Early Triple-negative Breast Cancer Research Articles

Distribution of PD-L1, TROP2 and HER2- “lowness” in early triple-negative breast cancer: an opportunity for treatment de-escalation

BackgroundHER2, TROP2 and PD-L1 are novel targets in triple-negative breast cancer (TNBC). The combined expression status of these targets, and whether they can define prognostic subgroups, is currently undefined.MethodsImmunohistochemistry was used to determine HER2, TROP2 and PD-L1 levels in 459 TNBC cases, that received in the adjuvant/neoadjuvant setting active surveillance, CMF, anthracycline-, anthracycline plus taxane-, or carboplatin-containing regimes.ResultsHER2-low patients with PD-L1 > 1 CPS (double-positive, herein “DP”) had a mean PFS of 4768 days (95% CI: 4267–5268) versus 3522 days (95% CI: 3184–3861) for non-DP patients (P = 0.002). Regarding the received adjuvant treatment, DP patients (versus non-DP) receiving anthracyclines plus taxanes exhibited a mean PFS time of 4726 (95% CI: 4022–5430) versus 3302 (95% CI: 2818–3785) days (P = 0.039). Finally, 100% of DP patients that received a carboplatin-based regimen were long-term disease-free.ConclusionsEarly HER2-low, PD-L1-positive TNBC patients have a very good prognosis, particularly if treated with anthracycline/taxane- or carboplatin-containing regimes.

Prognostic Value of Immunohistochemistry-based Subtyping Before and After Neoadjuvant Chemotherapy in Patients with Triple-negative Breast Cancer.

To assess the predictive and prognostic value of a subtyping method based on immunohistochemistry in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC). This study included patients with TNBC treated with anthracycline- and taxane-based NAC and curative surgery. Immunohistochemical (IHC) subtyping was performed using core needle biopsy specimens before NAC (pre-NAC) and residual tumors after NAC (post-NAC). Logistic regression was performed to identify predictive biomarkers of pathological complete response (pCR). Invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed using the log-rank test and Cox proportional hazards regression. A total of 230 patients were followed up for a median of 59 months. Clinical lymph node status and the pre-NAC subtype were independent predictors of pCR (P=0.006 and 0.005, respectively). The pre-NAC subtype was an independent prognostic factor for long-term survival (iDFS: P < 0.001, DDFS: P=0.010, and OS: P=0.044). Among patients with residual disease (RD) after NAC, approximately 45% of tumors changed their IHC subtype. Furthermore, the post-NAC subtype, but not the pre-NAC subtype, was strongly associated with the survival of patients with RD (iDFS: P < 0.001, DDFS: P=0.005, and OS: P=0.006). The IHC subtype predicted response to NAC and long-term survival in patients with early TNBC. In patients with RD, almost 45% of the tumors changed subtype after NAC. The IHC subtype should be considered when planning additional therapies pre- and post-NAC.

2232O Atezolizumab (atezo) and tumour microenvironment in early triple-negative breast cancer (eTNBC): Exploratory biomarker analysis from IMpassion031

2232O Atezolizumab (atezo) and tumour microenvironment in early triple-negative breast cancer (eTNBC): Exploratory biomarker analysis from IMpassion031

253P Is 6-weekly administration of pembrolizumab in combination with chemotherapy for early triple-negative breast cancer safe? A real-world early comparison of q6w versus q3w administration of pembrolizumab in two large cancer centres in the UK

253P Is 6-weekly administration of pembrolizumab in combination with chemotherapy for early triple-negative breast cancer safe? A real-world early comparison of q6w versus q3w administration of pembrolizumab in two large cancer centres in the UK

254P Effects of delaying adjuvant chemotherapy initiation on clinical outcomes in early triple-negative breast cancer patients

254P Effects of delaying adjuvant chemotherapy initiation on clinical outcomes in early triple-negative breast cancer patients

Fungal Depletion Bolsters Anti-Tumor Immune Response Elicited by Anti-PD1 Alone and in Combination with Radiation Therapy

