Factor Receptor 2-negative Breast Cancer Research Articles

Late onset toxicities associated with the use of CDK 4/6 inhibitors in hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) metastatic breast cancer patients: a multidisciplinary, pan-EU position paper regarding their optimal management. The GIOCONDA project

The personalization of therapies in breast cancer has favoured the introduction of new molecular-targeted therapies into clinical practice. Among them, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have acquired increasing importance, with the approval in recent years of palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy. Currently, no guidelines are available to monitor and manage potential long-term toxicities associated with the use of these drugs. A multidisciplinary panel of European oncologists, was supported by a pharmacologist, a hematologist, a hepatologist and a pulmonologist to discuss the management of long-term toxicities, based on the literature review and their clinical experience. The panel provided detailed roadmaps to manage long-term toxicities associated with the use of CDK4/6 inhibitors in clinical practice. Knowing the frequency and characteristics of the toxicity profile associated with each CDK4/6 inhibitor is important in the decision-making process to match the right drug to the right patient.

Trends in Locoregional Therapy in Older Women with Early-Stage Hormone Receptor-Positive Breast Cancer by Frailty and Life Expectancy.

In women ≥ 70 years of age with T1N0 hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, breast surgery type and omission of axillary surgery or radiation therapy (RT) do not impact overall survival. Although frailty and life expectancy ideally factor into therapy decisions, their impact on therapy receipt is unclear. We sought to identify trends in and factors associated with locoregional therapy type by frailty and life expectancy. Women ≥ 70years of age with T1N0 HR+/HER2- breast cancer diagnosed in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between 2010 and 2015 were stratified by validated claims-based frailty and life expectancy measures. Therapy trends over time by regimen intensity ('high intensity': lumpectomy + axillary surgery + RT, or mastectomy + axillary surgery; 'moderate intensity': lumpectomy + RT, lumpectomy + axillary surgery, or mastectomy only; or 'low intensity': lumpectomy only) were analyzed. Factors associated with therapy type were identified using generalized linear mixed models. Of 16,188 women, 21.8% were frail, 22.2% had a life expectancy < 5 years, and only 12.3% fulfilled both criteria. In frail women with a life expectancy < 5 years, high-intensity regimens decreased significantly (48.8-31.2%; p<0.001) over the study period, although in 2015, 30% still received a high-intensity regimen. In adjusted analyses, frailty and life expectancy < 5 years were not associated with breast surgery type but were associated with a lower likelihood of axillary surgery (frailty: odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76-0.96; life expectancy < 5 years: OR 0.22, 95% CI 0.20-0.25). Life expectancy < 5 years was also associated with a lower likelihood of RT receipt in breast-conserving surgery patients (OR 0.30, 95% CI 0.27-0.34). Rates of high-intensity therapy are decreasing but overtreatment persists in this population. Continued efforts aimed at appropriate de-escalation of locoregional therapy are needed.

Use of the Gene Expression Test Prosigna® in Premenopausal Patients with HR+, HER2− Early Breast Cancer: Correlation of the Results with the Proliferation Marker Ki-67

Introduction: In hormone receptor-positive (ER+/PR+) and human epidermal growth factor receptor 2-negative (HER2−) early-stage breast cancer (EBC), gene expression tests such as the Prosigna are increasingly used since classic clinicopathological parameters and the proliferation factor Ki-67 often do not allow a definite therapy decision regarding an adjuvant chemotherapy. While the Prosigna test has been validated for postmenopausal patients, few data are available regarding its use in premenopausal patients. The present study compared the Prosigna test with the Ki-67 index in premenopausal patients. Materials and Methods: Premenopausal patients with HR+ HER2−, pN0-1, G1-2 EBC were retrospectively enrolled (n = 55). The Prosigna assay was performed in formalin-fixed paraffin-embedded tumor samples of surgical resection specimens. Ki-67 was reassessed in original diagnostic core needle biopsy specimens and defined as low, intermediate, or high with the threshold of <10%, 10–24%, ≥25%. Results: According to Ki-67, patients were in the low (LR)-, intermediate (IR)-, and high-risk (HR) groups in 40%, 36%, and 24% of the cases. The Prosigna gene signature assay assessed the risk of recurrence as LR for 45% of the patients, IR for 35%, and HR for 20%. The most frequent intrinsic subtypes were luminal A in 73% and luminal B in 24% of the patients. A moderate correlation was found between Prosigna and Ki-67 scores with a Pearson correlation coefficient of 0.51. In the overall cohort, 47% of the Ki-67-based therapy decision would correspond to those based on the Prosigna score. After exclusion of IR patients, matching of low/low or high/high results was observed in 57% of the cases. Conclusion: According to the present study, there is only limited concordance regarding the risk group stratification between Ki-67 and Prosigna-based risk assessment. The relevance and frequency of premenopausal breast cancer emphasizes the need for further evaluation of gene expression analyses in this setting and the correlation with classic clinicopathological parameters regarding therapy decision-making.

