Breast Cancer Recurrence Research Articles

HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.

Lipid profiling of RON and DEK-dependent signaling in breast cancer guides discovery of gene networks predictive of poor outcomes.

Recurrent and metastatic breast cancer is frequently treatment resistant. A wealth of evidence suggests that reprogrammed lipid metabolism supports cancer recurrence. Overexpression of the RON and DEK oncoproteins in breast cancer is associated with poor outcome. Both proteins promote cancer metastasis in laboratory models, but their influence on lipid metabolite levels remain unknown. To measure RON- and DEK-dependent steady-state lipid metabolite levels, a nuclear magnetic resonance (NMR)-based approach was utilized. The observed differences identified a lipid metabolism-related gene expression signature that is prognostic of overall survival (OS), distant metastasis-free survival (DMFS), post-progression survival (PPS), and recurrence-free survival (RFS) in patients with breast cancer. RON loss led to decreased cholesterol and sphingomyelin levels, whereas DEK loss increased total fatty acid levels and decreased free glycerol levels. Lipid-related genes were then queried to define a signature that predicts poor outcomes for patients with breast cancer patients. Taken together, RON and DEK differentially regulate lipid metabolism in a manner that predicts and may promote breast cancer metastasis and recurrence.

Statin use and risks of breast cancer recurrence and mortality.

Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.

Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC

In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator’s choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

Breast cancer recurrence in relation to mode of detection: implications on personalized surveillance.

The effectiveness of current follow-up guidelines after breast cancer treatment is uncertain. Tailored surveillance based on patient age and tumor characteristics may be more adequate. This study aimed to analyze the frequency of ipsilateral locoregional recurrences (LR) and second primary breast cancers (SP) detected outside of scheduled surveillance and to analyze risk factors associated with these events. Patients with surgically treated early-stage breast cancer from the Malmö Diet and Cancer Study (MDCS), 1991-2014 (n = 1080), and the Västernorrland region, 2009-2018 (n = 1648), were included. Clinical and pathological information on the primary tumor and recurrences was retrieved from medical records. The mode of recurrence detection was defined as detection within (planned) or outside (symptomatic) of scheduled surveillance. The median follow-up was 6.5 years. Overall, 461 patients experienced a recurrence. The most common initial event was distant metastasis (47%), followed by locoregional recurrence (LR) (22%) and second primary (SP) (18%). 56% of LR and 28% of SP were identified outside of scheduled surveillance. Logistic regression analysis revealed that younger age (under 50 years) (OR 2.57, 95% CI 1.04-6.88), lymph node-positive breast cancer (OR 2.10, 95% CI 1.03-4.39) and breast cancer of the HER2 positive subtype (OR 5.24, 95% CI 1.40-25.90) were correlated with higher odds of detecting a recurrence outside of planned surveillance. Most recurrent events were detected outside of scheduled surveillance, particularly for locoregional recurrences. Risk-based surveillance, which takes into account patient and tumor characteristics, might be more suitable for specific patient subsets.

ThP2.2 - Breast cancer in the very young

Abstract Aims A small proportion of breast cancer (BC) affects women under 35 years old: very young breast cancer (VYBC). We conducted a retrospective cohort study of VYBC treated by our breast unit with the aim of adding to the existing, limited literature. Methods All patients treated between January 2012 and July 2023 were included. Case notes, MDT outcomes, operative findings and histology reports were cross-referenced. The primary outcome assessed was overall survival. Other factors investigated were parity, genetics, treatment plans and some, specific, psychosocial concerns. Results There were 95 women with VYBC in this 11-year study period. The median age at diagnosis was 32 years, and median length of follow-up was 5 years. 81% of the cohort had early BC, and 28% of carcinomas were triple negative. Overall survival was 87%. 16% of women either presented with or developed distant metastases, with a survival rate of less than 27% in this group. BC recurrence affected 21% of women. Surgery was performed in 94% of patients, with 64% having at least a unilateral mastectomy. Ahead of treatment, fertility concerns were expressed by at least 45% of women. 85% of the cohort were genetically tested, revealing a genetic mutation in 20% of these patients. Conclusions This study demonstrates the outcomes of VYBC within our breast unit, which are comparable to published reports. It also highlights unique, psychosocial challenges faced by these women. Long term follow-up of this group is recommended.

