Receptor-negative Tumors Research Articles

Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials

Distant recurrence in women with oestrogen receptor-positive early breast cancer persists at a constant rate for more than 20 years after diagnosis, with little equivalent data for oestrogen receptor-negative breast cancer. Using the database of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) we investigated rates of distant breast-cancer recurrence in oestrogen receptor-positive and oestrogen receptor-negative tumours and trends in outcomes over time. In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650 000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with oestrogen receptor-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or oestrogen receptor-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with oestrogen receptor-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded. The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment. Of the 652 258 women with early breast cancer in the EBCTCG database on Jan 17, 2023, patient-level data were available from 151 randomised trials that included 155 746 women. Rates of distant tumour recurrence improved similarly in women with oestrogen receptor-positive and oestrogen receptor-negative tumours. 80·5% of the improvement for oestrogen receptor-positive disease and 89·8% of the improvement for eostrogen receptor-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p<0·0001). More recently diagnosed patients were more likely to have node-negative disease. 10-year distant recurrence risks during 1990-99 versus 2000-09 were as follows: for node-negative disease, 10·1% versus 7·3% for oestrogen receptor-positive disease and 18·3% versus 11·9% for oestrogen receptor-negative disease; for disease with one to three positive nodes, 19·9% versus 14·7% for oestrogen receptor-positive disease and 31·9% versus 22·1% for oestrogen receptor-negative disease; and for disease with four to nine positive nodes, 39·6% versus 28·5% for oestrogen receptor-positive disease and 47·8% versus 36·5% for oestrogen receptor-negative disease. After adjustment for therapy, rates were reduced by 25% (oestrogen receptor-positive disease) and 19% (oestrogen receptor-negative disease) after 2000 versus the 1990s, with similar improvements observed in oestrogen receptor-positive disease beyond 5 years. Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. After adjustment, women diagnosed since 2000 have about a fifth lower rate of distant recurrence than the 1990s. Long-term risks of distant recurrence for oestrogen receptor-positive disease remain, but are about a tenth lower now than in our previous report. Cancer Research UK, UK Medical Research Council.

The Clinicopathological and Prognostic Significance of the Expression of PD-L1 and MET Genes in Breast Cancer: Potential Therapeutic Targets.

The heterogeneity of breast cancer requires exploring novel prognostic biomarkers as well as therapeutic targets for the treatment of the disease. The METABRIC dataset was used to describe the gene expression of the programmed death-ligand 1 (PD-L1) and the hepatocyte growth factor receptor (MET) and their association with the tumor clinicopathologic characteristics and overall survival in breast cancer. The expression of the PD-L1 and MET genes correlated positively with the Nottingham Prognostic Index (NPI) (p=0.003 and p < 0.001, respectively). The expression of the two genes correlated inversely with luminal A and luminal B tumors (r= - 0.089, p= 0.021 and r= - 0.116, p= 0.013, respectively). The PD-L1 mRNA levels were significantly higher in hormone receptor-negative and HER2-positive tumors. MET mRNA expression levels were significantly higher in hormone receptor-negative, HER2-enriched, and non-luminal breast cancers. The PD-L1/MET double-high expression was associated with younger age of patients at diagnosis, higher NPI scores, larger tumors, advanced stage, high-grade, hormone receptor-negativity, HER2-positivity, and non-luminal tumors. None of the genes or their double expression status was significantly associated with overall survival in this analysis. The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

Abstract C024: Evaluation of PI3K/AKT/mTOR pathway signaling as a prognostic indicator in Hispanic Mexican women with breast cancer