Pembrolizumab in combination with chemotherapy has become the standard of care treatment for both metastatic and early-stage triple negative breast cancer (TNBC). Clinical trials are currently underway investigating the use of pembrolizumab with radiation in the neoadjuvant setting in early TNBC. Several groups have described a link between the microbiome and the efficacy of chemotherapy and anti-PD1 immune checkpoint inhibitors (ICIs) in preclinical models. Recent work from our lab has shown that targeting commensal fungi in the microbiome enhances the radiation induced antitumor immune response. Therefore, we hypothesized that fungal depletion might positively impact anti-PD1 therapy and combination treatment with anti-PD1 and radiation therapy (RT). This study utilized an orthotopic syngeneic breast tumor model in which the syngeneic cell line E0771 was injected into the mammary fat pad of female C57BL/6 mice. Tumor-bearing mice were then treated with and without the antifungal fluconazole, anti-PD1, and radiation (16 Gy single fraction) using the X-RAD SmART platform with CT guidance. Tumor volumes were compared using 2-way ANOVA and survival curves analyzed using log rank. In a separate set of experiments, tumor-infiltrating immune cells were isolated and analyzed by high-dimensional multiplex flow cytometry. We found that fungal depletion with fluconazole prior to treatment with anti-PD1 reduced the tumor volume and significantly improved survival in comparison to those treated with anti-PD1 alone (P = 0.0016). To identify what changes in the tumor immune microenvironment is driving this increased anti-tumor response, we performed flow cytometry on immune cells isolated from the tumors. We found that the use of fluconazole prior to anti-PD1 treatment reduced the proportion of CD11b+F4/80+ tumor-associated macrophages (TAMs) (P = 0.01) and increased tumor infiltrating cytotoxic T cell population (P = 0.04) when compared with the use of anti-PD1 alone. We also evaluated the effect of fungal depletion on combination therapy with RT and anti-PD1. Strikingly, we found that mice depleted of fungi with fluconazole prior to radiation and anti-PD1 therapy, have decreased tumor burden and significantly increased survival when compared to their fungally-intact counterparts (P = 0.043). Our data indicates that the depletion of the gut fungal populations induces an increased antitumor response following anti-PD1 alone and in combination with radiation. This increased antitumor immune response is associated with an increase in the cytotoxic CD8+ T cell compartment with concomitant decrease in immunosuppressive tumor associated macrophages.

Ganglioside GD2 Expression Is Associated With Unfavorable Prognosis in Early Triple-negative Breast Cancer.

Gangliosides (acidic glycosphingolipids) have crucial regulatory roles in normal physiological processes, as well as in pathological conditions, including tumor onset and progression. GD2 is highly expressed in triple-negative breast cancer (TNBC), particularly in cancer stem cells. However, little is known on the clinical impact of GD2 expression on the prognosis of TNBC. Consequently, we aimed to investigate the association between GD2 expression in TNBC and the prognosis of TNBC. We assessed GD2 expression in 76 patients with primary TNBC who had undergone surgery at our Institute between 2012 and 2015 using immunohistochemical analysis with a tissue microarray technique. We investigated the relationship between GD2 expression and clinicopathological factors in TNBC, recurrence-free survival (RFS), and overall survival (OS). Increased GD2 expression was observed in 45% of TNBC patients. There was no significant association between GD2 expression and clinicopathological factors in TNBC. The 5-year RFS rate among patients with GD2-positive TNBCs was significantly worse than that among patients with GD2-negative TNBCs (75.4% and 94.9%; HR=4.931; 95%CI=1.024-23.752; p=0.027). The OS in patients with GD2-positive TNBCs tended to be inferior to that of patients with GD2-negative TNBCs (HR=5.357; 95%CI=0.599-47.939; p=0.092). Interestingly, in patients with GD2-positive TNBCs, a higher grade of tumor-infiltrating lymphocytes (TILs) displayed a significantly better impact on OS (TILs-high vs. TILs-low; p=0.04). Both univariate and multivariate analyses showed that GD2 expression negatively affected RFS (p=0.027, p=0.021, respectively). GD2 expression is an independent unfavorable prognostic factor for TNBC.

