HER2-negative Breast Cancer Patients Research Articles

The ratio of PD1+CD8+T cells in stromal area of tumor tissue is associated with the effect of neoadjuvant chemotherapy in HER2 negative breast cancer patients.

e12626 Background: For patients diagnosed with early breast cancer, surgery remains the standard of care. Early patients achieving pathological complete response (pCR) after neoadjuvant therapy have been proved to be associated with improved survival. However, the accurate prediction of pCR in a clinical setting remains challenging. Tumor infiltrating lymphocyte (TIL) levels have recently been identified as an independent predictor of pCR in breast cancer. However, due to extremely complex tumor microenvironment within tumor, the role of different immune cell subtypes in neoadjuvant chemotherapy (NAC) is inconclusive. This study aimed to explore the potentially predictive role and dynamic changes of immune cell subsets in patients with HER2 negative breast cancer receiving NAC. Methods: Since January 2020, tumor tissue samples of 12 HER2 negative breast cancer patients were collected at baseline and after NAC. Several kinds of immune cells including CD3+T cells, CD4+T cells, CD8+T cells, PD-1+CD8+T cells, Tregs, M1/M2 tumor associated macrophages(TAM), PD-L1+CD68+TAM, B cells, CD56bright NK cells and CD56dim NK cells in the tumor tissue were evaluated by multiple fluorescence immunohistochemistry (mIHC) and counted in intratumoral and stromal area for density and ratio. T test was used for the comparison of immune cells and statistical significance was set at p = 0.05. Results: We examined immune cell subtypes and PD-L1/PD-1 expression of 12 HER2 negative breast cancer patients. According to achieving pCR or not, these 12 patients were divided into two groups, pCR (n = 3) and non-pCR group (n = 9). The results showed that the ratio of PD1+CD8+T cells in stromal area of baseline tumor tissue of pCR group was significantly higher than non-pCR group (median ratio, pCR group vs. non-pCR group = 17.3% vs. 3.6%, p = 0.029).In addition, the ratio of PD1+CD8+T cells in stromal area of pCR group was still significantly higher than that of non pCR patients after NAC (median ratio, pCR group vs. non-pCR group = 20.7% vs. 2.6%, p = 0.0003). Conclusions: Whether at baseline or after NAC, the ratio of PD1+CD8+T cells in stromal area is associated with the effect of NAC in HER2 negative breast cancer.

FTO genotype was associated with breast cancer in HER2 negative patients.

The fat mass and obesity-associated (FTO) gene may influence the risk of breast cancer (BC). The single nucleotide polymorphisms (SNPs) of FTO gene may exert different impacts on different types of BC. In this study, we investigated the association between FTO SNP rs9939609 and the status of estrogen receptor (ER), progesterone receptor (PR), P53, and human epidermal growth factor receptor-2 (HER-2) in BC patients. Our case-control study was included 540 Iranian participants aged 35 to 70 (180 women with BC as the case group and 360 healthy controls). After genotyping for risk allele rs9939609 of the FTO gene, a logistic regression was applied to elucidate the association between FTO SNP rs9939609 and BC risk based on the receptor status. The number of HER-2 negative patients was significantly higher in FTO rs9939609 risk allele carrier group (61.5% vs. 41.4%, P<0.05). A significant association was found between BC and rs9939609 FTO gene polymorphism only in HER2 negative BC patients (OR=1.79, CI95%: 1.2-3.56, P=0.03). No association was identified between FTO rs9939609 polymorphism and the status of ER, PR, and P53. We indicated that FTO SNP rs9939609 can be a potential therapeutic target particularly in HER-2 negative BC cases. The importance of this risk allele in BC pathogenesis needs to be further highlighted.

Differences in tumor microenvironment between HER2-positive and HER2-negative breast cancer.

e12562 Background: The tumor microenvironment of breast cancer is extremely complex, which containing different types of lymphocytes, macrophages, NK cells and other immune cell subtypes. At present, the relationship between immune cell subtypes and molecular subtypes of breast cancer is still unclear. Methods: Tumor tissue samples of 20 breast cancer patients were collected from January 2020. Then the density (number of positive cells/mm2) and ratio of immune cells in intratumoral area and stromal area were detected by multiple fluorescence immunohistochemistry (mIHC), the detection range was included CD3+T cells, CD4+T cells,CD8+T cells,PD-1+CD8+T cells,Tregs,M1/M2 tumor associated macrophages (TAM), PD-L1+CD68+TAM,B cells,CD56bright NK cells and CD56dim NK cells and so on. The immune cell subtypes of all area were included both intratumoral area and stromal area. Graphpad prism (version 7.01) was used for t test and the statistical significance was set at p=0.05. Results: These 20 patients were divided into two groups, HER2 positive (n=8) and HER2 negative group (n=12). The density of CD3+T cells in all area (including intratumoral area and stromal area) of tumor tissue in HER2 positive breast cancer patients were significantly higher than that of HER2 negative breast cancer patients (median density, HER2 positive group vs. HER2 negative group=2998 vs. 1520/mm², p=0.031) as well as the CD8+T cells (median density, HER2 positive group vs. HER2 negative group=536 vs. 175/mm², p=0.015). Meanwhile, the density of Tregs in all area of tumor tissue in HER2 positive breast cancer patients was also significantly higher (median density, HER2 positive group vs. HER2 negative group=119 vs. 27/mm², p=0.022).However, there was no significant difference in the other subtypes of immune cells infiltrated in tumor tissue between HER2 positive and HER2 negative samples, such as CD4+T cells, M1/M2 macrophages, B cells and so on (p＞0.05). Conclusions: Our research indicates that the patterns of immune cell subtypes in different types of early breast cancer are different. Further exploration of the immune microenvironment in different molecular types of breast cancer may provide additional targets for immunotherapy.

Identification of immune-related biomarkers for predicting neoadjuvant chemotherapy sensitivity in HER2 negative breast cancer via bioinformatics analysis.

