Luminal HER2-negative Breast Cancer Research Articles

The choice of optimal therapy for ER+ HER2-metastatic breast cancer (PROMETHEUS): all-Russian analysis of physicians’ preferences – updated survey results

Cyclin-dependent kinase 4/6 inhibitors (iCDK4/6) are the generally accepted standard of care for the treatment of luminal HER2-negative metastatic breast cancer (ER+HER2- mBC). Data from randomized and observational studies have proven the high effectiveness of the combination of iCDK4/6 and endocrine therapy (ET) both in the 1st and in subsequent lines. The use of new drugs in real clinical practice is determined by a number of factors, including the awareness of doctors, their personal experience and subjective preferences, as well as financial support and availability in a particular region. To assess the frequency of prescription of CDK4/6, as well as other types of treatment in the 1st‑2nd line of therapy for ER+ HER2- mBC in real clinical practice in Russia, as well as to determine the factors and preferences of doctors influencing their choice, the National Association of Oncomammologists (NAOM) conducted a survey “Prometheus” of oncology specialists. From February 15 to August 30, 2023, a web survey of healthcare professionals who treat patients with mBC was conducted on the website anketolog.ru. An invitation to survey was sent out through the NAOM database, 112 questionnaires were received and processed. Earlier, in 2020, the “Prometheus” survey was conducted on the territory of the Russian Federation for a similar purpose. In this paper, we present the results of an updated and expanded survey and evaluate changes that have occurred over the past 3 years in actual clinical practice. The results of a 2023 survey conducted in the Russian Federation on the choice of early-line therapy for ER+HER2- mBC showed that, compared with the 2020 survey, the level of “trust” in iCDK4/6 has increased among practicing physicians, and the indications for their use have expanded, including visceral metastases (and even pending visceral crisis), the indications for prescribing chemotherapy in the 1st line have narrowed. When using monoET in the 1st line, the majority of respondents prescribe iCDK4/6 in the 2nd line. Obviously, the wider use of iCDK4/6 is associated not only with the accumulation of clinical knowledge and experience in the use of drugs, but also with improved drug supply. However, the main limitations to the use of iCDK4/6 are still insufficient funding and organizational difficulties. However, it should be noted that 1/5 of the respondents do not face any restrictions and widely prescribe combination therapy.

The role of tumor-associated neutrophils in early luminal HER2-negative breast cancer progression

BACKGROUND: Luminal HER2-negative breast cancer is the most common type of tumor in women diagnosed with early-stage breast cancer. Stromal cells and immune cells in tumor microenvironment have been reported to play a significant role in cancer prognosis. The prognostic role of tumor-associated neutrophils in early breast cancer remains mostly unclear. AIM: To study predictive role tumor-associated neutrophils in early luminal HER2-negative breast cancer. MATERIALS AND METHODS: The dataset consisted of 60 patients with early luminal HER2-negative breast cancer treated in S.P. Botkin City Clinical Hospital (Moscow, Russia). We first estimated basic morphological signs: tumor size, tumor grade (by Nottingham Histologic Score), tumor-infiltrating lymphocytes, lymphovascular invasion, hormonal receptors status, proliferative index, regional lymph nodes status. The expression of intratumoral neutrophils was studied using immunohistochemistry with CD15. RESULTS: High tumor-associated neutrophils concentration was correlated with tumor size, high grade tumors, proliferative index, tumor-infiltrating lymphocytes, lymphovascular invasion and positive regional lymph nodes. CONCLUSION: Tumor-associated neutrophils predicted a worse prognosis in early luminal HER2-negative breast cancer.

Predictive and prognostic features of early and locally advanced <i>PIK3CA</i>-mutated luminal HER2-negative breast cancer

