Positive Breast Cancer Research Articles

The cardiovascular and metabolic effects of ovarian suppression in combination with tamoxifen or an aromatase inhibitor as adjuvant therapy for early estrogen receptor-positive breast cancer: a systematic review

Adjuvant endocrine therapy is a key treatment in oestrogen receptor positive early breast cancer (BC). For premenopausal women ovarian function suppression (OFS) in combination either tamoxifen or aromatase inhibitor (AI) is utilised in high-risk cases. The resultant suppression of circulating oestradiol from OFS could have adverse cardiovascular and metabolic effects, subsequently increasing the risk of cardiovascular disease. Our study highlights the potential cardio-metabolic impact endocrine therapy and OFS have on premenopausal women with BC. It also highlights the pressing need for standardisation of routine collection and recording of cardiometabolic history and risk factors as part of baseline assessment and adverse event reporting to better understand the cardiometabolic impact these treatment has on our patients. Further studies, with particular focus on baseline and subsequent development of cardiovascular risk factors are needed to explore the impact of these drugs on the cardiovascular health of these young women with BC

Application of 21-gene recurrence risk score in patients with breast cancer

Objective: To investigate the relationship between 21-gene recurrence risk score (21-Gene RS) and the prognosis and clinicopathological features of hormone receptor (HR) positive, HER2-negative early breast cancer patients who did not receive neoadjuvant therapy. Methods: A total of 469 patients with HR positive and HER2-negative early breast cancer who received surgical treatment in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2014 to October 2017 were selected. Their clinicopathological data were retrospectively analyzed. Tumor tissue samples were collected from patients, and the expression of 21-gene was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The 21-Gene RS was calculated according to the Trial Assigning Individualized Options for Treatment (TAILORx) RS grouping and National Surgical Adjuvant Breast and Bowel Project B-20 (NSABP B-20) RS grouping principles. Patients were divided into low (21-Gene RS<11 or 21-Gene RS<18), intermediate (11≤21-Gene RS<26 or 18≤21-Gene RS<31) and high (21-Gene RS≥26 or 21-Gene RS≥31) risk groups, and the clinicopathological features and prognostic differences of patients in different risk groups were compared. Statistical data were compared by chi-square test. Survival analysis was performed using Kaplan-Meier curve analysis and the differences between groups were compared using Log-rank test. Multivariate analysis was conducted by COX regression analysis. Results: Based on TAILORx RS grouping, the proportions of low-risk, intermediate-risk and high-risk groups among the 469 patients were 18.8% (88/469), 48.2% (226/469) and 33.0% (155/469), respectively. Based on NSABP B-20 RS grouping, the proportion of low-risk, intermediate-risk and high-risk groups were 43.1% (202/469), 37.5% (176/469) and 19.4% (91/469), respectively. The association of 21-Gene RS with histological grading, luminal typing, Ki-67 expression, and chemotherapy and treatment modalities were statistically significant (P<0.05) regardless of TAILORx RS grouping or NSABP B-20 RS grouping. Kaplan-Meier survival curve suggested poor prognosis in high-risk group (P<0.05, Log-rank test). Multivariate COX regression analysis showed that surgical method and 21-Gene RS were risk factors affecting the prognosis of patients. Conclusions: 21-Gene RS is significantly associated with the prognosis of patients with HR-positive, HER2-negative, early-stage breast cancer not receiving neoadjuvant therapy, as well as with their clinicopathological characteristics such as patients' histologic grade, luminal typing, Ki-67 expression, and whether or not they are treated with chemotherapy or other treatment modalities.The 21-Gene RS threshold of 11 and 26 or 18 and 31 can be used to grade the prognosis in Chinese patients with early-stage breast cancer. More researches are needed to guide the selection of postoperative adjuvant therapy for patients with HR-positive and HER2-negative early-stage breast cancer.