Neoadjuvant chemotherapy (NAC) is an important treatment for breast cancer (BC) patients. However, due to the lack of specific therapeutic targets, only 1/3 of human epidermal growth factor receptor 2 (HER2)-negative patients reach pathological complete response (pCR). Therefore, there is an urgent need to identify novel biomarkers to distinguish and predict NAC sensitive in BC patients. The GSE163882 dataset, containing 159 BC patients treated with NAC, was downloaded from the Gene Expression Omnibus (GEO) database. Patients with pathological complete response (pCR) and those with residual disease (RD) were compared to obtain the differentially expressed genes (DEGs). Functional enrichment analyses were conducted on these DEGs. Then, we intersect the DEGs and immune-related genes to obtain the hub immune biomarkers, and then use the linear fitting model ("glm" package) to construct a prediction model composed of 9 immune biomarkers. Finally, the single sample gene set enrichment analysis (ssGSEA) algorithm was used to analyze immune cell invasion in BC patients, and the correlation between immune cell content and immune gene expression levels was analyzed. Nine immune-related biomarkers were obtained in the intersection of DEGs and immune-related genes. Compared with RD patients, CXCL9, CXCL10, CXCL11, CXCL13, GZMB, IDO1, and LYZ were highly expressed in pCR patients, while CXCL14 and ESR1 were lowly expressed in pCR patients. After linear fitting of the multi-gene expression model, the area under the curve (AUC) value of the ROC curve diagnosis of pCR patients was 0.844. Immunoinfiltration analysis showed that compared with RD patients, 15 of the 28 immune cell types examined showed high-infiltration in pCR patients, including activated CD8 T cells, effector memory CD8 T cells, and activated CD4 T cells. This investigation ultimately identified 9 immune-related biomarkers as potential tools for assessing the sensitivity of NAC in HER2-negative BC patients. These biomarkers have great potential for predicting pCR BC patients.

Eribulin combined with anlotinib for patients with HER2-negative metastatic breast cancer: A single-arm, multicenter, phase II study.

e13051 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor with a distinct mode of action which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of combined treatment with eribulin and anlotinib in patients with HER2-negative metastatic breast cancer (NCT04624711). Methods: This open-label, single-arm, phase II study enrolled females with HER2-neagtive breast cancer who underwent ≥1 line chemotherapy, including anthracyclines and taxanes, for metastatic breast cancer. Patients with hormone receptor positive breast cancer have underwent ≥1 line endocrine therapy. All patients were treated with Eribulin mesylate (1.4mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to February 2022, 25 patients were enrolled in this study. Median follow-up was 3.45 months (95% CI 3.16-5.06). Median PFS was 4.6 months (95% CI 3.55-5.65). Of all the patients whose efficacy could be evaluated (21/25), no patient achieved complete response (CR); 9 (40.91%) and 10 (45.45%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 40.91% and DCR was 86.36%. OS has not reached. The major treatment-related adverse events (incidence≥10%) were neutropenia(48.00%), anemia(37.93%), platelet count decreased (34.48%), fatigue (31.03%), hypoalbuminemia (20.69%), constipation (13.79%), elevated lactate dehydrogenase(13.79%), lymphocyte count decreased (10.34%) and hypertriglyceridemia (10.34%). The most common grade 3/4 adverse events were neutropenia (20.00%). 16.00% (4/25) of patients had dose reductions. Conclusions: The combination of eribulin and anlotinib showed a better treatment response and tolerable toxicity in HER2-negative metastatic breast cancer patients. Further studies enrolling more patients are still needed. Clinical trial information: NCT04624711.

Prophylactic use of metformin in patients on alpelisib treatment.

e13040 Background: Alpelisib-induced hyperglycemia (HG) is the most common adverse event leading to interruption, reduction or withdrawal of the treatment. HG is an on-target effect that depends on the baseline metabolic status of the patient. In SOLAR-1 90,6% patients with high-risk at baseline HG G3/G4 was reported. Prophylactic use of metformin may prevent HG in patients at risk. Methods: HR+ HER2-negative advanced breast cancer patients were stratified to low-, moderate- or high-risk groups of HG based on the algorithm published in [1] before starting alpelisib 300 mg + fulvestrant (Alp + Fulv). Moderate- and high-risk patients used prophylactic metformin at 500-1000 mg or 2000 mg BID with breakfast and dinner (Table). Metformin was started at least one-week prior Alp administration. Fasting plasma glucose (FPG) was monitored qw and bw in low- and moderate-risk patients, and daily with home glucometer in addition to bw FPG for high-risk patients. The primary endpoint of retrospective analysis was to assess the incidence of HG G3/G4 in different risk groups based on CTCAE V4.03 guidelines. Results: A cohort of 18 patients (median lines of previous treatment in advanced disease was five, all patients has received CDK4/6 inhibitors) treated with Alp+Fulv in the Loginov Moscow Clinical Scientific Centerin 2020-2021 included 7 low-, 3 moderate- and 8 high-risk patients. Any grade HG was reported in 13 out of 18 pts; no cases of HG G2 or G4 were detected. HG G3 was reported in 5 out of 18 patients including in 2 out of 3 moderate-risk patients, and in 3 out of 8 high-risk patients. Anti-HG drugs used included metformin (6/18); empagliflozin (4/18), and linagliptin (1/18); 1 patient required Alp dose reduction to 250 mg due to HG G3; none discontinued Alp due to AEs. Other AEs included rash (7/18; no grade 4; grade 3 in 4/18), and blood creatinine increase (8/18 – all grade 1-2).The median PFS on treatment with Alp+Fulv was 7 months. Conclusions: Prophylactic use of metformin in patients with high risk of hyperglycemia could markedly reduce frequency and severity of hyperglycemia on alpelisib.[Table: see text]

Prognostic implications of HER2Neu-low in metastatic breast cancer.