Atezolizumab in the treatment of patients with breast cancer

Immunotherapy is a modern method of treatment which is being tested in breast cancer patients. The first approved drug in this group was atezolizumab introduced for the treatment of patients with locally advanced and inoperable or metastatic triple-negative breast cancer (TNBC) with expression of programmed death receptor type 1 (PD-L1) on immunologic cells (IC) of ≥1%, who had not received prior chemotherapy for advanced disease. The results of the registration study IMpassion130 indicated that atezolizumab improved patient outcomes when used in combination with nab-paclitaxel. This article summarizes the most important analyzes of that study. The necessity to use the validated VENTANA SP142 assay to assess PD-L1 expression, which is necessary for the qualification of patients for this therapy, was emphasized. Additionally, the available data on the first results of the studies in patients with early TNBC as well as with human epidermal receptor type 2 (HER2)-positive and estrogen receptor (ER)-positive HER2-negative cancers treated with atezolizumab are discussed.

Clinical utility of genomic signatures for the management of early and metastatic triple-negative breast cancer.

This comprehensive review aims to provide timely and relevant insights into the current therapeutic landscape for triple-negative breast cancer (TNBC) and the molecular features underlying this subtype. It emphasizes the need for more reliable biomarkers to refine prognostication and optimize therapy, considering the aggressive nature of TNBC and its limited targeted treatment options. The review explores the multidisciplinary management of early TNBC, which typically involves systemic chemotherapy, surgery, and radiotherapy. It highlights the emergence of immune checkpoint inhibitors (ICIs), poly(ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs) as promising therapeutic strategies for TNBC. Recent clinical trials investigating the use of ICIs in combination with chemotherapy and the approval of pembrolizumab and atezolizumab for PD-L1-positive metastatic TNBC are discussed. The efficacy of PARP inhibitors and ADCs in treating TNBC patients with specific genetic alterations is also highlighted. The findings discussed in this review have significant implications for clinical practice and research in TNBC. The identification of distinct molecular subtypes through gene expression profiling has enabled a better understanding of TNBC heterogeneity and its clinical implications. This knowledge has the potential to guide treatment decisions, as different subtypes display varying responses to neoadjuvant chemotherapy. Furthermore, the review emphasizes the importance of developing reliable genomic and transcriptomic signatures as biomarkers to refine patient prognostication and optimize therapy selection in TNBC. Integrating these signatures into clinical practice may lead to more personalized treatment approaches, improving outcomes for TNBC patients.

PRMT5 triggers glucocorticoid-induced cell migration in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are the most aggressive breast cancers, and therapeutic options mainly rely on chemotherapy and immunotherapy. Although synthetic glucocorticoids (GCs) are given to alleviate the side effects of these treatments, GCs and their receptor, the glucocorticoid receptor (GR), were recently associated with detrimental effects, albeit the mechanisms involved remain elusive. Here, we identified the arginine methyltransferase PRMT5 as a master coregulator of GR, serving as a scaffold protein to recruit phospho-HP1γ and subsequently RNA polymerase II, independently of its methyltransferase activity. Moreover, the GR/PRMT5/HP1γ complex regulated the transcription of GC-target genes involved in cell motility and triggering cell migration of human TNBC cells in vitro and in a zebrafish model. Of note, we observed that GR/PRMT5 interaction was low in primary tumors but significantly increased in residual tumors treated with chemotherapy and GCs in neoadjuvant setting. These data suggest that the routine premedication prescription of GCs for early TNBC patients should be further assessed and that this complex could potentially be modulated to specifically target deleterious GR effects.

Neoadjuvant Immunotherapy: A Promising New Standard of Care.