Possible protective effect of rosuvastatin in chemotherapy-induced cardiotoxicity in HER2 positive breast cancer patients: a randomized controlled trial

Cardiotoxicity is a side effect of chemotherapy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients receiving both anthracyclines and trastuzumab. We looked for a possible protective effect of rosuvastatin against chemotherapy-induced cardiotoxicity. Methods: 50 newly diagnosed HER2 positive breast cancer patients were randomly allocated into two groups: 25patients in each. Group 1(control group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy. Group 2 (treatment group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy and 20 mg of oral rosuvastatin 24 h before the first cycle of chemotherapy and once daily for the rest of the follow-up period (6 months). Transthoracic echocardiography was done, and blood samples were collected for patients 24 h before the initiation of therapy, after 3 months and after 6 months to assess serum levels of high sensitivity cardiac troponin I (hs-cTnI), Myeloperoxidase (MPO), Interleukin-6 (IL-6) and Alanine aminotransferase (ALT). The study was retrospectively registered in Clinical Trials.gov in April 2022. Its ID is NCT05338723. Compared to control group, Rosuvastatin-treated group had a significantly lower decline in LVEF after 3 months and after 6 months. They had significantly lower Hs-cTnI and IL-6 after 3 months and after 6 months, and significantly lower MPO after 6 months. Four patients in control group experienced cardiotoxicity while no one in rosuvastatin-treated group. Rosuvastatin attenuated cardiotoxicity, so it is a promising protective agent against chemotherapy-induced cardiotoxicity.

PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer

Although anti-HER2 therapy has made significant strides in reducing metastasis and relapse in HER2-positive breast cancer, resistance to agents like trastuzumab, pertuzumab, and lapatinib frequently develops in patients undergoing treatment. Previous studies suggest that the hyperactivation of the PI3K-AKT signaling pathway by PIK3CA/PTEN gene mutations is implicated in HER2 resistance. In this study, we introduce a novel PI3K-p110α Proteolysis TAargeting Chimera (PROTAC) that effectively inhibits the proliferation of breast cancer cells by degrading PI3K-p110α. When tested in two lapatinib-resistant cell lines, JIMT1 and MDA-MB-453, both of which harbor PIK3CA mutations, the PI3K PROTAC notably reduced cell proliferation and induced G1 phase cell cycle arrest. Importantly, even at very low concentrations, PI3K PROTAC restored sensitivity to lapatinib. Furthermore, the efficacy of PI3K PROTAC surpassed that of Alpelisib, a selective PI3K-p110α kinase inhibitor in clinic. The superior performance of PI3K PROTAC was also confirmed in lapatinib-resistant breast cancer xenograft tumors and patient-derived breast cancer organoids (PDOs). In conclusion, this study reveals that the novel PI3K PROTAC we synthesized could serve as an effective agent to overcome lapatinib resistance.

Targeted axillary dissection reduces residual nodal disease in clinically node- positive breast cancer after neoadjuvant chemotherapy

BackgroundAny advantage of performing targeted axillary dissection (TAD) compared to sentinel lymph node (SLN) biopsy (SLNB) is under debate in clinically node-positive (cN+) patients diagnosed with breast cancer. Our objective was to assess the feasibility of the removal of the clipped node (RCN) with TAD or without imaging-guided localisation by SLNB to reduce the residual axillary disease in completion axillary lymph node dissection (cALND) in cN+ breast cancer.MethodsA combined analysis of two prospective cohorts, including 253 patients who underwent SLNB with/without TAD and with/without ALND following NAC, was performed. Finally, 222 patients (cT1-3N1/ycN0M0) with a clipped lymph node that was radiologically visible were analyzed.ResultsOverall, the clipped node was successfully identified in 246 patients (97.2%) by imaging. Of 222 patients, the clipped lymph nodes were non-SLNs in 44 patients (19.8%). Of patients in cohort B (n=129) with TAD, the clipped node was successfully removed by preoperative image-guided localisation, or the clipped lymph node was removed as the SLN as detected on preoperative SPECT-CT. Among patients with ypSLN(+) (n=109), no significant difference was found in non-SLN positivity at cALND between patients with TAD and RCN (41.7% vs. 46.9%, p=0.581). In the subgroup with TAD with axillary lymph node dissection (ALND; n=60), however, patients with a lymph node (LN) ratio (LNR) less than 50% and one metastatic LN in the TAD specimen were found to have significantly decreased non-SLN positivity compared to others (27.6% vs. 54.8%, p=0.032, and 22.2% vs. 50%, p=0.046).ConclusionsTAD by imaging-guided localisation is feasible with excellent identification rates of the clipped node. This approach has also been found to reduce the additional non-SLN positivity rate to encourage omitting ALND in patients with a low metastatic burden undergoing TAD.

Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022

Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Pathological Changes Following Neoadjuvant Endocrine Therapy (NAET): A Multicentre Study of 391 Breast Cancers.

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma.

Concurrent use of Radiotherapy and Ribociclib: Preliminary Results and Review of the Literature.

In the recent MONALEESA-2, MONALEESA-3, and MONALEESA-7 clinical trials, the addition of ribociclib, a CDK4/6 inhibitor, to standard endocrine therapy significantly improved progression-free survival (PFS) compared with hormone therapy alone in the treatment of locally advanced or metastatic estrogen receptor-positive (ER) and HER2-negative breast cancer. However, its toxicity raises concerns when administered concomitantly with radiotherapy, leading most radiotherapists and medical oncologists to prefer to discontinue Ribociclib during radiotherapy (RT). Although there are insufficient published data on this combination, our preliminary experience with the first 2 patients treated at Institut Curie suggests promising results when using Ribociclib with Letrozole or Fulvestrant concurrently with palliative radiotherapy in the treatment of metastatic breast cancer. Our study aimed to evaluate the safety of combining Ribociclib with palliative radiotherapy in patients with metastatic breast cancer, providing crucial insights for clinical decision-making. A retrospective analysis was conducted on patients treated for hormone receptor-positive metastatic breast cancer with Ribociclib and concurrent radiotherapy at the Institut Curie (Paris, France) between September 2023 and April 2024. Among 38 patients who received Ribociclib and underwent irradiation, 36 temporarily suspended Ribociclib during radiotherapy, while 2 continued Ribociclib concurrently and were included in the analysis. Palliative radiotherapy was administered using volumetric modulated arc therapy, delivering 20Gy in 5 fractions to bone metastatic sites. Ribociclib was given at 600mg/day with hormonotherapy. Follow-up was conducted from the last day of RT until the last medical consultation. Toxicities were graded using CTCAE V5.0. Two patients received Ribociclib concomitantly with radiotherapy, experiencing pain relief without interruptions in RT. However, Ribociclib treatment was halted in both cases due to grade 3 neutropenia and grade 1 QTc interval prolongation, respectively. One patient had a dose reduction to 400mg due to neutropenia, with favorable outcomes observed. Both patients continued Ribociclib treatment, with one achieving complete remission and the other partial remission of bone disease. No late toxicities were observed. Despite the need for further investigation, our results suggest safety consistent with pivotal trials, advocating for a prospective cooperative data collection initiative to explore this combined strategy further, potentially revolutionizing metastatic breast cancer management.

P-376 Letrozole to minimise exposure to elevated serum estradiol during superovulation for breast cancer patients prior to chemotherapy. Real world experience from a statewide oncofertility service