Abstract Breast cancer (BC) is among the most commonly diagnosed cancer in women and a leading cause of cancer death worldwide. Hispanic/Latina women represent a heterogeneous group with diverse genetic backgrounds, including varying proportions of Native American, European, African and to a lesser extent Asian ancestry. In the US, Hispanic and African American women have lower BC incidence overall yet higher incidence of triple negative breast cancer (TNBC). Furthermore, African American and Hispanic women tend to present with more aggressive disease, at younger ages and worse survival compared to women of European ancestry. These disparities have been attributed to biologic and non-biologic socioeconomic factors. Genomic analyses of Hispanic Mexican (HM) women have revealed specific genetic signatures distinct from those of non-Hispanic women. These variations include AKT kinase mutations activating PI3K/AKT/mTOR signaling pathway and PI3KCA mutations which could potentially benefit from targeted therapies. 4EBP1 phosphorylation by mTORC1 is generally considered a marker of activated mTOR signaling and high levels in tumors associate with worse outcomes in different cancers. To evaluate clinical significance of PI3KCA expression and PI3K/AKT/mTOR signaling, we performed immunohistochemical (IHC) analyses of tissue microarrays (TMA) including 272 BC patient samples from HM women. Protein expression of PI3KCA and p4EBP1 were evaluated quantitatively by receiver operator characteristics (ROC) curves based on area under the curve (AUC) as well as sensibility and specificity. p4EBP1 levels were associated with clinicopathological characteristics. Chi-squared and Fisher’s Exact tests showed higher p4EBP1 expression correlated with estrogen (P=0.001) and progesterone receptor negative BC (P=0.003), TNBC (P&amp;lt;0.001), tumor size (P&amp;lt;0.090), and advanced stage (P&amp;lt;0.001). PI3KCA expression was positively correlated with 4EBP1 expression (P=0.044) as shown by Mann Whitney U tests; but PI3KCA lacked prognostic value after screening through ROC curves. However, uni- and multi-variate Cox regression analyses did show that increased 4EBP1 expression correlates with worse OS. Overall, our study indicates that higher p4EBP1 expression is an independent prognostic factor of worse OS in BC patients. The activation of 4EBP1 may result from several upstream oncogenic alterations or mutations, representing a potential therapeutic target and biomarker. Further research is necessary to better define biological differences in Hispanic women to advance understanding and targeting of health disparities. [Funded by California Breast Cancer Research Program Idea Award B27IB3869, JCCC Breast Cancer Award, Hickey Family Foundation, NCI U54 CA143930, Team Research Grant, UCLA TDG, CIRM DISC2-14166]. Citation Format: Mario Morales Martinez, Giovanny Soca-Chafre, Altagracias Maldonado-Valenzuela, Clara M Rivera-Pazos, Gabriela Antonio-Andres, Mayra Montecillo-Aguado, Georgina Rocha-Lopez, Berenice Alcala-Mota-Velazco, Anel Gomez-Garcia, Madhuri Wadehra1, Richard J Pietras, Sergio Gutierrez-Castro, Sara Huerta-Yepez, Diana Marquez-Garban. Evaluation of PI3K/AKT/mTOR pathway signaling as a prognostic indicator in Hispanic Mexican women with breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C024.

Benefits of adjuvant treatment with the Pingxiao capsule in patients with early breast cancer: A single‑center retrospective cohort study.

Early breast cancer (EBC) is cancer that has not spread beyond the breast or the axillary lymph nodes. The present retrospective cohort study investigated the efficacy and safety of the Pingxiao capsule (PXC), which contains a formula of traditional Chinese herbs, as adjuvant therapy in patients with EBC in a single Chinese academic medical center. Patients with EBC who had received surgery and chemotherapy were analyzed and divided into the PXC and non-PXC groups. Disease-free survival (DFS) time, overall survival (OS) time, demographic characteristics and adverse events were examined. Kaplan-Meier survival curves were used to compare the differences in DFS and OS. A total of 371 participants with a median age of 54 years were included in this study. The median DFS time of all patients was 101 months. The overall DFS rate was 72.1% in the PXC group compared with 63.6% in the non-PXC group. For women with hormone receptor-negative tumors, the DFS rate in the PXC group was significantly higher than that in the non-PXC group, irrespective of node status. Adjuvant treatment with PXC for ≥3 months was associated with significantly longer median DFS time compared with that in the non-PXC group. In addition, the incidence of neutropenia rated to be grade 2 or higher was significantly lower in the PXC group compared with that in the control group, and a markedly, but non-significantly, lower prevalence of nausea was observed in PXC group (0 vs. 4.1%). In conclusion, PXC as an adjuvant therapy along with chemotherapy is associated with prolonged DFS times in patients with EBC when compared with chemotherapy alone. The therapeutic value of combined PXC and systemic chemotherapy should be further elucidated by rigorous prospective clinical trials.