Background. Data on the prognostic role of the PIK3CA mutation in hormone receptor-positive (HR+) HER2-negative (HER2–) breast cancer (BC) are contradictory; nevertheless, there are indications of its negative predictive and prognostic significance. This dictates the need for early genetic testing of BC to predict the clinical course, select a primary therapy option and individualize systemic treatment with disease progression. Investigation of regulation of the tumor cell cycle, as well as the relationship between genetic markers, infiltration of tumor-infiltrating lymphocytes (TILs) and subpopulations of immune cells is strategically important for the search for drug therapy targets.Aim. To search for predictive and prognostic markers of the clinical course of PIK3CA-associated HR+ HER2– BC.Materials and methods. The clinical, morphological and molecular features of the tumor of 101 BC patients with PIK3CA mutations (100 women and 1 man) were analyzed. Early and locally advanced HR+ HER2– BC is present in 81 % of cases, where neoadjuvant chemotherapy (NAPCT) was performed in 28 % of patients. Primary metastatic disease was detected in 17 % of cases. An immunohistochemical evaluation was performed on sections from paraffin blocks using monoclonal antibodies to estrogen receptors, progesterone receptors, HER2, Ki-67, CD8, CD4, CD68, CD163, Bcl-2, p53, cyclin D1. TILs were evaluated when stained with hematoxylin and eosin. TILs were evaluated in the stromal component of the tumor. The correlation of clinical and morphological parameters with the type of mutation and clinical outcomes of treatment of patients with early and locally advanced HR+ HER2– BC was evaluated. The statistical analysis was performed using the IBM SPSS Statistics v. 22 statistical package.Results. In BC with the PIK3CA mutation, a low level of TILs infiltration was detected (1 point), which does not differ depending on the presence of mutations in exon 20 and exon 9 (p >0.05). However, the E545K mutation is characterized by a higher TILs level (2 points) (p = 0.05). CD4+ T-TILs and CD8+ T-TILs levels are statistically significantly higher with mutations in exon 20 compared to exon 9 of the PIK3CA gene (p = 0.017 and 0.013, respectively). At the same time, in comparison with other mutations, tumors with H1047R and E545K mutations (p = 0.05) were characterized by a higher level of CD4 and CD8 expression. Regardless of the mutated exon, a high level of CD68+ tumor-associated macrophages (Me = 80 %), was detected due to the CD163+ fraction of immunosuppressive M2-polarized tumor-associated macrophages (Me = 70 %). A feature of the regulation of the PIK3CA-mutated BC cell cycle is the high level of cyclin D1 expression, the absence of p53 expression and the positive expression of the antiapoptotic marker Bcl-2. The median disease-free survival in early and locally advanced HR+ HER2– BC with the PIK3CA mutation was 36 months (95 % confidence interval (CI) 24.720–47.280). The risk of progression was increased by NAPCT (hazard ratio 3.389; 95 % CI 1.530–7.504; p = 0.003). The risk of progression was reduced by age younger than 49 years (hazard ratio 0.54; 95 % CI 0.30–0.96, p = 0.0359) and the absence of expression of the antiapoptotic marker Bcl-2 (hazard ratio 0.36; 95 % CI 0.14–0.97; p = 0.0425).Conclusion. The data obtained indicate that BC with the PIK3CA mutation is a kind of biological subtype of HR+ HER2– BC, which shows the lack of significant efficacy of NAPCT, probably due to the immunosuppressive microenvironment and low TILs levels. At the same time, the predominant population was M2-polarized tumor-associated macrophages. Moreover, the administration of NAPCT and the positive expression of Bcl-2 reduce disease-free survival, which can be explained by the possible effect of increasing the invasiveness and migration potential of the tumor cell. It is important to continue investigation of identified clinical and morphological prognostic markers when planning and developing new strategies for the treatment of early and metastatic HR+ HER2– BC with the PIK3CA mutation, as well as the use of specific targeted therapy at early metastatic disease.

Efficacy of dose-dense versus standard neoadjuvant chemotherapy regimensin luminal HER2-negative breast cancer: Interim results of single-centre study