Neoadjuvant immunotherapy has emerged as a promising approach in the treatment of various malignancies, with preclinical studies showing improved immune responses in the preoperative setting. FDA-approved neoadjuvant-immunotherapy-based approaches include triple-negative breast cancer and early non-small cell lung cancer on the basis of improvement in pathological response and event free survival. Nevertheless, current trials have only shown benefits in a fraction of patients. It is therefore crucial to identify predictive biomarkers to improve patient selection for such approaches. This review aims to provide an overview of potential biomarkers of neoadjuvant immunotherapy in early triple-negative breast cancer, bladder cancer, melanoma, non-small cell lung cancer, colorectal cancer and gastric cancer. By the extrapolation of the metastatic setting, we explore known predictive biomarkers, i.e., PD-L1, mismatch repair deficiency and tumour mutational burden, as well as potential early-disease-specific biomarkers. We also discuss the challenges of identifying reliable biomarkers and the need for standardized protocols and guidelines for their validation and clinical implementation.

Does timing of neoadjuvant chemotherapy influence the prognosis in patients with early triple negative breast cancer?

PurposeFor patients with triple negative breast cancer (TNBC), the optimal time to initiate neoadjuvant chemotherapy (TTNC) is unknown. This study evaluates the association between TTNC and survival in patients with early TNBC.MethodsA retrospective study using data from of a cohort of TNBC patients diagnosed between January 1, 2010 to December 31, 2018 registered in the Tumor Centre Regensburg was performed. Data included demographics, pathology, treatment, recurrence, and survival. Interval to treatment was defined as days from pathology diagnosis of TNBC to first dose of neoadjuvant chemotherapy (NACT). The Kaplan–Meier and Cox regression methods were used to evaluate the impact of TTNC on overall survival (OS) and 5 year OS.ResultsA total of 270 patients were included. Median follow up was 3.5 years. The 5-year OS estimates according to TTNC were 77.4%, 66.9%, 82.3%, 80.6%, 88.3%, 58.3%, 71.1% and 66.7% in patients who received NACT within 0–14, 15–21, 22–28, 29–35, 36–42, 43–49, 50–56 and > 56 days after diagnosis. Patients who received systemic therapy early had the highest estimated mean OS of 8.4 years, while patients who received systemic therapy after more than 56 days survived an estimated 3.3 years.ConclusionThe optimal time interval between diagnosis and NACT remains to be determined. However, starting NACT more than 42 days after diagnosis of TNBC seems to reduce survival. Therefore, it is strongly recommended to carry out the treatment in a certified breast center with appropriate structures, in order to enable an adequate and timely care.

Clinicopathology in Early Triple-Negative Breast Cancer in H. Adam Malik Hospital Medan

Clinicopathology in Early Triple-Negative Breast Cancer in H. Adam Malik Hospital Medan

Predictive Roles of Baseline Stromal Tumor-Infiltrating Lymphocytes and Ki-67 in Pathologic Complete Response in an Early-Stage Triple-Negative Breast Cancer Prospective Trial

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff &gt; 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.

Targeting CaMKK2 inhibits actin cytoskeletal assembly to suppress cancer metastasis.

Triple-negative breast cancers (TNBCs) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Further, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.

Neoadjuvant tislelizumab plus nab-paclitaxel and carboplatin followed by adjuvant tislelizumab in patients with early triple-negative breast cancer.