1044 Background: HER2-Low (or HER2-equivocal, FISH negative) breast cancer has historically been treated as HER2-negative; however, recent evidence suggests that there may be prognostic and/or predictive differences between the two. We explore demographic characteristics and clinical outcomes of HER2-negative and HER2-low metastatic breast cancer (MBC) patients using real world data. Methods: We queried the National Cancer Database to identify MBC patients that were HER2 0, HER2 1+, or HER2 2+ per immunohistochemical staining, with the latter two defined as HER2-low and the former HER2-negative. A multivariable binomial regression analysis identified demographic and clinical correlates of each subtype. A Cox multivariable regression analysis (MVA), propensity matched to HER2 status, was performed to identify correlates of survival. Results: After excluding missing data, 24,636 MBC patients diagnosed between 2008-2015 were identified, 6,865 (27.9%) of whom were HER2-negative and 17,771(72.1%) of whom were HER2-low. There were no differences between the two groups with respect to age, race, year treated, location, income, insurance status, Charles Deyo comorbidity score, laterality, T stage, N stage, or use of systemic therapy. HER2-low tumors were half as likely to have concomitant hormone receptor-negative status (OR = 0.49, 95% CI 0.46-0.53). The 3-year survival rate among hormone receptor-negative patients was 33.8% for HER2-low and 32.2% for HER2-negative, and 60.9% and 55.6% in HER2-low and HER2-negative cases among hormone receptor-positive patients, respectively. HER2-low cases were associated with better survival on MVA (HR = 0.91, 95% CI 0.87-0.95), and remained superior with propensity-matching (HR = 0.92, 95% CI 0.89-0.96). In a subset analysis isolated to hormone receptor-positive cases, HER2-low remained correlated with improved survival (HR = 0.93, 95% CI 0.89-0.98) with propensity-matched MVA. Correlates of worse survival include older age as a continuous variable (HR = 1.02), Black race (HR = 1.13), uninsured (HR = 1.18), comorbidity score &gt; 0 (HR = 1.28), higher T stage (HR = 1.17 to 2.34), node positivity (HR = 1.17) and, as the most influential, hormone receptor-negative status (HR = 1.94) [all P &lt; 0.01]. Conclusions: Consistent with recent data in non-MBC, our study demonstrates a small but statistically significant association with improved survival for HER2-low tumors compared to HER2-negative tumors in MBC. Randomized data are necessary to further validate this discrepancy and determine if different management is warranted for each subtype.

Single center experience with alpelisib-fulvestrant in heavily pretreated women with HR(+), HER-2 (−) metastatic breast cancer.

e13034 Background: HR-positive, Her2-negative metastatic breast cancer patients harboring PIK3CA mutations are associated with resistance to endocrine therapy and worse prognosis. Results from the phase III SOLAR-1 trial demonstrate improved PFS for patients treated with Alpelisib-Fulvestrant after failure on first or second line treatment with aromatase inhibitor. Methods: Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations. New generation sequencing (NGS) was the preferred technique to identify carriers with PIK3CA mutations on soft tissue or liquid biopsy. Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy. Results: Among 32 patients (pts) screened, 13 (40,6%) had a PIK3CA mutation. In total, 11 pts received alpelisib. Median age at diagnosis was 57.5 years (range, 39-69). Eight pts (72.7%) had been operated for early-stage breast cancer, 6 (54.5%) had received adjuvant chemotherapy and 5 (45.5%) had received adjuvant radiotherapy. Of 11 pts with evaluable histology, 3 pts (27.3%) had high grade tumors at diagnosis. Ten pts (90.9%) had PR positive tumors. Median Ki67 was 20% (range, 2-80). Eight pts (72.7%) had PIK3CA exon 20 and 3 (27.3%) had exon 9 mutations. Six pts (54.5%) had received prior chemotherapy in the metastatic setting and 10 (90.9%) prior CDK4/6 inhibitor. Three pts (27.3%) received Alpelisib as 2nd line and all remaining patients received alpelisib beyond 3rd line treatment. All pts (100%) had metastasis to the bones, 8 pts (72.7%) to the liver, 6 pts (54.5%) to the lungs and 2 pts (18.2%) to the brain. Until the date of last assessment, Alpelisib was administered for a median of 5.1 months (range, 0.4-21.3). Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response. Median duration of disease control was not reached. Baseline characteristics were not associated with disease control. Adverse events noticed were thrombocytopenia grade II (1/11), diarrhea grade II (2/11), skin rash grade I &amp;II (4/11), weakness grade III (1/11) and hyperglycemia (3/11). Conclusions: Prevalence of PIK3CA mutations is consistent with published data. Furthermore, combination of Alpelisib-Fulvestrant is a highly active line of therapy even in heavily pretreated patients.

Maintenance endocrine therapy plus bevacizumab for advanced or metastatic breast cancer.

Endocrine therapy is the preferred option for patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, first-line chemotherapy is used in approximately half of this patient population, notably in the context of organ failure or resistance to endocrine therapy. 2 Werutsky G Reinert T Rosa ML Barrios CH Real-world data on first-line systemic therapy for hormone receptor-positive HER2-negative metastatic breast cancer: a trend shift in the era of CDK 4/6 inhibitors. Clin Breast Cancer. 2021; 21: e688-e692 Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar In these patients, chemotherapy is frequently stopped, despite disease stabilisation, because of acute and cumulative toxic effects. 4 Giuliano M Schettini F Rognoni C et al. Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis. Lancet Oncol. 2019; 20: 1360-1369 Summary Full Text Full Text PDF PubMed Scopus (66) Google Scholar Switching to maintenance endocrine therapy after first-line induction chemotherapy has been proposed to improve disease control and to maintain quality of life (QOL). Switch maintenance therapy is regularly used in clinical practice, 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar , 3 Jacquet E Lardy-Cléaud A Pistilli B et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer. 2018; 95: 93-101 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar although clinical trials attesting to its relevance are scarce. 5 Ren W Yu Y Hong H et al. Clinical evidence of chemotherapy or endocrine therapy maintenance in patients with metastatic breast cancer: meta-analysis from randomized clinical trials and propensity score matching of multicentre cohort study. Cancer Res Treat. 2022; (published online Feb 4.)https://doi.org/10.4143/crt.2021.698 Crossref PubMed Google Scholar Moreover, the first-line combination of bevacizumab (an anti-angiogenic monoclonal antibody) plus chemotherapy has been shown in clinical trials to improve progression-free survival, although its effect on overall survival remains controversial. 6 Miyashita M Hattori M Takano T Toyama T Iwata H Risks and benefits of bevacizumab combined with chemotherapy for advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer. 2020; 27: 347-354 Crossref PubMed Scopus (7) Google Scholar These results have led to the consideration of this combination as an acceptable first-line strategy. 1 Gennari A André F Barrios CH et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32: 1475-1495 Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Similarly, bevacizumab plus endocrine therapy is efficacious in improving progression-free survival and overall survival while being well tolerated as a first-line treatment for advanced or metastatic breast cancer. 7 Martín M Loibl S Hyslop T et al. Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006–11_GBG51) and CALGB 40503 (Alliance) trials. Eur J Cancer. 2019; 117: 91-98 Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Switch maintenance endocrine therapy plus bevacizumab after bevacizumab plus paclitaxel in advanced or metastatic oestrogen receptor-positive, HER2-negative breast cancer (BOOSTER): a randomised, open-label, phase 2 trialSwitch to maintenance endocrine therapy plus bevacizumab with the possibility of weekly paclitaxel reinduction if needed is an efficacious alternative, with a better safety profile, to continuing weekly paclitaxel plus bevacizumab in patients with ER-positive, HER2-negative advanced or metastatic breast cancer who have responded to induction therapy. Full-Text PDF

