcomes. The U.S. Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for the approval of new drugs in the neoadjuvant setting in high-risk early-stage breast cancer. However, though the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) pooled analysis in 2014 showed that at the patient level achieving pCR was associated with longer overall survival (OS) and event-free survival (EFS), at the trial-level the association between high pCR rate and better OS and EFS outcomes was weak (coefficient of difference [R2]; 0.03 and 0.24, respectively) among all subtypes of breast cancer. A recent study reported that this association at the trial-level was similarly weak among Human Epidermal Growth Factor Receptor-2 (HER-2) positive breast cancer (R2; 0.02 and 0.23, respectively). However, the potential surrogacy of pCR rate for OS and EFS in triple-negative breast cancer (TNBC) in the neoadjuvant setting has not been well studied in a comprehensive manner. Moreover, because of significant advances in systemic treatment strategies in TNBC over the past decade including a combination of immune checkpoint inhibitors (ICIs) with conventional cytotoxic agents, the trial-level surrogacy needs to be reassessed in recently published neoadjuvant clinical trials for TNBC. Our primary objective is to assess the association between pCR rate and survival outcomes in neoadjuvant clinical trials for TNBC by collecting data from articles published after the CTNeoBC article in 2014. Methods: We performed a systematic literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed, Cochrane Library, and Web of Science databases. Articles published between January 1, 2014, and March 31, 2023, were searched. We included only randomized control trials of neoadjuvant treatments for clinical stage I-III TNBC that compared two or more regimens followed by curative intent breast surgery. The selected trials had data for odds ratio (OR) for pCR and hazard ratios (HRs) either for OS or for EFS or disease-free survival (DFS). We excluded trials including estrogen receptor positive, progesterone receptor-positive, or HER-2 positive diseases, and those without data enough to obtain ORs for pCR, HRs for OS, EFS, or DFS. Unpublished data as a full article was also excluded. If EFS could not be obtained from the articles, DFS was used in place of EFS. Two independent investigators (TY and TF) searched and extracted data. Any disagreement was resolved by discussion with the third author (ZZ). A linear regression model on a logarithmic scale weighted by the sample size of each trial was performed and the R2 was used to assess the trial-level association between OR for pCR and HRs for OS or EFS. Results: We identified eight trials with a total of 2,926 patients. Three of the eight trials used ICIs in the intervention arm. One trial did not provide OS data and was not included in the OS analysis. In four trials, EFS was not available and DFS was used for EFS analysis. The R2 was 0.191 (95% confidence interval [CI], 0.165 to 0.218) for OS and 0.193 (95% CI, 0.167 to 0.219) for EFS. Conclusions: Similarly to the previous reports, our findings suggest that the surrogacy of the pCR rate for OS and EFS in recent neoadjuvant clinical trials for TNBC is weak. At this moment, there is no strong evidence to support using pCR as a surrogate for long-term survival outcomes in neoadjuvant clinical trials for TNBC. Citation Format: Toru Yoshino, Zao Zhang, Ryota Sato, Stanley Lipkowitz, Takeo Fujii. Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level [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 PO1-03-07.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [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 PO2-20-07.

Abstract PO2-03-06: Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC)