GATA3 and markers of epithelial-mesenchymal transition predict long-term benefit from tamoxifen in ER-positive breast cancer

GATA binding protein 3 (GATA3) is essential for normal development of the mammary gland and associated with ER-positive breast cancer. Loss of GATA3 has been associated with epithelial-mesenchymal transition (EMT) in experimental studies. We investigated tumoral GATA3 in a cohort of postmenopausal patients with lymph-node negative breast cancer, randomized to adjuvant tamoxifen or control. Nuclear GATA3 expression was assessed with immunohistochemistry and GATA3 gene expression with Agilent microarrays. High GATA3 nuclear expression was associated with a lower rate of distant recurrence in ER-positive breast cancer (HR = 0.60, 95% CI 0.39–0.93). Low gene expression of GATA3 was associated with limited long-term benefit from adjuvant tamoxifen (interaction: p = 0.033). GATA3 gene expression was associated with the epithelial markers CDH1 (E-cadherin) and FOXA1, whereas negatively associated with several mesenchymal markers. Low expression of CDH1 was associated with marginal tamoxifen benefit (HR = 0.80 (0.43–1.49)), whereas patients with higher expression showed a significant benefit (HR = 0.33 (0.20–0.55), interaction: p = 0.029). In ER-positive breast cancer, diminished expression of GATA3 is associated with markers of EMT and poor long-term benefit from tamoxifen.

Distribution characteristics of immune infiltration and lymphovascular invasion in patients with breast cancer skin recurrence

BackgroundTo assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients.MethodsWe retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal–Wallis one-way ANOVA.ResultsA total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS.ConclusionThe immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.

Complete response and long-term survival to endocrine monotherapy in a patient with metastatic breast cancer in a low-income country: a case report

BackgroundBreast cancer is the most common cancer in women. Progression-free survival for hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer treated with endocrine therapy in combination with cyclin4/6-dependent kinase is approximately 25 months. This case represents metastatic breast cancer treated with endocrine therapy, leading to long-term survival.Case presentationA 40-year-old Syrian woman diagnosed with hormone receptor-negative breast cancer was treated surgically with adjuvant chemotherapy and radiotherapy. She developed local and nodal recurrences that were hormone receptor-positive, followed by a recurrence of malignant pleural effusion. She was initially treated with chemotherapy and then placed on endocrine therapy with a complete response from 2014 until now. The patient also suffered from adverse events of medications, such as heart failure and osteoporosis, which were treated appropriately.ConclusionThis case demonstrates a long-lasting complete response to metastatic breast cancer with malignant pleural effusion. This shows the validity of endocrine therapy in recurrent hormone receptor-positive breast cancer, especially in countries that cannot afford targeted therapies or genetic tests. It also highlights the necessity for a better understanding of the prognostic and predictive factors.

Diagnostic Accuracy of Cancer Antigen 15-3 as a Seromarker Among Recurrent Breast Carcinoma in Bangladesh.

The diagnosis of recurrent breast carcinoma is crucial for patient treatment. The present study aimed to assess the diagnostic accuracy of cancer antigen 15-3 (CA 15-3)as a sero-marker among recurrent breast carcinoma patients. This prospective observational study evaluated the serum CA 15-3 among women (age ≥18 years) with recurrent breast carcinoma. The CA 15-3 was measured by the enzyme-linked immunosorbent assay (ELISA), and concentrations were stratified using a cut-off value of 30 U/mL. The receiver operating characteristic (ROC) curve observed that the sensitivity and specificity of the CA 15-3 cut-off value and the area under the AUROC curve demonstrate the goodness-of-fit of the prediction model. A total of 50 patients were recruited, with a mean age of 48.4 ±9.7years. The majority (n=28, 56.0%) of patients were 41 to 50 years old. Further, a total of 42 (84%) patients had high serum levels of CA 15-3, with a mean value of 72.7±9.5 U/mL. At the cut-off level of 30 U/mL, the ROCcurve demonstrated sensitivity, specificity, positive predictive value, and negative predictive value of 95.7%, 69.4%, 84.1%, and 72.8%, respectively, to diagnose recurrent breast carcinoma. Nonetheless, the area under the ROC (AUROC) curve was 0.712, indicating a satisfactory fit for the prediction model. We found that CA 15-3 level ≥30 U/mL is highly sensitive and specific as a seromarker for detecting recurrent breast cancer among the Bangladeshi population. We recommend routinely monitoring breast cancer survivors using CA 15-3 biomarkers.