Role of Oncotype-DX testing in older versus younger women with hormone receptor positive & Her-2 negative early stage breast cancer

Introduction: Oncotype DX Breast Recurrence Score (RS) has proven to be useful in predicting the risk of recurrence and the potential benefit of chemotherapy in hormone-receptor positive, HER-2 negative early-stage breast cancer patients. The aim of this study (part of service evaluation) was to explore the role of Oncotype DX recurrence scores in the treatment of older versus younger women, treated within the Hywel Dda Health-Board between 2010 to 2018.

57TiP SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA trial

The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is »60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis.

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors.

BackgroundBreast cancers are heterogeneous with variable clinical courses and treatment responses.ObjectiveWe sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.Patients and MethodsNewly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment.ResultsThirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2−/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029).ConclusionsSerial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy.Clinical trial registrationClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-022-00886-x.

Repercussions of COVID-19 pandemic impacts on non-metastatic HER2-negative breast cancer diagnosis and neoadjuvant treatment over patients’ quality of life and mental health/ Repercussões dos impactos da pandemia COVID-19 no diagnóstico e tratamento neoadjuvante de câncer de mama HER2-negativo não metastático sobre a qualidade de vida e saúde mental das pacientes

OBJECTIVE: To understand if COVID-19 pandemic impacts on delays in non-metastatic HER2-negative breast cancer diagnosis and in the beginning/development of neoadjuvant chemotherapy, as well as on changes in treatment plan to Paclitaxel intensification doses, impaired patients’ quality of life and mental health. METHODS: This is a cross-sectional study of 67 women diagnosed with non-metastatic HER2-negative breast cancer during the first sixteen months of COVID-19 pandemic and receiving neoadjuvant treatment due to pandemic impossibility of immediate definitive cancer surgery following the neoplasm diagnosis. Sociodemographic, Functional Assessment of Cancer Therapy Scale - General, Beck Anxiety and Depression Inventory were used for outcomes assessment. Inferential analysis was performed by Mann-Whitney, Pearson's chi-squared, and Fisher's exact tests. The adopted significance was 5%. RESULTS: The study revealed that the oncological diagnosis delays caused a worsening of the patients' physical (8 x 21; p = 0.001), functional (13 x 21; p = 0.03) and general (61 x 83; p = 0.004) well-being; retardment in the beginning of neoadjuvant chemotherapy decreased physical well-being (13 x 21; p = 0.01). Changes in treatment plan, to Paclitaxel doses intensification, had a negative effect on functional well-being (20 x 25.5; p = 0.04). COVID-19 pandemic impacts on neoplasm diagnosis and neoadjuvant treatment delays were also associated with psychosocial manifestations, including higher levels of severe anxiety (60% x 14.5%; p = 0.03 and 40% x 14%; p = 0.04) and depression (40% x 3.2%; p = 0.004 and 60% x 5.3%; p = 0.03) respectively. CONCLUSION: The present study shows that COVID-19 pandemic impacts on non-metastatic HER2-negative breast cancer patients’ diagnosis and neoadjuvant chemotherapy impaired patients' quality of life and mental health.

Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1

IntroductionThe combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2−) advanced breast...