Differential expression of NAT1 pharmacogene in hormone receptor positive vs. negative female breast tumors may affect drug treatment.

Studies have reported overexpression of NAT1 gene for xenobiotic metabolizing arylamine N -acetyltransferase type 1 in estrogen receptor positive breast tumors, and this association has been linked to patient chemoresistance and response to tamoxifen. We probed the expression of NAT1 , using quantitative reverse transcription PCR to screen clinically characterized breast cancer tissue cDNA arrays. Primers detecting all NAT1 alternative transcripts were used, and the protocol and results are reported according to consensus guidelines. The clinical information about 166 tumor samples screened is provided, including tumor stage, estrogen and progesterone receptor status and HER2 expression. NAT1 was found to be significantly ( P < 0.001) upregulated in hormone receptor positive vs. negative tumors. No correlation was apparent between NAT1 and tumor stage or HER2 expression. Our findings demonstrate a strong correlation between the expression of NAT1 and steroid hormone receptors in breast tumors, supporting its possible utility as a pharmacogenetic biomarker or drug target. Of the two polymorphic NAT genes, NAT1 is the one primarily expressed in breast tissue, and is subjected to regulation by two differential promoters and more than one polyadenylation signal. Hormonal factors may enhance NAT1 gene expression at the transcriptional or epigenetic level, and tamoxifen has additionally been shown to inhibit NAT1 enzymatic activity. The outcome of tamoxifen treatment is also more favorable in patients with NAT1 overexpressing tumors. The study adds to the growing body of evidence implicating NAT1 in breast cancer and its pharmacological treatment.

ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.

Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

Atypical memory B cells increase in the peripheral blood of patients with breast cancer regardless of lymph node involvement

BackgroundBreast cancer is the most common cancer in females. The immune system has a crucial role in the fight against cancer. B and T cells, the two main components of the adaptive immunity, are critical players that specifically target tumor cells. However, B cells, in contrast to T cells, and their role in cancer inhibition or progression is less investigated. Accordingly, in this study, we assessed and compared the frequency of naïve and different subsets of memory B cells in the peripheral blood of patients with breast cancer and healthy women.ResultsWe found no significant differences in the frequencies of peripheral CD19+ B cells between the patients and controls. However, there was a significant decrease in the frequency of CD19+IgM+ B cells in patients compared to the control group (P=0.030). Moreover, the patients exhibited higher percentages of atypical memory B cells (CD19+CD27‒IgM‒, P=0.006) and a non-significant increasing trend in switched memory B cells (CD19+CD27+IgM‒, P=0.074). Further analysis revealed a higher frequency of atypical memory B cells (aMBCs) in the peripheral blood of patients without lymph node involvement as well as those with a tumor size greater than 2cm or with estrogen receptor (ER) negative/progesterone receptor (PR) negative tumors, compared with controls (P=0.030, P=0.040, P=0.031 and P=0.054, respectively).ConclusionAtypical memory B cells (CD19+CD27‒IgM‒) showed a significant increase in the peripheral blood of patients with breast cancer compared to the control group. This increase seems to be associated with tumor characteristics. Nevertheless, additional research is necessary to determine the precise role of these cells during breast cancer progression

Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &amp;lt; 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive 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 PO2-18-12.