602 Background: Triple-negative breast cancer (TNBC) is the subtype with the least favorable outcomes. However, TNBC is associated with higher immune cell abundance than other subtypes, making it a good candidate for immunotherapy. Neoadjuvant chemotherapy is the preferred treatment approach for early TNBC. Emerging evidence shows that additional immune checkpoint inhibitors (ICI) in neoadjuvant therapy significantly increases pathological complete response (pCR) and event-free survival in early TNBC. Treatment regimens of paclitaxel and carboplatin (TP) is class I recommendation for TNBC neoadjuvant therapy, the application of ICI with TP regimens is worth exploring. Methods: In this multicenter, open-label, phase II study, patients with untreated, histologically confirmed TNBC in stage II-III (per AJCC 8th edition) were enrolled. Patients received six cycles of neoadjuvant therapy with tislelizumab at 200 mg once every 3 weeks plus nab-paclitaxel (125 mg/m2 on days 1 and 8) and carboplatin (at a dose based on an area under the concentration 2 on days 1 and 8) every 3 weeks. Patients who either completed or discontinued the neoadjuvant treatment would undergo definitive surgery. After surgery, the patients received adjuvant tislelizumab every 3 weeks for up to 12 cycles. The primary endpoint was the rate of pCR (ypT0/Tis ypN0). The secondary endpoints included 1-, 2-, 3-year event free survival rates and overall survival rates. Based on the Simon’s Two-Stage design, if &gt; 13 of 32 patients achieved pCR, the enrollment would proceed to full accrual of 62 patients as planned. If &gt; 29 of 62 patients achieved pCR, we would deem the study to have met the primary endpoint. Results: From Mar 2021 to Jan 2022, 32 patients were enrolled; 18 of them achieved pCR, and therefore the study proceeded to complete the enrollment of 62 patients. At the data cut-off of Oct 13, 2022, 62 patients were enrolled, among which 50 patients received neoadjuvant treatment and underwent definitive surgery. The median age was 50 years. 36 (72.0%) patients had stage II breast cancer at diagnosis. 31 of the 50 patients achieved pCR (ypT0/Tis ypN0), and the pCR rate was 62.0% (95% CI, 47.2-75.4). Patients with immune cell PD-L1 expression ≥10% had numerically higher pCR rate (81.8% vs 53.6%) than those with PD-L1 expression ≥1%. All 50 (100%) patients reported any grade of neoadjuvant treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 27 (54%) patients. The rate of immune-related adverse events (irAEs) was 34% (17/50), with the common occurring (10%) irAE of hypothyroidism (n = 8, 16%). 2 (4.9%) patients experienced grade ≥3 irAEs. Severe adverse events were reported in 5 (10%) patients. Conclusions: The study has met its primary endpoint. Tislelizumab plus nab-paclitaxel and carboplatin achieved a higher pCR and was generally well tolerated in the neoadjuvant treatment of early TNBC. Clinical trial information: ChiCTR2100041675 .

Neoadjuvant single-dose trilaciclib prior to combination chemotherapy in patients with early triple-negative breast cancer: Safety, efficacy, and immune correlate data from a phase 2 study.

603 Background: Trilaciclib, an intravenous CDK4/6 inhibitor, induces transient G1 cell cycle arrest. In preclinical studies, trilaciclib demonstrated immune-modulating effects by enhancing T-cell activation, favorably altering the tumor microenvironment (TME), and improving long-term immune surveillance. Preliminary data from this phase 2, single-arm, open-label study of neoadjuvant trilaciclib in triple-negative breast cancer (TNBC; NCT05112536) showed that single-dose trilaciclib increased CD8+ T-cell/Treg ratios within the TME. Here, we combine immune analysis with clinical outcomes to identify correlates of treatment response. Methods: Patients (pts) with early-stage TNBC received single-dose trilaciclib followed by trilaciclib + dose-dense anthracycline/cyclophosphamide and taxane (AC/T). Per investigator discretion, pts received pembrolizumab (pembro) 400 mg Q6W from cycle 1 and/or carboplatin (carbo) AUC 1.5 QW from cycle 5. Tumor biopsies and blood samples were collected prior to treatment, 7 days post single-dose trilaciclib, and during surgery, with an additional blood sample at cycle 2. PDL1 status was assessed per Ventana SP142 assay (positive immune cell score ≥ 1%). The primary objective is to evaluate the immune-based mechanism of action of single-dose trilaciclib. Results: As of January 3, 2023, 18/24 pts had completed treatment and/or had definitive surgery; 1 pt with neuroendocrine features discontinued due to disease progression. Median age was 57 years. At diagnosis, 79% of pts had stage II tumors (88% with ductal carcinoma; 38% with PDL1+ tumors). 18 pts received pembro + carbo, 3 pts pembro only, and 3 pts carbo only. Common treatment-related adverse events (TRAEs) were fatigue (79%), nausea, (67%), alopecia (67%), and neutropenia events (63%); 42% of pts had grade 3/4 neutropenia events. 4 serious TRAEs occurred in 2 (8%) pts: pembro-related colitis and hypertransaminasemia, trilaciclib/paclitaxel-related urosepsis, and AC-related febrile neutropenia. Response data were available for 15 pts; pathologic complete response (pCR) was observed in 7 (47%) pts, with pCR rates of 86% vs 13% for pts with PDL1+ vs PDL1– tumors, respectively. Immune analysis of the TME post trilaciclib monotherapy demonstrated several pCR-related features, such as increased stromal tumor-infiltrating lymphocytes and granzyme B+ cells. Correlative blood analysis revealed increased circulating baseline CD8+ T cells in pts achieving pCR. Conclusions: Safety and tolerability data are encouraging for trilaciclib in combination with AC/T ± pembrolizumab ± carboplatin in the neoadjuvant setting for early-stage TNBC. Preliminary efficacy data align with standard neoadjuvant chemotherapy regimens. Final pCR data from all pts and immune correlates from tumor and blood samples will be presented. Clinical trial information: NCT05112536 .