Abstract P4-06-03: Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint

Abstract Background: MammaPrint (MP) is an FDA approved early breast cancer prognostic genomic assay that examines the expression levels of 70 genes and classifies clinically high-risk patients with early-stage breast cancer into low or high risk of distant metastasis. Current ASCO guidelines do not support using MP testing in clinically low-risk patients. Historically, assessing a patient’s clinical risk for breast cancer recurrence has relied on a subjective evaluation of histologic factors, immunohistochemical features, and clinical characteristics. Genomic assay testing provides more objective prognostic and predictive information than those more traditional methods; however, several studies have shown that statistical models using standard histologic variables can give valuable prognostic information, and might be used as an alternative approach to genomic assays for clinical risk-assessment and risk-stratification, particularly in lower risk breast cancer patients, potentially resulting in significant cost savings for health care systems. One of these statistical models, the average Modified Magee equation, has been shown to be prognostic for a low risk of recurrence in ER positive Her2 negative breast cancer patients who have an average Modified Magee score (aMMs) of ≤ 12. The aMMs has been shown to correlate well with the Oncotype DX recurrence score; however, there is limited data on the correlation between the aMMs and MP. In this study, we evaluated the concordance between the aMMs and the MP index (MPI). Methods: 222 consecutive patients with a new diagnosis of hormone receptor positive Her-2 negative breast cancer at the University of Rochester between April 2020 and December 2020 were sent for MP testing. The aMMs was determined for each patient based on the estrogen receptor status, progesterone receptor status, HER-2 status, Ki-67 proliferation index, Nottingham score, and tumor size. Based on the previous literature, patients were risk-stratified by the aMMs into three groups: 1) low risk (aMMs ≤ 12; n = 75); 2) low - intermediate risk (aMMs &amp;gt;12 and ≤ 18; n = 96); and, 3) high risk (aMMs &amp;gt;18, n = 51). Based on the previous literature, patients were risk-stratified by the MPI into two groups: 1) low risk (MPI 0 to +1); and, 2) high risk (MPI -1 to 0). The correlation between the aMMs and the MPI was evaluated using the Pearson correlation coefficient. Results: The aMMs showed a negative correlation (r= -0.55) with the MPI, consistent with a lower risk aMMs more likely being associated with a lower risk MPI. 92% of patients with an aMMs ≤ 12 (very low risk) were classified as low risk by MP. 72% of patients with an aMMs &amp;gt; 12 and ≤ 18 (low - intermediate risk) were classified as low risk by MP. 47% of patients with an aMMs &amp;gt; 18 (high risk) were classified as high risk by MP (Table 1). All patients with an aMMs ≥ 24.7 (n=8) were classified as high risk by MP. Conclusion: Our study suggests that hormone receptor positive, Her-2 negative breast cancer patients with a lower risk aMMs are likely to have a lower MPI, suggesting that these patients have a decreased risk for breast cancer recurrence. As the aMMs approaches higher risk, the concordance with the MPI decreases; however 100% of patients with an aMMs ≥ 24.7 were classified as high risk by MP. The aMMs can be helpful in clinical risk-assessment prior to making a decision about sending a patient specimen out for MP testing. Additional studies are warranted. Table 1.Risk of recurrence using the average Modified Magee score (aMMs) and the MammaPrint (MP) IndexaMMs Risk-stratification categoryMP Low risk n (%)MP High risk n (%)Very low (aMMs ≤ 12)69 (92%)6 (8%)Low - Intermediate (aMMs &amp;gt; 12 and ≤ 18)69 (72%)27 (28%)High (aMMs &amp;gt;18)27 (53%)24 (47%) Citation Format: Hani Katerji, Huina Zhang, David Hicks, Bradley M Turner. Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-03.

Abstract P4-06-07: Clinical risk-assessment, risk-stratification, and outcomes of ER positive, HER2 negative breast cancer patients using the Rochester modified Magee algorithm (RoMMA)

Abstract INTRODUCTION: In 2013, Klein and Dabbs et al. published three linear regression equations (the new Magee equations) using different combinations of standard histopathologic variables. In 2015, our group published a modification of the new Magee equations. Based on this modification, we published an algorithmic approach using an average Modified Magee equation. This algorithmic approach supported reflex Oncotype DX (ODX) testing based on several cutoff points using an average Modified Magee score. In 2019, we validated this algorithmic approach as the Rochester Modified Magee Algorithm (RoMMA) in a multi-institutional study, with outcome data in 247 patients, suggesting that ER positive breast cancer patients with an average Modified Magee score of ≤ 12 had a low risk of breast cancer recurrence. There has been limited published outcome data on the Magee equation since that 2019 study. We have further refined our risk-stratification approach, with additional outcome data in 416 ER positive breast cancer patients. METHODS: 416 patients with an ODX recurrence score who had at least five years of follow-up data or a breast cancer recurrence were included in the final outcome analysis (2008-2017). All patients received either Tamoxifen or an aromatase inhibitor. None of the patients received adjuvant systemic chemotherapy. The average Modified Magee score was calculated and patients were stratified into four risk-stratification categories: 1) very low, 2) low ≤ 50 years of age, 3) low &amp;gt; 50 years of age, and 4) high. We compared these four risk-stratification categories, with outcomes, between the average Modified Magee score and the ODX recurrence score. A p-value of &amp;lt; 0.05 was considered statistically significant. RESULTS: 27/416 (6.5%) patients had a recurrence of breast cancer. When comparing the same risk category groups, there was no significant difference between the average Modified Magee score and the ODX recurrence score (Table 1). CONCLUSION: Our study further reinforces that breast cancer patients can be confidently stratified into low and high risk recurrence groups using the average Modified Magee score. The average Modified Magee score may be an alternative to ODX for clinical risk-assessment and risk-stratification, particularly in lower risk patients, offering breast cancer patients increased access to clinical risk-assessment and risk-stratification, both domestically and internationally, with a potential significant cost savings for health care systems. A large prospective evaluation, similar to the studies done by ODX, using multi-institutional data or data from studies like the NSABP trial B-14 and the NSABP trial B-20, is necessary. Table 1.Risk-stratification categories and outcomes using the average Modified Magee score (aMMs) and the Oncotype DX recurrence score (ODXRS)RECURRENCENO RECURRENCEP-VALUEVERY LOW (N)aMMs ≤ 12 (76)1 (1.3)75 (98.7)0.65ODXRS &amp;lt; 11 (108)4 (3.7)104 (96.3)LOW ≤ 50 years of age (N)aMMs &amp;gt; 12, ≤ 18 (50)3 (6.0)47 (94.0)1.0ODXRS 11 - 15 (32)1 (3.1)31 (96.9)LOW &amp;gt;50 years of age (N)aMMs &amp;gt; 12, ≤ 18 (153)8 (5.2)145 (94.8)0.52ODXRS 11 - 25 (214)16 (7.5)198 (92.5)HIGH (N)aMMs &amp;gt; 18 (137)15 (10.9)122 (89.1)1.0ODXRS ≥ 16 - 25 (33)* and ODXRS &amp;gt; 25 (29)**6 (9.7)56 (90.3)* Patients ≤ 50 years of age with an ODXRS of ≥16 - 25. ** All patients with an ODXRS of &amp;gt; 25 Citation Format: Numbereye Numbere, Ioana Moisini, Ajay Dhakal, Kristin Skinner, Michelle Shayne, Mary Ann Gimenez Sanders, Huina Zhang, David Hicks, Bradley M Turner. Clinical risk-assessment, risk-stratification, and outcomes of ER positive, HER2 negative breast cancer patients using the Rochester modified Magee algorithm (RoMMA) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-07.