Abstract PO1-16-11: Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study

Abstract Background: BC is the most incident cancer worldwide in &amp;lt; 40 years old (y) women. Increasing body mass index and changes in reproductive history contribute to the growing incidence of premenopausal BC. A higher proportion of luminal B-like and estrogen receptor negative (ER─) tumors, an increased risk of early relapse, and more unfavorable longer-term outcomes for young women with ER+ tumors when compared to older women, have been reported. In this analysis, we focus on age-specific BC characterization from a real-world population-based perspective. Methods: Pts were enrolled in the non-interventional and ambispective RegistEM study in ABC diagnosed between 2016 and 2019. We describe the features and outcomes of &amp;lt; 50 y pts at their initial BC diagnosis according to their BC subtype. BC subtypes were based on the most recent tumor tissue sample (distant metastasis, and in its absence, primary BC). Comparisons between &amp;lt; 40 and ≥ 50 y groups were performed. Results: Pts &amp;lt; 50 y represent 39% (n=685) of total pts with available data (n=1739, any age group) in the registry. By age, 12% (n=212) were &amp;lt; 40y, and 27% (n=473) 40-49y. At first BC diagnosis, 75% and 25% pts had early BC (EBC) and de novo metastatic BC (MBC), respectively. In EBC pts, stage II (50%) and III (28%) were the most frequent at diagnosis; invasive non-special type carcinoma was the predominant morphology, and grade 2 was the most common histological grade, but grade 3 was predominant in TN pts and HER2+ &amp;lt; 40y pts. The median time to recurrence was &amp;lt; 2y in TN pts, 3y in HER2+ pts, and 6y in luminal HER2─ pts. At ABC diagnosis, the median age was 47y, all pts were female but one, 98% white, and 60% premenopausal (94% were premenopausal at EBC diagnosis). A family history of BC and/or ovarian cancer was reported in 34% pts, and a hereditary-risk genetic test was performed in 39% (254 of 652) pts; 12% (n=30) had BRCA1/2 mutations, with a proportion higher in TN pts (9 of 33, 27%) vs. luminal HER2─ (21 of 183, 12%) and HER2+ (0 of 38) pts. Visceral disease was the most frequent in all subgroups, highlighting statistical differences (p=0.022) between age groups ( &amp;lt; 40y 55% vs. ≥50y 71%) only in TN pts. 60% had ≤ 2 locations involved, similarly in all subgroups. The presence of &amp;gt;2 metastatic locations was statistically higher in HER2+ pts ≥50y (54%) vs both &amp;lt; 40y (32%) and 40-49y (48%). Brain disease was more present at ABC diagnosis in TN (9%) and HER2+ (7%) than in luminal HER2─ (3%). Median no. of treatment lines (L) was 3 (range 0-11), and median follow-up 44 mo (95% CI: 41-44). 99% pts received 1L, the distribution of treatments by BC subtype within each age subgroup was similar; median duration of 1L was 21 months (mo) in luminal HER2─, 17 mo in HER2+, and 5 mo in TN pts. 68% of pts who received 1L, reached 2L. Duration of 2L dropped dramatically: 8 mo in luminal HER2─, 6 mo in HER2+, and 2 mo in TN pts. No differences between ≥50y and the rest of pts were observed in PFS for any treatment line. 49% pts had died at the database cut-off date (05-April-23), with no differences between age groups, but TN pts had the highest death rate (80%). Additional data according to BC subtypes and age groups are in the table. Conclusions: Luminal HER2─ was the predominant BC subtype in all age subgroups. Visceral disease was more prevalent in young TN pts compared to older pts. TNBC pts experienced a shorter median time to recurrence and the highest mortality rate regardless of age, compared to HER2+ and luminal HER2- pts, indicating the need for targeted interventions in this subgroup. Citation Format: Sara López-Tarruella, Angel Guerrero, Isabel Álvarez, Silvia Antolin Novoa, Ariadna Tibau, Josefina Cruz, César A Rodríguez, Purificación Martínez, J. Ignacio Chacón, María Hernández, Mireia Margelí, Encarna Adrover, Catalina Falo, Iria González, Álvaro Rodríguez-Lescure, María Marín, César Gómez, Juan de la Haba-Rodríguez, J. José Illaramendi, Raquel Andrés, Andrea Blasco, Mª José Escudero, Susana Bezares, Federico Rojo. Real-world features and outcomes of young advanced breast cancer (ABC) patients (pts) from RegistEM (GEICAM/2014-03) study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-11.

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic 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 PS12-06.