Clinical and pathological description of patients with triple negative breast cancer undergoing neoadjuvant chemotherapy and pembrolizumab in a Brazilian cancer center.

e14632 Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). In TNBC, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials, in this last scenario the addition of pembrolizumab to platinum containing NACT resulted in a significant increase of pathological complete response. Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab treaties from January 2022 to January 2023, in AC Camargo Cancer Center, São Paulo, Brazil, to evaluate their clinical-pathological characteristics. Results: All 52 patients were women, 60,4% premenopausal, with a median age of 42 years old when diagnosed, 59.6% had comorbidities, most commonly hypertension, and 1.9% had an autoimmune disease. About 16.7% germline mutation in the BRCA 1 and 8.3% in the BRCA 2 gene. Regarding pathological characteristics of the tumor, 98% were invasive ductal carcinoma, 78% with histological grade III, 89.8% had nuclear grade III, 51.1% with score 3 mitoses. There were 56,3% with weak, 35,4% with moderate, and 8,3% with intense Tumor Infiltrating Lymphocytes Stromal (TILS). In 47.1% of cases, the ki67 was greater than 80%. The expression of HER 2 was low in 23,8%. About the clinical stage of the tumor 65.4% were cT2 and 17.3% cT3, being cN0, cN1 and cN2a was 40.4%, 36.5% and 13.5%, respectively and grouped clinical stage 40.45 IIA, 25% IIB and 19.2% IIIA. Treatment-related toxicities 20% patients had immune related toxicities, being the main one 30% endocrinologic and 20% hepatic, being that 36.4% occurring after the second cycle. Due to the toxicities, 22.2% of the patients had their treatment delayed. In terms of treatment, 68.6% had begun with platinum and taxane, and 7.8% received dense dose AC (ACdd). Now, only 42.6% of the patients have completed all NACT and 53.2% are still on treatment. From these, 56.8% had complete clinical response, 2.3% stable disease and and those who have already finished and operated 66.7% complete pathological response. Conclusions: Our cohort is mostly pre-menopausal cT2, cN0, stage IIA. Twenty percent of them had IRT, the most common being endocrine and hepatic, which occurred early after the second cycle, leading to treatment delay in 22.2%. About 8% received ACdd, of the patients who completed the treatment and underwent surgery, 66.7% had a complete pathological response.

National trends in neoadjuvant chemotherapy utilization for cT1-2 N0 triple negative breast cancer: Did the CREATE-X trial impact treatment patterns?