Abstract P1-08-18: Impact of gene expression profile testing for lymph node positive (LN+) , hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer (BC) patients on the use of adjuvant chemotherapy in a large community cancer center

Abstract Background: Use of gene expression profiling (GEP) is considered standard of care, in deciding use of adjuvant chemotherapy in patients with LN negative breast cancer. However, there are limited data for the use of GEP in LN+ disease. Both Mammaprint™ and Oncotype Dx 21 gene recurrence score™ (RS) have been evaluated in LN+ disease, the data are not as robust as in the LN- population. Based on data from the RXPONDER trial and the MINDACT trial, the NCCN has recently recommended the use of Oncotype Dx to help decide the utility and benefit of adjuvant chemotherapy after resection in LN- , Hormone receptor Positive (HR+), HER2 negative (HER2-) breast cancer patients. Because of the potential major impact of these data on patient management and healthcare utilization, we decided to explore the uptake and implementation of this testing at a large community cancer center in order to assess and report real world data pertaining to this novel standard of care. Methods: Database search of the Electronic Medical Records used at Ironwood Cancer Center, revealed 2455 newly diagnosed patients with early stage breast cancer during the period from 1/1/2018 till 6/1/2021. HIPAA deidentified data was extracted with inclusion criteria of newly diagnosed women with LN+ (1-3 nodes), HR+, and Her2- which yielded 403 patients. Demographics &amp; treatment data: Characteristics included menopausal status (Premenopausal 23%, Post Menopausal 77%), Surgery type (mastectomy 44%, breast conservation surgery 56%), size of primary tumor (0-1 cm 16 %, 1-2 cm 28%, 2-5 cm 43%, and &amp;gt; 5 cm 13%), LNs resected (Range 0-37, Median 4), # of LNs +(1-60%, 2-25%, 3-15%), and Tumor Grade (Grade 1-23%, 2-56%, 3-21%). GEP was performed in 62% of the patients. 49% received adjuvant chemotherapy (61% anthracycline based, 39% non anthracycline based). Of the patients tested, 41% received adjuvant chemotherapy. Adjuvant antihormonal therapy included aromatase inhibitors in 86% and Tamoxifen in 14%. 81% of the pre-menopausal patients received complete ovarian suppression. Results: Logistical Regression analysis in a non linear fashion, R2 data and Chi-square analysis was used to test the statistical significance of the observed relationship with respect to the expected relationship. The data was divided into 6 monthly intervals to allow comparison of the uptake of the test and impact on adjuvant chemotherapy decision making. There was a significant increase in GEP profile testing percentages when these intervals were compared across the years (R2 =0.69). Increase in GEP profiling was associated with lower utilization of adjuvant chemotherapy (R2= 0.84). There was a non-significant decline in the use of adjuvant chemotherapy (Chi2 NS, p value 0.22). Menopausal status, grade/size of tumor did not meet the statistical significance for the likelihood of utilization of the test. Currently multivariate analysis is being performed to examine the interplay between the numerous clinical factors on which the data was collected. This analysis will allow us to decide if we can longitudinally explore recurrence rates in each of these subsets. Conclusion: GEP has seen a significant uptake to help with adjuvant chemotherapy decision making in LN + (1-3) patients in the community cancer center setting over the last 4 years. These real world data also showed that increased testing was associated with decreased chemotherapy use which has translated to lowering health care resources and minimizing patient morbidity. Recommendations from the expert guidelines and clinical trial data have helped accelerate the use of this technology in the decision making to undergo adjuvant chemotherapy in the LN+, HR+, HER2- patients with breast cancer. Citation Format: Nisha Rao Kalmadi, Andrew Brown, Manas Sharma, Mikhail Shtivelband, Joshua Rifkind, Sujith Kalmadi, Rajesh Bagai, Emily Ho, Patricia Clark, Christopher Kellogg, Parvinderjit Khanuja. Impact of gene expression profile testing for lymph node positive (LN+) , hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer (BC) patients on the use of adjuvant chemotherapy in a large community cancer center [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-18.

Abstract P2-07-01: Blood tumor mutational burden (bTMB) and blood copy number burden (bCNB) by genome-wide circulating tumor DNA (ctDNA) assessment predict outcome and resistance in hormone-receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients (pts) treated with CDK4/6 inhibitor (CDK4/6i)