Abstract PO4-15-10: HER2-low Status among Patients with Li-Fraumeni Syndrome and Breast Cancer

Abstract Background: The HER2-low status has gained significance as a target for HER2-directed antibody drug conjugates in breast cancer. It is observed in approximately 60% of hormone receptor-positive (HR+) tumors and 30% of hormone receptor-negative (HR-) tumors. Some studies suggest that the HER2-low status by itself does not influence tumor biology or prognosis. Breast cancer in the context of Li-Fraumeni (LFS) syndrome has been characterized by an enrichment in HER2-positive (HER2+, defined as +3 in the immunohistochemistry [IHQ] or +2 in the IHQ with positive in situ hybridization [ISH]) disease. Considering this, we aimed to evaluate whether LFS patients with breast cancer also exhibit a higher frequency of HER2-low status. Methods: This retrospective-prospective cohort study included patients diagnosed with breast cancer who had a pathogenic/likely pathogenic TP53 germline variant and were treated at two cancer institutions between 1999 and 2023. The primary objectives were to determine the overall proportion of HER2-low status and its distribution according to hormone receptor status. HER2-low was defined as IHQ +1 or IHQ +2 with negative ISH. Results: Fifty-three patients (52 female and 1 male) were included in the study. The most common germline TP53 variant was the TP53 R337H (71.7%). The median age at breast cancer diagnosis was 39 years (range 21–62). The majority of patients had breast cancer of no special type (79%) or lobular carcinoma (11.3%), grade 2 (54.7%) or grade 3 (24.5%), and stage I-II (67.9%). Breast cancer subtypes would classically be classified as HER2+ in 34%, HR+HER2- in 58.5%, and triple-negative breast cancer (TNBC) in 7.5% of the patients. Biopsy samples were obtained from the primary tumor in 96.3% of the cases and from lymph nodes in 3.7%. Overall, 15.1% of the cases exhibited HER2-low status, 34% were HER2-negative, and 17% were HER2-negative without IHC details (Table). In a hypothetical scenario assuming all cases without IHC details were HER2-low, the maximum estimated frequency of HER2-low status would be 32.1%. Among HR+ patients, 25.8% had HER2-low status, 45.2% were HER2-negative, and 29% were HER2-negative without IHC details. All four patients with TNBC exhibited HER2-zero status. Conclusion: Contrary to our initial hypothesis, the frequency of HER2-low status in this cohort of LFS patients with breast cancer was lower than anticipated. These results suggest that while breast cancer developing in the context of germline TP53 variants appears to be associated with HER2 amplification, it does not impact lower expressions of HER2. This observation reinforces the concept that HER2-low status does not seem to play a significant role as a driver of tumorigenesis. Further expansion of the study cohort and pathology analysis is planned to confirm these findings. Table HER2 status overall and according to hormone receptor-status (for HER2-negative patients). Abbreviations: IHQ, immunohistochemistry; HR+HER2- BC, hormone receptor-positive HER2-negative breast cancer; TNBC, triple-negative breast cancer. Citation Format: Luciana Auresco, Renata Colombo Bonadio, Vanessa Petry, Laura Testa, Camila Moniz, Jennifer Dos Santos, Maria Del Pilar Estevez-Diz, Rodrigo Santa Cruz Guindalini. HER2-low Status among Patients with Li-Fraumeni Syndrome and 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 PO4-15-10.

Association of Chlamydia trachomatis Infection With Breast Cancer Risk and the Modification Effect of IL-12

BackgroundChlamydia trachomatis (C. trachomatis) infection has been implicated in various cancers, yet its association with breast cancer remains unexplored. This infection triggers a cascade of immune responses primarily regulated by Interleukins-12 (IL-12). Thus, the objective of this case-control study was to investigate the link between C. trachomatis infection and breast cancer risk, as well as the modification effect of IL-12. MethodsWe assessed IgG levels against C. trachomatis in serum of 1,121 women with breast cancer (861 with estrogen receptor-positive (ER+) and 260 with estrogen receptor-negative (ER-) tumors) and 400 controls in Guangzhou, China. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk in association with C. trachomatis infection. The interaction between C. trachomatis infection and IL-12 on breast cancer risk was estimated by the product terms in the logistic regression models. ResultsSeropositivity of C. trachomatis IgG showed a slight association with an increased risk of breast cancer (OR = 1.20; 95% CI: 0.86∼1.78). This association was more pronounced among women with a higher (OR = 5.82; 95% CI: 1.31∼25.94) than a lower (OR = 0.73; 95% CI: 0.41∼1.30) level of IL-12, with a statistically significant interaction observed (Pinteraction = 0.013). In addition, C. trachomatis IgG seropositivity was related to an increased risk of breast cancer among PR+ patients (OR = 1.53; 95% CI: 1.04∼2.23). ConclusionsC. trachomatis infection may contribute to the development of hormone-responsive breast cancer in women with high levels of IL-12. Further studies are needed to uncover the underlying mechanisms.