Phase II study of apatinib plus exemestane in estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer

ABSTRACT Purpose Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR)-2. This study was conducted to assess the efficacy and safety of apatinib combined with exemestane in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Methods This single-center, single-arm phase II study enrolled patients with ER+/HER2- MBC progressed on previous letrozole or anastrozole. Stratified analysis was performed according to the number of chemotherapy regimens for metastatic disease. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS) and toxicity. Patients received apatinib at a starting dose of 500 mg/d and exemestane 25 mg/d on days 1–28 of each 4-week cycle. Results Thirty patients were enrolled with median four prior anticancer therapies. Eighty percent of patients received chemotherapy for metastatic disease. The median PFS (mPFS) and OS were 5.6 (95%CI: 4.3–6.9) months and 15.7 (95% CI: 9.7–21.7) months, respectively. The ORR, DCR, and CBR were 21.4%, 71.4%, and 46.4%, respectively. Patients with 0–1 line chemotherapy for MBC showed a slightly longer mPFS compared to those with ≥2 lines chemotherapy (mPFS: 6.4 months vs 4.8 months, P = .090). Most of the AEs were grade 1/2. One patient (3.3%) who suffered bone marrow metastases experienced grade 4 thrombocytopenia, and 14 experienced grade 3 AEs. Fifty percent of patients were given reduced dose for apatinib. Conclusions Apatinib plus exemestane exhibited objective efficacy in patients with ER+/HER2- MBC who have failed multiple lines of treatment. The AEs of apatinib required close monitoring and most of patients were well tolerated.

Adequate effectiveness of ribociclib plus letrozole or fulvestrant in patients with advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated in routine Bulgarian clinical practice

Randomized controlled trials (RCTs) are typically conducted in highly selected patient populations to ideally demonstrate unconfounded clinical efficacy of a drug. In the real world, there may be confounding factors, such as comorbidities or less frequent monitoring. It has therefore become standard practice in many countries to validate findings from RCTs against available real-world datasets. The present analysis investigated a real-world evidence (RWE) cohort of Bulgarian patients treated with ribociclib in combination with letrozole or fulvestrant and compared the clinical benefit rate (CBR, defined as complete remission [CR] or partial remission [PR] or stable disease [SD]) and progression-free survival (PFS) and overall survival (OS) with pivotal RCTs. Data from 812 patients treated between 2018 and 2022 were used. The number of patients at risk was statistically robust to compare PFS and OS during the earlier periods of the real-world data analysis with the corresponding RCTs. Baseline characteristics (age, hormone receptor status, status of newly diagnosed vs. existing, previous treatments, performance status and tumor stage) were largely comparable between the RWE cohort and the RCTs. The RWE cohorts corroborated RCT findings of a CBR benefit of the ribociclib plus letrozole or fulvestrant combination compared to letrozole or fulvestrant alone. In the periods of adequate statistical robustness, PFS and OS were comparable within 95% confidence intervals (CIs) with RCT findings. This analysis found that patients with comparable characteristics use ribociclib in the real-world similarly to what has been investigated in the RCTs. Real-world effectiveness and outcomes of ribociclib combination therapy were comparable with observations from RCTs.