Abstract BACKGROUND: Patients with stage III inflammatory breast cancer (IBC) are treated with tri-modality therapy consisting of neoadjuvant systemic therapy followed by modified radical mastectomy and post-mastectomy radiation therapy. Triple negative IBC (TN-IBC) is the subtype of IBC associated with the worst survival outcomes. Pathological complete response (pCR) rates after neoadjuvant chemotherapy have been historically low, with reports ranging between 13% and 42%. It is unknown if the addition of immune checkpoint inhibition to chemotherapy leads to improved pCR rate in TN-IBC as these patients were underrepresented in the seminal studies that led to the approval of chemoimmunotherapy for high-risk early-stage triple negative breast cancer (TNBC). METHODS: We conducted a retrospective analysis of patients with stage III TN-IBC who underwent breast surgery after receiving neoadjuvant chemoimmunotherapy. Patients were seen at Dana-Farber Cancer Institute (DFCI) or MD Anderson Cancer Center (MDACC). The analysis population consisted of all patients that were seen at either institution no more than 30 days after starting immunotherapy. The primary objective was the estimation of the pCR rate. An additional cohort of patients with TN-IBC treated with neoadjuvant chemotherapy and pembrolizumab while participating in the multi-institutional PELICAN trial (NCT03515798) will be added to the analysis at the time of the meeting. RESULTS: Thirty-seven patients (16 DFCI, 21 MDACC) were identified as having stage III TN-IBC and having received neoadjuvant chemoimmunotherapy. Twenty-five patients met criteria for inclusion in the analysis population. Patients in the DFCI cohort initiated treatment with chemoimmunotherapy between May 2021 and June 2022, and in the MDACC cohort between June 2021 and October 2022. Most patients were White (N=20, 80%), premenopausal (N=15, 60%) and overweight/obese (N=19, 76%). All patients received pembrolizumab-based therapy (Table 1). Among the 25 patients in the analysis population, 10 (40%) (95% CI: 21% to 61%) achieved a pCR, 6 patients experienced RCB-II and 9 RCB-III. At the time of last follow up, 84% of patients were alive. The results will be updated at the time of the meeting to include an additional cohort of 17 patients from the PELICAN trial. CONCLUSIONS: The addition of immune checkpoint inhibition to neoadjuvant chemotherapy led to a higher pCR rate in TN-IBC than most historical estimates. However this is still lower than what has been reported in TNBC in general. The investigation of novel systemic therapies is warranted in TN-IBC. Table 1. Patient characteristics and treatment received (analysis population) Citation Format: Filipa Lynce, Samuel Niman, Anthony Gonçalves, Megumi Kai, Sean Ryan, Elizabeth Troll, Rachel Layman, Antonio Giordano, Azadeh Nasrazadani, Faina Nakhlis, Jennifer Bellon, Laura Warren, Caroline Block, Susan Schumer, Anthony Lucci, Savitri Krishnamurthy, Florence Lerebours, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Trédan, Sylvain Ladoire, Leonor Lopez Almeida, Christophe Zemmour, Sara Tolaney, Vicente Valero, François BERTUCCI, Meredith Regan, Wendy Woodward. Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC) [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 PO2-03-06.

Abstract PO3-17-10: Real-World evidence for Pembrolizumab-based neoadjuvant chemotherapy in early-stage triple negative breast cancer: a single institution experience

Abstract Introduction The improved pathologic complete response (pCR) and event-free survival observed in Keynote-522 trial (NCT03036488) led to the adoption of (neo)adjuvant pembrolizumab (pembro)-based chemotherapy (CT) for high-risk early-stage triple-negative breast cancer (eTNBC) in various jurisdictions. However, Real-World Evidence (RWE) for (neo)adjuvant pembro in this setting would further support its ongoing funding and utilization. The aim of this study was to provide RWE for (neo)adjuvant pembro in eTNBC in the United Arab Emirates (UAE), where patients often present with more-advanced disease stages and poorer prognostic profiles compared with North America and Europe. Method This is a retrospective cohort study involving all patients treated with pembro-based neoadjuvant chemotherapy (NACT) for eTNBC at a major cancer center (Tawam Hospital) in the UAE between October 2021 and June 2023. Patient characteristics, clinicopathologic features, immune related adverse events (irAE) and disease outcomes were reported by descriptive statistics. An exploratory analysis was also conducted to examine the associations between pCR and HER-2 status (HER2 negative vs HER2 low) as well pCR and treatment interruption (< vs = > 2 weeks). ResultA total of 41 patients, with a median age of 44 years, were included in this study. All had an ECOG status of 0-1. The clinical and pathological characteristics are provided in Table 1. Pathogenic germline BRCA (gBRCA) mutations were detected in 8 (21%) of the 38 patients who underwent testing, including 6 with gBRCA1 and 2 with gBRCA2), with additional TP53 and SMARC4 detected in one patient each. Approximately 66% of the patients (n = 27) completed surgery post neoadjuvant pembro+CT, of whom 18 (67%) had breast conserving surgery and 9 (33%) had mastectomy. Of the patients who underwent surgery, 60% (n = 16/27) achieved pCR including 68% (13/19) of the IHC 0+ and 37.5% (3/8) of the HER2 1+ or 2+ ISH negative (p-value = 0.429, Chi Square test). Of the total population, 16 (40%) did not complete NACT; 1 lost to follow-up, 9 were still on ongoing therapy, 2 discontinued therapy due to toxicity, and 4 developed progressions including 1 locoregional relapse, and 3 metastatic diseases. Of the 32 patients who completed at least 3 months of pembro-NACT, 14 (34%) reported any grade irAE: skin toxicity (N = 3, 21%), hypothyroidism (N = 8, 57%), Hyperthyroidism (N = 1, 7%), Hepatitis (N = 4, 28.5%), adrenal insufficiency (N = 1, 7%), and pneumonitis (N = 1, 7%). With a median follow up of 4.5 months, pembro was postponed in 4 patients and permanently discontinued in 1 secondary to severe pneumonitis requiring ICU admission. All irARs were graded at I and II, except for 1 grade III dermatitis, and 1 grade III pneumonitis. Interruption of IO was required for irAE in 5 (36%) patients, and steroids were administered in 4 (29%). pCR was observed in 6 (40%) patients out of 15 who experienced treatment interruption due to IrAE or CT and 10 out of 13 (77%) in those who did not experience treatment interruption (p = 0.04895, Chi-square test). Conclusion The pCR rates for Pembro-based NACT in this RWE study, involving patients with an overall higher risk disease, appeared to be consistent with those observed in keynote-522. Interestingly, pCR rates did not seem to differ between HER2 negative and HER2 low groups. However, pCR rates appeared to be lower in patients who experienced treatment interruptions. Approximately half of the patients developed irAE but the majority of the adverse events were of lower grade and did not require treatment interruptions. Overall, the RWE observed in this study supports the ongoing funding and utilization of Pembro-based NACT in eTNBC. Updated data, including the pCR rate and toxicity, will be presented at the meeting once most of the patients have completed surgery. Table 1: Clinical and Pathological Characteristics of patients (Nf41) XX- XX Citation Format: Aydah Al-Awadhi, Mouza AlShebli, Lina Wahba, Tallal Younis. Real-World evidence for Pembrolizumab-based neoadjuvant chemotherapy in early-stage triple negative breast cancer: a single institution experience [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 PO3-17-10.