Abstract Study question How effective is co-treatment with letrozole in supressing peak E2 in a real world setting? Summary answer We observed greater than anticipated supra-physiological serum estadiol concentrations in our cohort. What is known already Breast cancer occurs frequently in women of reproductive age, many of whom request oocyte or embryo cryopreservation before chemo/radiotherapy. Oncofertility treatment requires superovulation with resultant elevation of serum estradiol above concentrations seen physiologically. In order to avoid possible stimulation of estrogen receptor positive breast cancers, co-administration of letrozole is frequently recommended. A 67% lower mean serum estradiol in a letrozole treated group compared with an untreated superovulated comparison group has been reported in the literature, suggesting a protective mechanism. Peak E2 concentration across 4 cohorts of patients co-treated with letrozole has been reported to be 103 – 2350 (mean 564). Study design, size, duration We performed a retrospective cohort study of women referred for fertility preservation following diagnosis of breast cancer to the Fertility Research Centre at The Royal Hospital for Women, Sydney between Jan 2020 and Jan 2024. Women were identified from hospital outpatient paper and electronic medical records. 145 new referrals were received by our centre, with 88 patients undergoing 107 cycles. Participants/materials, setting, methods 145 women aged between 19 and 44 with newly diagnosed breast cancer were referred to our Statewide, multidisciplinary, public oncofertility service for consideration of treatment and review at our fertility multidisciplinary team meeting. Our oncofertility database and outpatient clinical records were used to identify new referrals to the service. Electronic and paper medical records including the ART database were used to obtain cycle information, blood results and demographic information Main results and the role of chance Peak estradiol concentrations (pMol/L) 35% of cycles resulted in peak E2 &amp;gt; 2000. 11% of cycles resulted in peak E2 &amp;gt; 4000 and 2% of cycles resulted in peak E2 &amp;gt; 7000. We calculated a mean E2 of 1837. The mean anti-mullerian hormone was 20.3 pMol/L and mean antral follicle count 19.7. The mean BMI was 24.7. The average stimulation length was 13 days (7-16 days) with an average cumulative gonadotrophin dose of 2769 IU. Average number of MII oocytes per cycle was 7.2. 16 % of patients elected to preserve embryos. The fertilisation rate was 50%, with 61% of fertilised eggs resulting in frozen blastocytes. There have been 2 pregnancies and one live birth to date. 32% of cycles had a germline genetic result prior to OPU, with 20% having a positive BRCA gene mutation. Breast cancer hormone status 56% were Estrogen Receptor positive. 38 % were Progesterone Receptor positive, 18% were HER2 positive, 24% were hormone receptor negative Complications 5% of cycles were cancelled prior to OPU, 8% of cycles resulted in no oocyte or embryo available for freezing. 3% of cycles were reviewed for OHSS symptoms with 2 confirmed cases of OHSS secondary to administration of Zoladex &amp;lt;24hrs following OPU. Limitations, reasons for caution This is a retrospective cohort study in a single academic centre. Our current study duration is too short to permit determination of recurrence rates of breast cancer in the letrozole treated cohort. Wider implications of the findings The impact of short, transient elevation of circulating estradiol during superovulation is uncertain, however it is prudent to try to minimise exposure of ER positive breast cancers to estrogen. Alternative strategies for limiting this phenomenon should be explored, more evidence is needed on oncological and fertility outcomes in this population. Trial registration number N/A

973 Managing Primary Endocrine Treatment (PET) in Breast Cancer Patients: An Audit of Resource Utilisation and Risks

Abstract Aim Primary endocrine treatment (PET) is considered in patients with oestrogen receptor (ER) positive breast cancer who decline or are deemed unfit for surgery. This treatment can affect bone density resulting in osteoporosis and risk of fractures. With increasing demand on resources, our aim was to examine clinical practices in this vulnerable patient group, balancing risks whilst ensuring good patient selection for treatments. Method We reviewed patients who had PET for ER positive breast cancer from a single consultant database in a district general hospital in South Wales between May 2018 and March 2023. We examined use of bone density (DEXA) scans, bone protection medications, outcomes, and complications. Results 48 patients were included, aged 50-95 years (median 80) and male: female (1:47). All were ER positive, excepting 2 with limited prognosis empirically started on treatment. Reasons for PET included patient choice (15%), palliative treatment (8%), co-morbidities (65%), late stage (4%) and other (8%). There were 27 deaths (54%), with mean time from diagnosis to death 14 months (range 1-50 months). 5 patients (10%) had DEXA scan and 16 (33%) were on bone protection. 3 patients had fractures whilst on PET, likely due to pre-existing conditions. Conclusions The frail breast cancer patient population has limited life expectancy and should not be over-investigated unnecessarily. It could be debated as to how much benefit bone protection provides, given the low fracture rate. Further studies are required to determine benefits of empirical bone protection in PET patients.

Denosumab Prevents Bone Loss and Microarchitectural Deterioration in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression Therapy: A Randomized Controlled Trial.

Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

EstroGene2.0: A multi-omic database of response to estrogens, ER-modulators, and resistance to endocrine therapies in breast cancer.