Mutational Status is Associated with a Higher Rate of Pathologic Complete Response After Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer.

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) occurs in up to 20% of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers. Whether this differs among BRCA mutation carriers is uncertain. This study compared pCR between BRCA1/2 mutation carriers and matched sporadic control subjects. From November 2013 to January 2022, this study identified 522 consecutive women with clinical stage I to III HR+/HER2- breast cancer treated with NAC and surgery. The study matched BRCA1/2 mutation carriers 1:2 to non-carriers in terms of age, clinical tumor (cT) and nodal (cN) stage, and differentiation. Two-sample non-parametric tests compared baseline characteristics. Multivariable logistic regression assessed pCR (i.e., ypT0/ispN0) by BRCA1/2 mutational status. Of the 522 women (median age, 50 years), 59 had BRCA1/2 mutations, 78% of which were clinically node positive. Anthracycline-based NAC was administered to 97%. More BRCA1/2 mutation carriers were younger, had cT1 tumors, and had poorly differentiated disease. After matching, 58 BRCA1/2 mutation carriers were similar to 116 non-carriers in terms of age (p = 0.6), cT (p = 0.9), cN stage (p = 0.7), and tumor differentiation (p > 0.9). Among the mutation carriers, the pCR rate was 15.5% for BRCA1/2, 38% (8/21) for BRCA1, and 2.7% (1/37) for BRCA2 versus 7.8% (9/116) for the non-carriers (p < 0.001). After NAC, 5 (41.7%) of the 12 BRCA1 mutation carriers converted to pN0 versus 10 (37%) of the 27 BRCA2 mutation carriers and 19 (20.9%) of the 91 non-carriers (p = 0.3). In the multivariable analysis, BRCA1 mutation status was associated with higher odds of pCR than non-carrier status (odds ratio [OR] 6.31; 95% confidence interval [CI] 1.95-20.5; p = 0.002), whereas BRCA2 mutation status was not (OR 0.45; 95% CI 0.02-2.67; p = 0.5). This study showed that BRCA1 mutation carriers with HR+/HER2- breast cancers have a higher rate of pCR than sporadic cancers and may derive greater benefit from chemotherapy. The use of NAC to downstage these patients should be considered.

THU259 Alpelisib-induced Diabetic Ketoacidosis: Call For A Multidisciplinary Approach

Abstract Disclosure: N. Kalara: None. P. Rios: None. F. Vendrame: None. Introduction: Alpelisib is a p110a subunit phosphatidylinositol-3kinase inhibitor (PI3K) approved for treating hormone receptor-positive, human epidermal growth factor receptor 2-negative, PIK3CA mutated, advanced or metastatic breast cancer. PI3K signaling is essential for the metabolic action of insulin and the inhibition of p110a subunit is associated with hyperinsulinemia and hyperglycemia. In the combination (Alpelisib-Fulvestrant) arm of phase III SOLAR-1 study the all-grade incidence of hyperglycemia was 63%, but diabetic ketoacidosis (DKA) was also observed and reported in 0.7% of patients. To the best of our knowledge, less than 10 cases of Alpelisib-induced DKA have been reported in the literature. Here we describe an additional case. Case Description: A 62-year-old female with a history of metastatic breast cancer, hypertension, and prediabetes, presented with 3 days of nausea, vomiting, abdominal pain, weakness, polyuria, and polydipsia. Fifteen days prior to the presentation the HbA1c was 6.1% for which she was started on metformin 500 mg daily. Alpelisib 150 mg PO BID and Fluvestrant (Estrogen receptor antagonist) were also started the same day. The patient was told to stop the PIK3 inhibitor if the blood glucose increased above 200 mg/dL. The review of system was positive for fatigue, decreased appetite, malaise, 5 lbs weight loss during the previous week, and headache. She had no family history of any endocrinologic disease. The physical exam was unremarkable with no signs of insulin resistance. Laboratory tests revealed pH 7.31 (7.35-7.45), HCO3 10 mmol/L (22-26), PCO2 21 mmHg (35-45), glucose 884 mg/dL (74-106), sodium 120 mmol/L (136-145), K 5.2 mmol/L (3.5-5.1), Cl 93 mmol/L (98-107), CO2 7 mmol/L (21-32), anion gap 22 mmol/L (5-15), GFR 30 mL/min/1.73m2 (&amp;gt;60), Cr 1.80 mg/dL (0.5-1.02), BUN 43 mg/dL (7-18), beta-hydroxybutyrate 3 mmol/L (0.4-0.5), HbA1c 9.2% (4.2-5.6). Additional testing revealed C-peptide 2.3 ng/ml (1.1-4.4) with glucose 397 mg/dL. Results suggested a combined DKA and hyperosmolar hyperglycemic state (HHS). Alpelisib was discontinued and the patient was managed with insulin drip, fluids, electrolyte replacement, and eventually transitioned to a basal-bolus regimen (0.5U/kg). The patient was discharged on metformin and Insulin glargine with the recommendation to follow up with endocrinology and oncology. Conclusion: Our case highlights the importance of blood glucose and HbA1c screening before starting Alpelisib with emphasis on a multidisciplinary approach to monitor blood glucose levels to prevent DKA. Reference: 1. Farah SJ, Masri N, Ghanem H, Azar M. Diabetic ketoacidosis associated with alpelisib treatment of metastatic breast cancer. AACE Clin Case Rep. 2020;6(6):e349-e351. doi: 10.4158/ACCR-2020-0452 Presentation: Thursday, June 15, 2023