Real-world data of HER2-negative early breast cancer patients treated with anthracycline and/or taxane regimens in Japan

BackgroundAnthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan.MethodsThis observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021.ResultsOf 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities.ConclusionsApproximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan.

Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer

Antibiotic exposure during immunotherapy (IO) has been shown to negatively affect clinical outcomes in various cancer types. The aim of this study was to evaluate whether antibiotic exposure in patients with high-risk early-stage HER2-negative breast cancer (BC) undergoing treatment with neoadjuvant pembrolizumab impacted residual cancer burden (RCB) and pathologic complete response (pCR) in the pembrolizumab-4 arm of the ISPY-2 clinical trial. Patients received pembrolizumab for four cycles concurrently with weekly paclitaxel for 12 weeks, followed by four cycles of doxorubicin plus cyclophosphamide every 2 or 3 weeks. Patients who received at least one dose of systemic antibiotics concurrently at the time of immunotherapy (IO) were included in the antibiotic exposure group (ATB+). All other participants were included in the control group (ATB-). RCB index and PCR rates were compared between the ATB+ and ATB- groups using t-tests and Chi-squared tests, and linear and logistic regression models, respectively. Sixty-six patients were included in the analysis. 18/66 (27%) patients were in the ATB+ group. Antibiotic use during IO was associated with a higher mean RCB index (1.80 ± 1.43 versus 1.08 ± 1.41) and a lower pCR rate (27.8% versus 52.1%). The association between antibiotic use and the RCB index remained significant in multivariable linear regression analysis (RCB index-coefficient 0.86, 95% CI 0.20–1.53, P = 0.01). Our findings suggest that concurrent antibiotic exposure during neoadjuvant pembrolizumab in HER2-negative early-stage BC is associated with higher RCB. Further validation in larger cohorts is needed to confirm these findings.

Cost-Effectiveness of Adjuvant Olaparib for Patients With Breast Cancer and Germline BRCA1/2 Mutations

The OlympiA trial found that 1 year of adjuvant olaparib therapy can improve distant disease-free survival and overall survival from early-stage breast cancer in patients with a germline BRCA1/2 mutation. However, olaparib, an oral poly-adenosine diphosphate ribose polymerase inhibitor, is estimated to cost approximately $14 000 per month in the US. To estimate the incremental cost-effectiveness of adjuvant olaparib compared with no olaparib in eligible patients. In an economic evaluation from a health care system perspective, the cost-effectiveness of adjuvant olaparib was analyzed using a Markov state-transition model. The model simulated costs and lifetime health outcomes of 42-year-old women with high-risk early-stage breast cancer and a known BRCA1/2 mutation who completed definitive primary therapy and neoadjuvant or adjuvant systemic therapy. The study was conducted from August 2021 to July 2023. The effectiveness of olaparib was based on the findings of the OlympiA randomized clinical trial, and other model parameters were identified from the literature. The model was calibrated to the 1-, 2-, 3-, and 4-year distant disease-free and overall survival observed in the OlympiA trial, and olaparib was assumed to reduce the risk of distant recurrence only in the first 4 years. One year of adjuvant olaparib or no adjuvant olaparib. Incremental cost-effectiveness ratio (ICER) in 2021 US dollars per quality-adjusted life-year (QALY) gained. All outcomes were discounted by 3% annually. In the base case, adjuvant olaparib was associated with a 1.25-year increase in life expectancy and a 1.20-QALY increase at an incremental cost of $133 133 compared with no olaparib. The resulting ICER was approximately $111 000 per QALY gained. At a willingness-to-pay threshold of $150 000 per QALY, olaparib was cost-effective at its 2021 price and in more than 92% of simulations in probabilistic sensitivity analysis. The results were sensitive to assumptions about the effectiveness of olaparib and quality of life for patients with no disease recurrence. In this study, from a US health care system perspective, adjuvant olaparib was a cost-effective option for patients with high-risk, early-stage breast cancer and a germline BRCA1/2 mutation.