e12599 Background: Neoadjuvant chemotherapy (NAC) for operable breast cancer allows for in-vivo assessment of chemotherapy response with survival and therapeutic implications. In 2017, the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial demonstrated significant improvement in survival with the addition of adjuvant capecitabine in patients with triple negative breast cancer (TNBC) and residual disease after NAC. These results provided the rationale for NAC even in early stage TNBC. The aim of this study was to assess U.S. national rates of NAC utilization in early-stage node-negative TNBC patients before and after the release of CREATE-X and to assess factors associated with receiving NAC vs adjuvant chemotherapy (AC). Methods: The National Cancer Database was queried for women with cT1-2N0M0 TNBC from 2014–19. NAC utilization was collected and categorized as 2014-15 (pre-CREATE-X), 2016-17 (transition yrs), and 2018-19 (post-CREATE-X). Those who did not receive chemotherapy were excluded. NAC use over time was analyzed via multivariable logistic regression (MLR). Clinical and demographic factors associated with NAC vs AC utilization were assessed using ANOVA, Chi-squared, and Fisher Exact tests. A MLR model was used to determine predictors of receipt of NAC vs AC. Results: 55,633 women were treated from 2014-19: 26.9% with NAC, 52.4% with AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71yrs, respectively, p &lt; 0.01). Most had cT1c (32.7%, n = 18,190) or cT2 (41.95%, n = 23,331) tumors and 99% had invasive ductal pathology. NAC utilization significantly increased over time, 19.5% (n = 3,465 of 17,777) in 2014-15, 27.1% (n = 5,140 of 18,985) in 2016-17, and 33.6% (n = 6,337 of 18,871) in 2018-19 (p &lt; 0.01). On MLR analysis, increased use of NAC was associated with younger age ( &lt; 50yrs), non-Hispanic white patients, having no comorbidities, having a cT2 tumor, grade 2 disease, and care at an academic or integrated network cancer program (p &lt; 0.05 for all). Patients with Medicare and Medicaid insurance were less likely to receive NAC (p &lt; 0.01). Patients who traveled &gt; 60 miles to their treating facility were more likely to receive NAC (p &lt; 0.01). Conclusions: From 2014–19, NAC utilization increased for patients with cT1-2N0M0 TNBC coinciding with the release of the CREATE-X results. Findings demonstrate the significance of the multidisciplinary oncology team in developing individualized treatment plans based on emerging clinical trial evidence. Racial, socioeconomic, and access disparities were observed in NAC utilization and warrants further investigation and interventions to ensure equitable care. [Table: see text]

Association between genomic alterations and response of triple-negative breast cancers (TNBC) to talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy (NACT).

598 Background: TVEC is an engineered oncolytic virus (OVs) approved for the treatment of melanoma. We published a phase 1/2 trial combining TVEC with NACT in early stage TNBC demonstrating increased pathologic complete response (pCR) compared to expected rates with NACT. RNAseq was performed on 37 pretreatment samples from enrolled patients to identify potential predictive genomic alterations. Methods: Transcriptomic RNA sequencing analysis was performed on macrodissected tumor tissue through the Moffitt Molecular Genomics core using Illumina Truseq RNA exome kits. Read adapters were detected using BBMerge (v37.88) and removed with cutadapt (v1.8.1). For gene expression analysis, processed raw reads were aligned to human genome HG19 using STAR (v2.5.3a). Gene expression was evaluated as read count at gene level with HTSeq (v0.6.1) and Gencode gene model v19. Gene expression data were normalized and differential expression between experimental groups were evaluated using DEseq2 (v 1.38.2). Ensembl was used for SNP data search. Results: Tumor mutation burden was not significantly different between pCR and non-pCR samples (median 227 vs 222 mut/MB, p = .11). Top 5 upregulated non-immunoglobulin genes associated with pCR in baseline samples were MYBL1, DNAH8, NR2E1, FGFR2, and SLC12A1 (FDR &lt; 1%). A single nucleotide polymorphism (SNP) of the EIF2A gene (c.C290G, p.T97S) was the top variant associated with response present in 21/37 samples (non-pCR = 17/21 vs. pCR = 4/21, FDR = &lt; 1%). This exon 4 coding region SNP is present in 17% of Black, 35% of White, and 46% of Asian individuals but its biologic or clinical significance is unknown. Lower EIF2A pathway activation was associated with inferior response to therapy. Additional data will be presented at the meeting. Conclusions: Genomic alterations including a EIF2A SNP were correlated with response to OV plus NAC in TNBC. EIF2A is an important mediator of cellular responses to OV and may play a role in susceptibility to oncolysis. Additional investigation and validation of these variations in experimental models of OV susceptibility may provide predictive biomarkers for TNBC patients treated with OV plus NAC therapy. Clinical trial information: NCT02779855 .