167P A tumor immune microenvironment-based model for prediction of everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Preliminary results from MIRACLE trial

167P A tumor immune microenvironment-based model for prediction of everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Preliminary results from MIRACLE trial

281P Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: A meta-analysis of randomized clinical trials

281P Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: A meta-analysis of randomized clinical trials

Shared Decision-Making on Using a CDK4/6 Inhibitor plus an Aromatase Inhibitor for HR+/HER2- Metastatic Breast Cancer: A Podcast.

Shared decision-making involves patients engaging with their physicians to make informed decisions regarding treatment selection, a process that empowers patients and ensures that treatment decisions reflect their individual values and preferences. However, shared decision-making can be challenging to implement for various reasons, including time, staffing, or resource limitations at community practices and differences in patients' cultural backgrounds or health literacy. In this podcast, we discuss how to ensure that individual patients' needs and concerns are addressed, including an overview of different approaches for initial consultations, strategies for tailoring conversations based on a patient's background or health literacy, and trustworthy resources that can help improve patients' understanding. As an illustrative example, we focus on how to implement shared decision-making to address the needs of a patient with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer who is eligible for combination therapy with a cyclin-dependent kinase 4/6 inhibitor plus an aromatase inhibitor. Overall, this podcast illustrates how shared decision-making is an achievable goal, even in small or underresourced practices, and provides an instructive guide on how to facilitate shared decision-making for patients with HR+/HER2- metastatic breast cancer. Podcast Discussion (MP4 29880 KB) INFOGRAPHIC.

Long Term Outcomes of Radiation (RT)-Monotherapy vs. Combined RT + Endocrine Therapy (RT+ET) in Low-Risk Early-Stage Breast Cancer Patients 70 Years or Older after Breast-Conserving Surgery (BCS)