326P Exploratory analysis of the association of systemic inflammation and breast cancer recurrence in the Optitrain randomised controlled trial

326P Exploratory analysis of the association of systemic inflammation and breast cancer recurrence in the Optitrain randomised controlled trial

411P Interim analysis of prospective observational study to evaluate the impact of cancer gene panel tests on treatment decision making in metastatic or recurrent breast cancer in Japan: JBCRG-C07 REIWA study

411P Interim analysis of prospective observational study to evaluate the impact of cancer gene panel tests on treatment decision making in metastatic or recurrent breast cancer in Japan: JBCRG-C07 REIWA study

Nomograms for predicting recurrence of HER2-positive breast cancer with different HR status based on ultrasound and clinicopathological characteristics.

This study aimed to identify ultrasound and clinicopathological characteristics related to recurrence in HER2-positive (HER2+) breast cancer, and to develop nomograms for predicting recurrence. In this dual-center study, we retrospectively enrolled 570 patients with HER2+ breast cancer. The ultrasound and clinicopathological characteristics of hormone receptor (HR)-/HER2+ patients and HR+/HER2+ patients were analyzed separately according to HR status. Eighty percent of the original samples from HR-/HER2+ and HR+/HER2+ patients were extracted by bootstrap sampling as the training cohorts, while the remaining 20% were used as the external validation cohorts. Informative characteristics were screened through univariate and multivariable Cox regression in the training cohorts and used to develop nomograms for predicting recurrence. The predictive accuracy was calculated using Harrell's C-index and calibration curves. Three informative characteristics (axillary nodal status, calcification, and Adler degree) were identified in HR-/HER2+ patients, and another three (histological grade, axillary nodal status, and echogenic halo) in HR+/HER2+ patients. Based on these, two separate nomograms were constructed to assess recurrence risk. In the training cohorts, the C-index was 0.740 (95% CI: 0.667-0.811) for HR-/HER2+ nomogram, and 0.749 (95% CI: 0.679-0.820) for HR+/HER2+ nomogram. In the validation cohorts, the C-index was 0.708 (95% CI: 0.540-0.877) for HR-/HER2+ group, and 0.705 (95% CI: 0.557-0.853) for HR+/HER2+ group. The calibration curves also indicated the excellent accuracy of the nomograms. Ultrasound performance of HER2+ breast cancers with different HR status was significantly different. Nomograms integrating ultrasound and clinicopathological characteristics exhibited favorable performance and have the potential to serve as a reliable method for predicting recurrence in heterogeneous breast cancer.

234MO Explaining the relationships between age, endocrine therapy persistence and risk of recurrence in hormone-positive early breast cancer: A nationwide cohort study

234MO Explaining the relationships between age, endocrine therapy persistence and risk of recurrence in hormone-positive early breast cancer: A nationwide cohort study

426P Impact of statin therapy on mortality and recurrence in female breast cancer: A meta-analysis

426P Impact of statin therapy on mortality and recurrence in female breast cancer: A meta-analysis

Tiaogan Bushen Xiaoji Formula Enhances the Sensitivity of Estrogen Receptor- Positive Breast Cancer to Tamoxifen by Inhibiting the TGF-β/SMAD Pathway.

The resistance to endocrine therapy can lead to recurrence and metastasis of breast cancer (BC), affecting the survival period. Tiaogan Bushen Xiaoji (TGBSXJ) Formula, a traditional Chinese medicine (TCM) decoction, has been widely used in the treatment of estrogen receptor-positive (ER+) BC. However, the underlying mechanism of TGBSXJ Formula in ER+BC treatment has not been totally elucidated. Network pharmacology (NP) and RNA sequencing were used to predict the candidate ingredients and explore the potential targets of TGBSXJ Formula. Then, the results of NP and RNA sequencing were investigated by in vitro experiments. Active ingredients of TGBSXJ Formula mainly included Mangiferin, Rutin, Anemarrhena asphodeloides saponin BII, Ganoderic acid A and Acacetin, etc. A protein-protein interaction (PPI) network was created based on the active ingredients of TGBSXJ Formula and target genes of ER+ BC, in which TGF-β, MMP2 and SMAD3 were defined as the hub genes. In vitro experiments showed that TGBSXJ Formula significantly inhibited the viability, colony ability and migration of ER+ BC cells, and significantly increased the sensitivity to TAM. Western blot analysis showed that TGBSXJ Formula significantly downregulated TGF-β, E-cadherin, MMP2, MMP9, N-cadherin, p-Smad2 and p-Smad3 in ER+ BC cells. TGBSXJ Formula increases the sensitivity of ER+ BC cells to TAM by inhibiting the TGF-β/Smad signaling pathway.