Endocrine therapies targeting the estrogen receptor (ER/ESR1) are the cornerstone to treat ER-positive breast cancers patients, but resistance often limits their effectiveness. Understanding the molecular mechanisms is thus key to optimize the existing drugs and to develop new ER-modulators. Notable progress has been made although the fragmented way data is reported has reduced their potential impact. Here, we introduce EstroGene2.0, an expanded database of its precursor 1.0 version. EstroGene2.0 focusses on response and resistance to endocrine therapies in breast cancer models. Incorporating multi-omic profiling of 361 experiments from 212 studies across 28 cell lines, a user-friendly browser offers comprehensive data visualization and metadata mining capabilities (https://estrogeneii.web.app/). Taking advantage of the harmonized data collection, our follow-up meta-analysis revealed substantial diversity in response to different classes of ER-modulators including SERMs, SERDs, SERCA and LDD/PROTAC. Notably, endocrine resistant models exhibit a spectrum of transcriptomic alterations including a contra-directional shift in ER and interferon signaling, which is recapitulated clinically. Furthermore, dissecting multiple ESR1-mutant cell models revealed the different clinical relevance of genome-edited versus ectopic overexpression model engineering and identified high-confidence mutant-ER targets, such as NPY1R. These examples demonstrate how EstroGene2.0 helps investigate breast cancer's response to endocrine therapies and explore resistance mechanisms.

Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage I-II Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer

BackgroundThe evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection. MethodsWe enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival. ResultsBetween 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100). ConclusionsPC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer.

Ferritin and Serum Iron in a Causal Relationship with Estrogen Receptor-Negative Breast Cancer: a Two-Sample Mendelian Randomization Study.

The aim of this study was to explore the causal relationship between different serum iron statuses (ferritin, transferrin, transferrin saturation, and serum iron) and the occurrence of estrogen receptor (ER)-positive or ER-negative breast cancer. The summary data on serum iron status exposure were gathered from the IEU OpenGWAS Project, the UK Biobank, and other databases. Concurrently, the summary data for ER+ and ER- breast cancer are sourced from the Breast Cancer Association Consortium (BCAC). By examining the causal link between iron status and breast cancer, we deployed five distinct Mendelian randomization (MR) algorithms, namely MR-Egger, inverse variance weighted (IVW), weighted median, simple mode, and MR-PRESSO. To assess heterogeneity and horizontal pleiotropy, Cochran's Q and MR-Egger algorithms were applied, respectively. Elevated ferritin levels are associated with an increased risk of ER-negative breast cancer (OR(IVW) = 1.042, 95% CI (1.005, 1.081), p = 0.025; OR (weighted median) = 1.050, 95% CI (1.001, 1.102), p = 0.046; and OR (MR-PRESSO) = 1.042, 95% CI (1.005, 1.081), p = 0.039). Conversely, an increase in the serum iron level is linked to a reduced risk of ER-negative breast cancer (OR (IVW) = 0.791, 95% CI (0.649, 0.962), p = 0.019; and OR (MR-PRESSO) = 0.791, 95% CI (0.649, 0.962), p = 0.028). However, there is no evidence of a causal relationship between transferrin, transferrin saturation, and ER-negative breast cancer. For ER-positive breast cancer, none of the four different iron statuses demonstrated a causal relationship. Ferritin is positively correlated with ER-negative breast cancer, while serum iron is negatively associated with ER-negative breast cancer. However, there is no causal relationship between the four iron statuses and ER-positive breast cancer.

Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer

There are insufficient data comparing 16α-18F-fluoro-17β-estradiol (FES) positron emission tomography (PET) computed tomography (CT) with standard-of-care imaging (SOC) for staging locally advanced breast cancer (LABC) or evaluating suspected recurrence. To determine the detection rate of FES PET/CT and SOC for distant metastases in patients with estrogen receptor (ER)-positive LABC and recurrences in patients with ER-positive BC and suspected recurrence. This diagnostic study was conducted as a single-center phase 2 trial, from January 2021 to September 2023. The study design provided 80% power to find a 20% detection rate difference. Participants included patients with ER-positive LABC (cohort 1) or suspected recurrence (cohort 2). Data were analyzed from September 2023 to February 2024. Participants underwent both SOC imaging and experimental FES PET/CT. When there were suspicious lesions on imaging, 1 was biopsied for histopathological reference standard to confirm presence (true positive) or absence (false positive) of malignant neoplasm. The outcome of interest was the detection rate of FES PET CT vs SOC for distant metastases and recurrences. A total of 124 patients were accrued, with 62 in cohort 1 (median [IQR] age, 52 [32-84] years) and 62 in cohort 2 (median [IQR] age, 66 [30-93] years). In cohort 1, of 14 true-positive findings, SOC imaging detected 12 and FES detected 11 (P > .99). In cohort 2, of 23 true-positive findings, SOC detected 16 and FES detected 18 (P = .77). In 30 patients with lobular histology, of 11 true-positive findings, SOC detected 5 and FES detected 9 (P = .29). There were 6 false-positive findings on SOC and 1 false-positive finding on FES PET/CT (P = .13). In this diagnostic study with pathological findings as the reference standard, no difference was found between FES PET/CT and current SOC imaging for detecting distant metastases in patients with ER-positive LABC or recurrences in patients with ER-positive tumors and suspected recurrence. FES PET/CT could be considered for both clinical indications, which are not part of current Appropriate Use Criteria for FES PET. The findings regarding FES PET/CT in patients with lobular tumors, and for lower false positives than current SOC imaging, warrant further investigation.