Combined Radiation and Endocrine Therapy (RT+ET) and ET Monotherapy are acceptable adjuvant strategies based on randomized trial data. Less is known about RT Monotherapy as a form of treatment de-escalation. Radiation delivery has become safer and more convenient. This study compares long-term outcomes in patients who opted for RT-Monotherapy versus combined RT+ET. This retrospective study included female patients from Swedish Cancer Institute breast cancer registry (Seattle, WA), aged ≥70 years with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) T1N0 breast cancer treated with BCS between 1995 and 2015. Patients with positive surgical margins, multifocality, histologic grade 3 and LVI were excluded. Patients were classified into 4 groups: (1) RT+ET (reference); (2) RT Monotherapy; (3) ET Monotherapy; and (4) neither RT nor ET (NT). Choice of therapy was determined by the treating physician and the patient. The primary endpoints were local recurrence (LR), distant metastasis (DM), disease specific survival (DSS), overall survival (OS), and second breast cancer events (SBCEs). Competing risk models were used to estimate cumulative incidence at varying lengths of follow-up and sub distribution hazard ratios (HR) between treatment groups. Significance was set at P ≤ .05. We analyzed 496 patients with a median age of 76 years and median follow-up of 9.6 years. 62% (N = 307) of patients received combined RT+ET, 30% (N = 148) RT Monotherapy, 4% (N = 20) ET alone and 4% (N = 21) no therapy, NT group. Only the RT monotherapy and combined RT+ET groups were large enough for a meaningful statistical analysis. RT monotherapy conferred non-inferior disease control compared to combined RT+ET. Recurrence events were extremely low. Incidence of SBCEs was not significantly different between treatments. For this favorable patient population, RT monotherapy was associated with equivalent long-term outcomes compared to combined RT+ET therapy. Recurrence rates stayed extremely low with long-term FU. RT monotherapy may be a reasonable de-escalation option for this older low risk patient population. Further prospective trials are needed to help refine treatment strategies that allow for more choices in treatment de-escalation.

Molecular classification of hormone receptor-positive HER2-negative breast cancer.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2- breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2- breast cancer.

Real-world treatment patterns and effectiveness of palbociclib plus an aromatase inhibitor in patients with metastatic breast cancer aged 75 years or older.

Elderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years treated in routine clinical practice in the United States. This retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis). A total of 961 patients aged ≥ 75 years with HR+/HER2- mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51-0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59-0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55-0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM. This real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2- mBC.

Is Palbociclib a cost-effective strategy in the second-line treatment of metastatic breast cancer in Iran?

ABSTRACT Background & Aims This study evaluates the cost-effectiveness of Palbociclib in the second-line treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in Iran. Methods The present economic evaluation used a partitioned survival model (PSM). This model compares lifetime costs and disease outcomes among groups receiving different medication combinations containing Palbociclib, Fulvestrant, Everolimus, Ribociclib, and Abemaciclib as the second-line therapy for HR+/HER2- MBC. The model was conducted from Iran’s healthcare perspective, structured with 1-month cycles, and the evaluation time horizon in the base analysis was set to 180 cycles (15 years). Transition probabilities were extracted using the survival curves. The cost information was extracted based on the year 2020. The Quality Adjusted Life Years (QALY) was considered the final outcome unit, and the cost-effectiveness of different combinations is calculated as cost per QALY. The annual discount rate of 5% was considered for costs and QALYs. Two times Iran’s GDP per capita (800,000,000 IRR = US$5934) was used as the threshold. Finally, due to the uncertainty of some parameters, deterministic and probabilistic sensitivity analyses were carried out. Results The base case results showed that the highest cost was for the ‘Ribociclib+ Fulvestrant’ combination (US$89,629.56), and the lowest price was for the ‘Iranian Everolimus + Fulvestrant’ combination (US$10,740.09). ‘Palbociclib + Fulvestrant’ brings about the highest value of 1.456 incremental QALYs compared to other strategies. Finally, the ‘Iranian Palbociclib + Fulvestrant’ was the cost-effective combination, with an incremental cost-effectiveness ratio (ICER) of US$4,201 compared to other strategies. The base case results were supported by the probabilistic sensitivity analysis. Deterministic sensitivity analysis showed that the cost of Iranian Palbociclib has a threshold of US$582.99. Conclusions The ‘Iranian Palbociclib + Fulvestrant’ combination was cost-effective in second-line therapy for HR+ HER2- MBC in Iran.