288P External validation of an AI-enabled digital test (PreciseDx Breast) to predict breast cancer recurrence within 6-years exhibited good independent performance on a comparable early-stage cohort from the Netherlands

288P External validation of an AI-enabled digital test (PreciseDx Breast) to predict breast cancer recurrence within 6-years exhibited good independent performance on a comparable early-stage cohort from the Netherlands

Longitudinal dynamics of circulating tumor DNA for treatment monitoring in patients with breast cancer recurrence

The prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with breast cancer recurrence or de novo metastatic cancer were examined in a retrospective analysis of a prospective observational cohort. Twenty-three recurrent/metastatic breast cancer cases (8 locoregional, 15 distant metastasis) were enrolled, and sequential plasma samples were obtained. Anchor mutations were selected from the target sequencing of each patient’s primary and/or metastatic tumor. An in-house developed assay (UHS assay) was employed for a tumor-informed ctDNA assay during treatment and follow-up. A median of three (range 1–5) anchor mutations per case were applied for ctDNA detection. ctDNA was detected in 14 (63.6%, 14/22) cases at the time of enrollment and 18 (78.5%, 18/23) cases during follow-up. More anchor mutations and higher tumor burden were significantly related to higher ctDNA positive rates (p-value 0.036, 0.043, respectively). The mean enriched variant allele frequency (eVAF) at each time point was significantly higher for stable or progressive disease responses (ANOVA test p-value < 0.001). Eight patients showed an increase in their ctDNA eVAF prior to clinical progression with a mean lead time of 6.2 months (range 1.5–11 months). ctDNA dynamics measured using personalized assay reflected the clinical course of breast cancer recurrence.

Surgical Management and Its Impact on Adjuvant Treatment in Recurrent Ipsilateral Breast Cancer: A Retrospective Cohort Study.

Background: Breast cancer (BC) recurrence, defined as the reappearance of cancer in the ipsilateral breast after primary treatment, poses significant challenges in clinical management. Despite advances in treatment, recurrence rates persist, ranging from 0.6 to 1.5% annually, reaching 10-15% at 20 years. This study aims to analyze the surgical and oncological characteristics of patients with BC recurrence. Methods: This retrospective study includes 56 patients diagnosed with recurrent BC between October 2018 and April 2022. Data were collected from a prospectively maintained surgical database. A descriptive analysis was performed on the initial BC, and the recurrence, including surgical complications, was classified using the Clavien-Dindo system. The success rates of selective sentinel lymph node (SLN) biopsies and aberrant drainages were assessed based on previous surgeries. Results: The cohort included 55 females and 1 male, with a median age of 65.3 years. The mean time to BC recurrence was 11.5 years. Among them, 26.8% underwent breast-conserving surgery, 41.1% had a mastectomy, 21.4% had a mastectomy with reconstruction, and 10.7% had an excision over a previous mastectomy. An SLN biopsy was performed in 78.6% of cases, with higher success rates in those without a previous axillary lymph node dissection (85.7% vs. 63.2%). Aberrant drainage was more frequent in patients with a previous ALND (44.4% vs. 20%). The median follow-up was 41.3 months, with 10.7% experiencing a second recurrence. Conclusions: Repeat breast-conserving surgery with re-irradiation for ipsilateral recurrence is feasible and does not significantly increase complications. SLN biopsy is valuable for restaging and tailoring adjuvant therapies, with ALND not being necessary if re-SLN biopsy shows no drainage. The management of aberrant drainage remains controversial.

Intraoperative Cavity Local Delivery System with NETs-Specific Drug Release for Post-Breast Cancer Surgery Recurrence Correction.

Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors-β (TGF-β) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio-safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF-β at tumor-resection sites, whose unique mechanism for local TGF-β amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti-TGF-β. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF-β and related indicators, impeding epithelial-mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.