Brain Radiotherapy Combined with Targeted Therapy for HER2-Positive Breast Cancer Patients with Brain Metastases.

Research on the sequencing of brain radiotherapy and targeted chemotherapy after brain metastasis (BM) in HER2-positive breast cancer patients is limited and inconclusive. This study investigated the efficacy of sequential delivery of radiotherapy and targeted therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with BM. Fifty-seven patients were categorized into two groups: the targeted-radiotherapy group (receiving 2-8 cycles of anti-HER2-targeted therapy followed by radiotherapy after BM) and the radiotherapy-targeted group (undergoing radiotherapy first, followed by regular anti-HER2-targeted therapy). The study endpoints were intracranial progression-free survival (iPFS) and overall survival. Factors associated with intracranial progression and mortality were assessed by univariate and multivariate Cox proportional hazards analysis. Patients in the radiotherapy-targeted group had better iPFS (P < 0.001), while there was no significant difference in overall survival between the two groups (P = 0.145). Multivariate Cox analysis showed that different sequential treatment groups were independent prognostic factors for iPFS. In patients with a modified breast graded prognostic assessment score of 3.5-4.0, the median survival time was 26 months in the radiotherapy-targeted group and 22 months in the targeted-radiotherapy group (P = 0.019). Overall, radiotherapy followed by targeted therapy may improve survival in HER2-positive breast cancer patients with BM, particularly in those with a modified breast graded prognostic assessment score of 3.5-4.0.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.

Concurrent epirubicin and trastuzumab use increases complete pathological response rate without additional cardiotoxicity in patients with human epidermal growth factor receptor 2-positive early breast cancer: A meta-regression analysis.

Due to cardiotoxicity concerns, the concurrent use of epirubicin and trastuzumab has not been fully studied. This study aimed to examine the cardiotoxicity and pathological complete response (pCR) rate associated with the concurrent regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). We conducted a systematic search for relevant literature in the NCBI/PubMed, the Cochrane database, and international conference abstracts for phase II or III randomized controlled trials between January 1, 2000, and February 28, 2021, focusing on the concurrent regimens in patients with HER2-positive EBC. To compare the risk of cardiotoxicity and the odds of the pCR rate, we performed linear meta-regression analyses to investigate the effects of multiple covariates. We analyzed 7 neoadjuvant trials involving the concurrent use of epirubicin and trastuzumab with 1797 patients. The median cumulative dose of epirubicin used was 300 mg/m2, with a total of 96 reported adverse cardiac events. The concurrent regimens did not result in a significant increase in cardiotoxicity compared to nonconcurrent regimens (risk ratio [RR] = 1.18, 95% confidence interval [CI] = 0.68-2.05). Compared with nonconcurrent or non-anthracycline-containing regimens, concurrent regimens were associated with a significant increase in the pCR rate (odds ratio = 1.48, 95% CI = 1.04-2.12). The linear fixed-effects meta-regression analysis indicated that in trials including more patients with hormone receptor-positive EBC, the RR of cardiotoxicity significantly increased with concurrent regimens, and the pCR rate became less significant. The combination of trastuzumab and a low dose of epirubicin positively impacted the pCR rate without a significant increase in cardiotoxicity. We recommend exploring concurrent regimens for HR-negative, HER2-positive tumors to enhance pCR rates, with caution advised for HR-positive tumors due to potential cardiotoxicity.