Second primary cancer risks according to race and ethnicity among U.S. breast cancer survivors.

Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIRAANHPI = 1.49, 95% CI = 1.44-1.54; SIRBlack = 1.41, 95% CI = 1.37-1.45; SIRLatina = 1.45, 95% CI = 1.41-1.49; SIRWhite = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.

Prognostic value of molecular classification in stage IV endometrial cancer

ObjectivesMultiple studies have proven the prognostic value of molecular classification for stage I–III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients...

MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II–III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study

Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. Roche Netherlands.

Real-world experience with pertuzumab and trastuzumab combined with chemotherapy in neoadjuvant treatment for patients with early-stage HER2-positive breast cancer: the NEOPERSUR study

PurposeHER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC.MethodsA retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR).ResultsA total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3–7.7) and 7.3 (95% CI 7.1–7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3–4 anti-HER2 related toxicities were reported in six (1.9%) patients.ConclusionNeoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.

Abstract 1201: Pervasive HLA disruption fuels cancer evolution

Abstract Disruption of the human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. However, although genomic loss of HLA is frequent in non-small cell lung cancer (NSCLC) and in some types of breast cancer, the extent and importance of transcriptomic disruption to HLA presentation, including transcript repression and alternative splicing (AS), remains unclear. To address this, we developed MHC Hammer, a tool to call HLA allele-specific mutations, loss of heterozygosity (LOH), transcriptional repression, and alternative splicing. We first assessed HLA allelic expression and the prevalence of AS in normal tissue. Applying MHC Hammer to 510 normal lung samples and 407 normal breast samples from the Genotype-Tissue Expression cohort, we identified extensive heterogeneity in HLA allelic expression depending on both the allele and tissue type. In addition, HLA allelic AS, occurring in at least 20% of the allele transcripts, was observed in 19% of normal lung and 13% of normal breast samples. Next, we applied MHC Hammer to 413 TRACERx NSCLCs and 743 TCGA breast tumours. While mutations were uncommon, HLA LOH was a frequent event, occurring in 32% of lung adenocarcinomas (LUAD) and 57% of lung squamous cell carcinomas (LUSC). We observed a similar rate of HLA LOH in estrogen receptor positive (ER+) and negative (ER-) tumors (ER+: 14%, ER-: 15%), while in triple negative breast tumours we observed a higher rate of LOH (31%). Due to the heterogeneity in HLA expression observed in the normal samples, to measure tumor specific HLA repression and alternative splicing, we restricted our analysis to tumours with WES, tumor and tumor-adjacent normal RNAseq data. This resulted in a cohort of 88 NSCLCs from the TRACERx study as well as 44 ER+ breast tumours from the TCGA cohort. 61% of LUAD, 75% of LUSC and 35% of ER+ tumours harbored class I HLA transcriptional repression that could not be explained by underlying genomic loss. 27% of LUAD, 7% of LUSC and 55% of ER+ breast tumor patients exhibited no HLA disruption. Tumor specific AS affecting HLA exons 2, 3 or 4, potentially disrupting HLA antigen presentation, was identified in 8% of LUADs, 11% of LUSC and 7% of ER+ breast tumours. Tumor specific AS of exon 5, yielding soluble HLA molecules without a transmembrane domain was identified in 20% of LUAD, 14% of LUSCs and 18% of ER+ breast tumours. LUAD and LUSC tumor regions without HLA LOH or repression were enriched for somatic HLA AS events and alleles with somatic HLA AS had a higher neoantigen burden than those without. We found no relationship between survival and HLA expression or AS in the normal tissue. However, consistent with the importance of HLA dysfunction in tumor evolution, LUADs with low HLA expression in at least one tumor region were associated with shorter disease-free survival, HLA LOH was more common in LUAD’s that metastasized and HLA repression was enriched in LUSC primary regions seeding metastases. Citation Format: Clare Puttick, Thomas P. Jones, Michelle Leung, Oriol Pich, Felipe Galvez Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Carlos Martinez-Ruiz, Robert Bentham, Krijn K. Dijkstra, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A. Quezada, Nicholas McGranahan, Charles Swanton. Pervasive HLA disruption fuels cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1201.

Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer

It is unclear whether breast cancer (BC) with low ERBB2 expression (ERBB2-low) is a distinct clinical, pathological, and epidemiological entity from BC classified as no ERBB2 expression (ERBB2-negative). To evaluate the clinical, pathological, and epidemiologic features of BC with ERBB2-low expression compared with ERBB2-negative BC in a large population study. This cohort study was conducted as part of the Pathways Study, a prospective, racially and ethnically diverse cohort study of women with BC enrolled between 2006 and 2013 in Kaiser Permanente Northern California (KPNC). The hematoxylin and eosin slides underwent centralized pathology review, including the percentage of tumor infiltrating lymphocytes (TILs). Breast biomarker results were extracted from pathology reports, and women were included if they had a documented ERBB2 value that was not classified ERBB2-positive. Data were analyzed from February 2023 through January 2024. Clinical and tumor characteristics associated with BC and ERBB2-low or ERBB2-negative status. ERBB2-low was defined as immunohistochemistry score of 1+ or 2+ (negative by in situ hybridization); ERBB2-negative was defined as immunohistochemistry score of 0+. Other data were collected by self-report or extraction from electronic health records, including BC risk factors, tumor characteristics, treatment modality, and survival outcomes, with recurrence-free survival (RFS) as the primary outcome and overall survival (OS) and BC-specific mortality (BCSM) as secondary outcomes. The clinical, pathological, and epidemiological variables were compared between ERBB2-low and ERBB2-negative BC. Of 2200 eligible patients (all female; with mean [SD] age, 60.4 [11.9] years), 1295 (57.2%) had tumors that were ERBB2-low. Hormone receptors were positive in 1956 patients (88.9%). The sample included 291 Asian patients (13.2%), 166 Black patients (7.5%), 253 Hispanic patients (11.5%), 1439 White patients (65.4%), and 51 patients (2.3%) who identified as other race or ethnicity (eg, American Indian or Alaska Native and Pacific Islander). Within the hormone receptor-negative group, patients whose tumors had ERBB2-low staining, compared with those with ERBB2-negative tumors, had better OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91; P = .02), RFS (HR, 0.53; 95% CI, 0.30-0.95; P = .03), and BCSM (HR, 0.43; 95% CI, 0.22-0.84; P = .01). In multivariable survival analysis stratified by hormone receptor status and adjusted for key covariates, patients with ERBB2-low and hormone receptor-negative tumors had lower overall mortality (HR, 0.48; 95% CI, 0.27-0.83; P = .009), RFS (HR, 0.45; 95% CI, 0.24-0.86; P = .02), and BCSM (subdistribution HR, 0.21; 95% CI, 0.10-0.46; P < .001) compared with patients with ERBB2-negative and hormone receptor-negative tumors. Within the hormone receptor-negative subtype, patients with ERBB2-low and high TILs tumors had better survival across all 3 outcomes compared with patients with ERBB2-negative and low TILs tumors. Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03). These findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

BIRC5 expression by race, age and clinical factors in breast cancer patients

PurposeSurvivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent.Experimental designWe studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger (< 50 years; n = 1137) participants with breast cancer. For comparison, similar analyses were conducted in The Cancer Genome Atlas [TCGA N = 1094, Black (n = 183), younger (n = 295)]. BIRC5 was evaluated as a continuous and categorical variable (highest quartile vs. lower three quartiles).ResultsUnivariate, continuous BIRC5 expression was higher in breast tumors from Black women relative to non-Black women in both estrogen receptor (ER)-positive and ER-negative tumors and in analyses stratified by stage (i.e., within Stage I, Stage II, and Stage III/IV tumors). Within CBCS and TCGA, BIRC5-high was associated with young age (< 50 years) and Black race, as well as hormone receptor-negative tumors, non-Luminal A PAM50 subtypes, advanced stage, and larger tumors (> 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)].ConclusionBlack and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.

Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.