Current treatment landscape of HR+/HER2− advanced breast cancer in the Nordics: a modified Delphi study

Background This Delphi study aimed to assess current perspectives on hormone receptor-positive/human epidermal growth factor receptor 2-negative(HR+/HER2−) advanced breast cancer (aBC) treatment strategies across the Nordics, and to establish where consensus exists across the Nordics on HR+/HER2− aBC treatment. Material and methods A modified, three-round Delphi method was followed. A steering committee was appointed for study coordination, panellist selection, and questionnaire development. The questionnaires covered relevant topics on HR+/HER2− aBC treatment: treatment patterns in different lines of therapy (first [1L], second [2L], and third [3L]), oligometastatic disease, de novo aBC, brain metastases, age as influential factor, visceral crisis, radiotherapy, diagnostics, and clinical guidelines. Both open and closed-ended questions were included. Consensus was defined as at least 70% agreement. Results In total, 28 experienced BC oncologists participated in the study from all five Nordic countries. Overall, topics reaching consensus included: preferred treatment approach in 1L and 2L therapy, treatment of oligometastatic disease, visceral crisis, brain metastases, and age-related treatment considerations. No consensus was reached for 3L therapy and local treatment for primary tumour in de novo aBC. Endocrine therapy (ET) combined with a cyclin-dependent kinase (CDK)4/6 inhibitor was the treatment of choice for 1L and 2L therapy. Treatment patterns in clinical practice did not always follow recommendations in current Nordic guidelines, as seen in the case of recently approved treatments. Discussion ET in combination with a CDK4/6 inhibitor is the preferred frontline treatment for HR+/HER2− aBC in the Nordics. The observed discrepancy between current guidelines and clinical practice could be due to differences in the reimbursement of novel treatments in the Nordics. Collaborative research efforts are warranted for topics that lack consensus.

Genetic Testing in Metastatic Breast Cancer in the USA: A Podcast.

This podcast highlights the importance of genetic testing in patients with metastatic breast cancer, with a specific focus on germline or inherited breast cancer susceptibility gene (BRCA) mutations. In the USA, national guidelines recommend that all patients with recurrent or metastatic breast cancer should be offered genetic testing for germline breast cancer susceptibility gene 1 or 2 (BRCA1 or 2) mutations to identify patients potentially suitable for treatment with a poly(ADP-ribose) polymerase inhibitor. However, a retrospective study indicated that only 43% of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who may be eligible for genetic testing have undergone germline BRCA1 or 2 testing. Therefore, a large national effort is required to offer genetic testing to more patients with recurrent or metastatic breast cancer. The aim of this podcast is to provide physicians with information to support the early engagement of patients in discussions about genetic testing, and guidance on how to manage patient concerns about the potential implications of testing. Here, a healthcare professional discusses germline genetic testing with a patient advocate and answers questions regarding the importance of testing in patients with metastatic breast cancer. Furthermore, the authors discuss what it means to receive a positive or negative result for a germline BRCA mutation and the impact this may have on the patient and their family members. Overall, the authors emphasize the importance of healthcare professionals providing every patient with metastatic breast cancer with the relevant information about genetic testing so that patients can make informed decisions. Podcast Audio and Infographic available for this article.Podcast Audio and Infographic available for this article.

Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials

The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/humanepidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. NCT01958021, NCT02422615, NCT02278120.

Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic BRCA1/2, Germline PALB2, or Homologous Recombination Deficiency Signature.

Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1/2 genes (gBRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1/2 mutations (sBRCA) or germline PALB2 mutations (gPALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with gBRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record-derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. Of 28,920 patients with mBC, gBRCA was detected in 3.4%, whereas the population with any BRCA alteration or gPALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and gPALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and gBRCA and sBRCA/gPALB2 cohorts were similar: gBRCA versus sBRCA/gPALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig- had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). Patients with sBRCA and gPALB2 derive similar benefit from PARPi as those with gBRCA alterations. In combination, HRDsig+, sBRCA, and gPALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial

Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer. Gilead Sciences.

Prevalence of PIK3CA mutations in Taiwanese patients with breast cancer: a retrospective next-generation sequencing database analysis.

Breast cancer is the most common cancer type that affects women. In hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population. This is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment. PIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR-/HER2+ subtype and 42% of patients with HR+/HER2- postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2- premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort. A high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.