Abstract Background: CDK4/6i combined with ET improves survival for pts with HR+, HER2- MBC. However, biomarkers to predict efficacy and resistance are needed. We hypothesized that a comprehensive next-generation sequencing (NGS)-based liquid biopsy assessment of ctDNA mutation and copy number analysis may identify novel prognostic and predictive biomarkers. Methods: We collected serial blood for ctDNA testing from the 51 pts with HR+, HER2- MBC enrolled in the Alt Dose Palbo trial (NCT03007979), a single-arm phase II study of palbociclib plus letrozole or fulvestrant at 5 days on/2 days off weekly schedule as the first- or second-line ET. The median follow up was 38.2 months at data cutoff for this analysis. Plasma collected at baseline (BL) from all 51 pts, at progression (PD) from all 20 pts who have progressed, and at additional interim timepoints from 2 pts to explore longitutinal changes, with paired germline DNA, were subjected to the PredicineWES+ assay and low-pass whole-genome sequencing (lpWGS). The PredicineWES+ assay provides deep sequencing of 600 genes in the PredicineATLAS panel combined with whole-exome sequencing (WES) of all exonic regions of 20,000 genes enabling genome-wide detection of somatic single nucleotide variation (SNV), indels, copy number variation (CNV) and determination of bTMB. LpWGS offers an unbiased and high-throughput assessment of CNVs and tumor fraction in cell free DNA to derive bCNB. Statistical associations of bTMB, bCNB, and individual alterations with clinical benefit (CB), defined as no PD at 24 weeks by RECIST 1.1, and progression-free survival (PFS) were examined by Fisher’s exact test, Kaplan-Meier analysis, and Cox model. P values were adjusted to control false discovery rate (FDR). Results: The BL median bTMB was 1.6 mutations per megabase pair [IQR 0.6-3.5]. Pts with CB (N=41, 80%) had significantly lower bTMB scores (median [IQR] 1.2 [0.6-2.6] vs. 8.3 [2.4-21.4], (P&amp;lt;0.01) and significantly lower bCNB (P=0.03). bTMB and bCNB were highly correlated (Spearman correlation ρ =0.77, P=6.2E-11). bTMB above the predefined cutoff of 16 identified pts with significantly shorter PFS (4.7 vs 18.2 months, HR 3.73, CI 1.24-11.27, P=0.01). In contrast, BL clinical features including ET sensitivity, bone only vs. visceral, or de novo vs. recurrent MBC, were not associated with CB. BL alterations (SNV or CNV) in 91 genes, occurring in at least 3 pts each, were significantly associated with worse PFS (adjusted P&amp;lt;0.05), 61 of which were outside of the 600-gene panel. The 91 genes included both novel and previously reported alterations implicated in CDK4/6i and ET resistance. Examples include AR, ATM, AURKA, BRCA2, CCND1, DDR2, ESR1, FAT1, FGFR4, FOXP1, MYC, RB1, and RUNX1T1, some of which were also enriched at PD. Additional novel variants were enriched at PD, including ABCC12, ABCA13, SHANK1, and TET1. Serial analysis at BL, cycle 1 day 15 (C1D15), C2D1, the last Q3-month staging scan without PD, and at imaging detection of PD from 2 pts revealed a decline in bCNB at C1D15, then plateau, followed by an increase in bCNB that preceded imaging detection of PD. Conclusion: The comprehensive ctDNA profiling approach with PredicineWES+ and lpWGS identified high BL bTMB and bCNB as poor prognostic biomarkers in pts on CDK4/6i and ET. Our study also discovered novel candidate genes involved in cell cycle and DNA damage repair pathways in association with poor outcome. Results from this study highlight the genomic heterogeneity of HR+, HER2- MBC and provide important insights in the understanding of CDK4/6i and ET resistance mechanisms to guide therapeutic development in pts with resistant disease. Citation Format: Andrew Davis, Jingqin Luo, Tiantian Zheng, Lu Tan, Amy Wang, Rama Suresh, Foluso Ademuyiwa, Caron Rigden, Timothy Rearden, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Pavan K Tandra, Tracy Summa, Brittney Haas, Shana Thomas, Leonel Hernandez-Aya, Lindsay Peterson, Shujun Luo, Bonnie L King, Shidong Jia, Jianjun Yu, Pan Du, Jairam Krishnamurthy, Cynthia X Ma, C Dai. Blood tumor mutational burden (bTMB) and blood copy number burden (bCNB) by genome-wide circulating tumor DNA (ctDNA) assessment predict outcome and resistance in hormone-receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients (pts) treated with CDK4/6 inhibitor (CDK4/6i) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-01.

Abstract P5-01-11: Nonclinical activity of fulvestrant in a panel of ER+ breast XPDX models representing clinically acquired and innate resistance to endocrine therapies

Abstract Background: Fulvestrant is a selective estrogen receptor modulator (SERM) approved as a single agent for estrogen receptor positive, HER2 negative breast cancer patients at various stages of disease and in combination with CDK4/6 inhibitors following endocrine therapy failure. Although this agent requires intramuscular injection, it has demonstrated superior activity and fewer side effects versus some oral endocrine treatments however, resistance to fulvestrant often develops. To better understand fulvestrant resistance and its utility in patients who have failed other endocrine therapies, we evaluated the agent in a panel of ER+ breast models established from patients at various stages of disease representing endocrine-sensitive and -resistant disease. Methods: Sixty-five previously developed ER+ breast XPDX models were evaluated in this study. Models were grown subcutaneously in female athymic nude mice supplemented with estradiol in drinking water when necessary. All models were characterized at early and late passages for estrogen receptor expression by immunohistochemistry and profiled using WES and RNAseq. For in vivo studies, fulvestrant was administered by subcutaneous injection at 2.5 or 5 mg per dose once weekly until study completion. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C&amp;lt;0) versus Day 0 tumor volume was also reported. Models were grouped by patient clinical treatment prior to sample collection and model establishment including chemo-naïve, endocrine therapies other than fulvestrant, non-endocrine therapies, and fulvestrant. Results: All models retained ER expression in evaluated passages with similar histology compared with archival clinical samples. DNA/RNA sequencing identified several model-specific variants including ESR1 point mutations and fusions. In this study, 22% of models represented chemo-naïve patients, 24% were from patients treated with non-endocrine therapies, 20% were from patients treated with fulvestrant and the remaining 34% from patients treated with endocrine therapies other than fulvestrant. In vivo, 40% of the chemo-naïve group reported sensitivity to fulvestrant including several models with tumor regressions. Activity of fulvestrant was reported in 25% of models in the non-endocrine therapies group and in 20% of models from patients treated with either fulvestrant or endocrine therapies other than fulvestrant. Several models resistant to fulvestrant from chemo-naïve or patients treated with non-endocrine therapies harbored driver mutations including ESR1, PIK3CA, and AKT1 variants or were HER2+. In models from patients pretreated with fulvestrant, those who had also received a CDK4/6 inhibitor were particularly resistant. Conclusion: We evaluated fulvestrant in a panel of ER+ breast XPDX models representing endocrine-sensitive and -resistant disease from both chemo-naïve and pretreated patients, and identified models responsive and resistant to fulvestrant therapy. This panel can be utilized as a valuable tool in better understanding fulvestrant and endocrine therapy resistance and in developing novel therapies for patients resistant to currently available hormonal therapies. Citation Format: April Cabang, Crystal Moreno, Johnnie R Flores, Jenna Boedeker, Alyssa Simonson, Jun Ma, Amy Lang, Gladys Rodriguez, Arthur Rosenthal, Kyriakos Papadopoulos, Amita Patnaik, Drew Rasco, Lon Smith, Murali Beeram, Ronald Drengler, Luis Rodriguez, Steven Abbate, Scott Ulmer, Michael J Wick. Nonclinical activity of fulvestrant in a panel of ER+ breast XPDX models representing clinically acquired and innate resistance to endocrine therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-11.