EE524 Cost-Effectiveness of Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab for High-Risk Early-Stage Triple Negative Breast Cancer in Costa Rica

EE524 Cost-Effectiveness of Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab for High-Risk Early-Stage Triple Negative Breast Cancer in Costa Rica

EE62 Cost-Effectiveness of Neoadjuvant Pembrolizumab Plus Chemotherapy Followed By Adjuvant Pembrolizumab for High-Risk Early-Stage Triple-Negative Breast Cancer (ETNBC) in France

EE62 Cost-Effectiveness of Neoadjuvant Pembrolizumab Plus Chemotherapy Followed By Adjuvant Pembrolizumab for High-Risk Early-Stage Triple-Negative Breast Cancer (ETNBC) in France

EE210 Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy as Neoadjuvant Therapy and Continued as a Single Agent as Adjuvant Therapy for High-Risk Early-Stage Triple-Negative Breast Cancer in Greece

EE210 Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy as Neoadjuvant Therapy and Continued as a Single Agent as Adjuvant Therapy for High-Risk Early-Stage Triple-Negative Breast Cancer in Greece

Thermally boosted interstitial high-dose-rate brachytherapy in high-risk early-stage breast cancer conserving therapy - large cohort long-term results.

Early-stage high-risk breast cancer (BC) is standardly treated with breast-conserving therapy (BCT), combined with systemic therapy and radiotherapy (RT) ± tumor bed boost, e.g., with interstitial high-dose-rate brachytherapy (HDR-BT). To improve local recurrence rate (LRR), BT radiosensitization (thermal boost, TB) with interstitial microwave hyperthermia (MWHT) may be an option. The paper aims to report a retrospective single-institutional study on 5- and 10-year local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), overall survival (OS), cosmetic outcome (CO), and late toxicity (fibrosis, fat necrosis) after thermally enhanced HDR-BT boost to the BC tumor bed. In 2006-2018, 557 early-stage (I-IIIA) high-risk BC patients were treated with BCT. If indicated, they were administered systemic therapy, then referred for 40.0-50.0 Gy whole breast irradiation (WBI) and 10 Gy interstitial HDR-BT boost (group A). Eligible patients had a single MWHT session preceding BT (group B). Based on present risk factors (RF), medium-risk (1-2 RF) and high-risk subgroups (≥ 3 RF) were formed. Patients were standardly checked, and control mammography (MMG) was performed yearly. Breast cosmesis (Harvard scale) and fibrosis were recorded. LC, DMFS, DFS, and OS were statistically analyzed. Out of 557 patients aged 57 years (26-84), 364 (63.4%) had interstitial HDR-BT boost (group A), and 193 (34.6%) were preheated with MWHT (group B). Patients in group B had a higher clinical stage and had more RFs. The median follow-up was 65.9. Estimated 5-year and 10-year LC resulted in 98.5% and 97.5%, respectively. There was no difference in LC, DMFS, DFS, and OS between groups A and B and between extracted high-risk subgroups A and B. Five- and ten-year OS probability was 95.4% and 88.0%, respectively, with no difference between groups A and B. Harvard criteria-based CO assessment revealed good/excellent cosmesis in 74.9-79.1%. Tumor bed hardening was present in 40.1-42.2%. Asymptomatic fat necrosis-related macrocalcifications were detected in 15.6%, more frequently in group B (p = 0.016). Thermally boosted or not, HDR-BT was locally highly effective as part of combined treatment. Five- and ten-year LC, DMFS, DFS, and OS were high and equally distributed between the groups, although TB was prescribed in more advanced one with more RFs. TB did not influence CO and fibrosis. TB added to late toxicity regarding asymptomatic fat necrosis detected on MMG.