Abstract PD14-09: APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD)

Abstract Background: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including BC. In our clinical experience, HR+HER2- BC with an APOBEC signature do poorly on standard of care (SOC) first line endocrine therapy (ET) + CDK4/6 inhibitor (CDK4/6i) and need additional treatment options. Here we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival (OS) on SOC and immune checkpoint inhibitors (ICI).Methods: Hybrid capture-based comprehensive genomic profiling (CGP) results from 29,833 formalin-fixed paraffin-embedded tissue biopsies of all BC subtypes were analyzed. For outcomes (TTD and OS), this study used a de-identified nationwide (US-based) BC clinico-genomic database (CGDB, ~800 sites of care, 1/2011 - 12/2020). HR+HER2- metastatic BC pts who received first line ET + CDK4/6i were included (CGDB cohort).TTD was defined as the difference between the first and last drug episode within a given line of treatment (LOT). LOT were derived based on FH algorithms. OS was defined as the time from LOT start to the date of death or data cutoff. Log-rank test and Cox model were used to evaluate the difference in outcomes. To reduce the impact of confounding variables (Age at Dx, Stage at Dx, Tumor Type, Metastases sites, TMB group (≥10 vs &amp;lt;10), SOC treatment group, PIK3CA), inverse probability of treatment weighting (IPTW) was used. Eligible pts from Mayo Clinic and Duke University were HR+HER2- mBC with sequencing data from FMI between 9/2013-7/2020. Clinical data were manually extracted from Mayo and Duke EHR. Results: Of all 29,833 BC samples in the CGP cohort, 7.9% were APOBEC+ with high rate in invasive lobular carcinoma (ILC) 16.7% vs. 4.9% in invasive ductal carcinoma (IDC) and metastatic lesions 9.7% vs. 4.3% from breast. APOBEC+ samples had a higher median TMB 12.5 vs. 2.5 mut/Mb. In CGDB, 857 HR+HER2- BC met inclusion criteria; 69 (8%) pts were APOBEC+ and 788 (9.2%) were APOBEC-. APOBEC+ pts had significantly shorter TTD on SOC ET+CDK4/6i than APOBEC- pts, 7.8 (95% CI 4.3-14.6) vs. 12.4 (95% CI 11.2-14.1) months (p=0.0036). APOBEC+ pts also had noticeably shorter OS compared to APOBEC- pts, 32.4 (95%CI 19.8-47.4) vs. 40.5 (95%CI 36.9-45.7) months (p=0.06).Cox regression results indicate that the relative risk of shorter TTD for the APOBEC+ vs the APOBEC- was 1.6 (95%CI 1.03-2.39). Also, APOBEC+ pts had almost twice the risk that APOBEC- pts had of death (HR=1.96, 95%CI 1.2-3.3). In CGDB, there were 10 APOBEC+ pts who received ICI, 9/10 had evaluable TTD data, 4/9 were still on treatment as of Dec 2020. 5/9 received ICI monotherapy, 4 pts received ICI + chemotherapy. TTD ranged from 0.3 to 11.3 mo, 1 pt’s TTD was &amp;gt; 6 mo. In Mayo and Duke cohort, there were 6 pts, 5/6 received ICI + chemotherapy. The TTD was 0.9-40.5 months with longest 2 pts receiving 5-FU plus ICI (11 and 40.5 months). To better understand the ICI treatment landscape, TTD in HR+HER2- hTMB MSS APOBEC- CGDB cohort (N=6) was analyzed: 5/6 had evaluable treatment data, 4/5 finished ICI treatment, 1 pt’s TTD was &amp;gt; 3 mo, 0/5 had TTD &amp;gt; 6 mo. Conclusions: APOBEC+ occurs in ~7% of BC and is more common in ILC and metastatic lesions. APOBEC+ HR+HER2- pts had shorter TTD and OS on SOC ET+CDK4/6i relative to APOBEC- pts. However, TTD on ICI tended to be longer in APOBEC+ pts, but our data is limited, and more research is needed. CGDB APOBEC+ vs. APOBEC- with SOC 1st lineAPOBEC+ (N=69)APOBEC- (N=788)p adjusted (FDR)*Age at Dx, Median (IQR)59.0 (53.0, 65.0)56.0 (47.0, 65.0)0.102Stage at Dx0.067- 0-III52 (75.4%)505 (64.1%)- IV11 (15.9%)245 (31.1%)- Not documented6 (8.7%)38 (4.8%)Metastasis free interval, yrs, Median (IQR)5.2 (3.0, 10.5)5.1 (2.8, 9.3)0.734Tumor Grade0.104- Grade 12 (2.9%)49 (6.2%)- Grade 234 (49.3%)259 (32.9%)- Grade 311 (15.9%)163 (20.7%)- Not documented22 (31.9%)317 (40.2%)Tumor Type0*- IDC7 (10.1%)251 (31.9%)- ILC30 (43.5%)138 (17.5%)- Other /Not documented32 (46.4%)399 (50.6%)Metastases sites0.734- Bone-only17 (24.6%)169 (21.5%)- CNS11 (15.9%)104 (13.2%)- Visceral41 (59.4%)514 (65.3%)TMB, Median (IQR)11.3 (8.8, 18.8)2.5 (1.3, 3.8)0*MSI0.946- MSI-H0 (0.0%)4 (0.5%)- MSI-I0 (0.0%)1 (0.1%)- MSS68 (98.6%)728 (97.2%)- Not documented1 (1.4%)16 (2.1%)BRCA5 (7.2%)45 (5.7%)0.734PIK3CA46 (66.7%)341 (43.3%)0.001*Treatments0.005*- AI + CDK4/6i31 (44.9%)510 (64.7%)- Fulvestrant + CDK4/6i38 (55.1%)278 (35.3%) Citation Format: Saranya Chumsri, Kira Raskina, Sarah Sammons, Laura Alder, Natalie Danziger, Alexa B Schrock, Kim McGregor, Ethan Sokol. APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-09.