Introduction. The efficacy of dose-dense AC in adjuvant chemotherapy of luminal breast cancer (ER+ BC) compared with the standard dosing regimen followed by switching to taxanes has been proven in numerous clinical trials and in a large meta-analysis of the EBCTCG group. However, no study about efficiency of this regimen in neoadjuvant setting has been published.The aim of the study. To assess the effectiveness of dose-dense regimens of neoadjuvant chemotherapy (NAC) of ER + HER2-BC (4 AC once every 2 weeks (dose dense, ddAC), then 4 courses of Docetaxel once every 3 weeks or 12 weekly injections of Paclitaxel [4D/12P]) and their comparison with the standard ones (AC once every 3 weeks [ACq3w], hereinafter 4D/12P). Primary end points are complete response rate (pCR) and RCB0–I.Methods. This retrospective study included patients with resectable or locally advanced luminal HER2-negative breast cancer who received NAC from Janu 2017 to Aug 2022. Statistical hypothesis – the dose-dense regimen AC increases the frequency of RCB0–I from 22 to 32% compared to the standard dosing regimen with subsequent switching to taxanes, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included in the study, of which 147 and 168 patients received dose-dense (ddAC) and standard chemotherapy (ACq3w), respectively. After propensity matching analysis 138 patients in each group were included in the final analysis.Results. The pCR rate was 18.84% in the ddAC group versus 14.49% in the AC q3w group, the differences were not statistically significant (p = 0.379). The frequency of RCB0–I was higher in the ddAC – group 33.33% versus 21.74% in the AC q3w (p = 0.040). According to the subgroup analysis, rate of RCB0–I was significantly higher in patients younger 50 years, cN0, with the expression of progesterone receptors in ≥ 20%.Conclusions. This is the first study to compare the efficacy of a ddAC NAC with a standard regimen for ER + HER2-BC. NAC with ddAC is associated with an increase in RCB0–I rate.

Relationship Between Daily Dose of Everolimus and Treatment Effect in Patients With Luminal HER2-negative Metastatic Breast Cancer.

Everolimus (EVE)-based treatment is an option for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), but a predictive marker has not yet been established. The recommended dose of EVE in combination with endocrine therapy is 10 mg/day, but due to adverse effects, patients are frequently forced to reduce the dose. However, the correct maintenance dose to achieve a therapeutic effect is still under debate. Employing real-world data, we examined clinicopathological factors to predict the efficacy of EVE-based treatment, particularly focusing on daily dose intensity (DDI). Ninety-five patients with MBC who received EVE-based treatment in combination with exemestane during the period from 2014 to 2022 were retrospectively investigated. Doses of EVE were reduced as needed and DDI was calculated with total doses of EVE and the duration of the treatment. Mean time-to-treatment-termination (TTT) was 25.4 weeks. Patients with tumors with a high Ki67 labeling index, low absolute lymphocyte count, and small DDI of EVE had significantly shorter TTT (p=0.006, 0.043, and 0.030, respectively). When patients were categorized based on DDI of EVE, patients with DDI ≤5 mg/day had significantly shorter TTT (p=0.002). There were no correlations between RDI and factors such as age, body weight, and numbers of previous treatments for MBC. Maintaining a DDI of at least 5 mg/day seems crucial to achieving a therapeutic effect. Our data might be useful for determining the dosage of EVE in clinical practice.

Place of fulvestrant in the treatment of patients with metastatic luminal Her2-negative breast cancer

Hormone therapy alone or in combination with targeted agents (CDK4/6 inhibitors, alpelisib, everolimus) is currently the standard treatment of metastatic luminal Her2-negative breast cancer. Aromatase inhibitors and fulvestrant are the main hormone therapy agents. Fulvestrant belongs to a special class of antiestrogens – selective estrogen receptor degraders (SERD) and does not have estrogen receptor agonist activity, unlike tamoxifen. In addition, the efficacy of fulvestrant does not depend on the presence of ESR1 mutations in the tumor. The combination of aromatase inhibitors with CDK4/6 inhibitors is the standard first-line treatment in patients with hormone-sensitive tumors, that is, with progression of more than 1 year after the end of adjuvant hormone therapy. Whereas fulvestrant ± CDK4/6 inhibitors are used for disease progression on adjuvant hormonal therapy in the 1st line or as 2nd line for progression on aromatase inhibitor therapy for metastatic cancer. The choice of treatment for patients with a PIK3CA mutation with progression on the 1st line of fulvestrant with a CDK4/6 inhibitor is difficult. This article presents a clinical example of the use of a combination of fulvestrant and alpelisib in a patient with secondary hormone resistance (progression on the adjuvant therapy with aromatase inhibitors) and progression on the first-line therapy with fulvestrant and palbociclib. Carrying out therapy with fulvestrant and alpelisib as the 2nd line provided a long-term (for 14 months) stabilization of the tumor process.

Clinical application of the 21-gene oncotype recurrence score in an older cohort: A single center experience

BackgroundIn early luminal breast cancer, the Oncotype DX® Recurrence Score (RS) prognostic and predictive value with regards to chemotherapy (CHT) application benefit has been broadly validated. In older patients its value has not been deeply addressed. This study aimed to evaluate the benefits of RS testing and to look at differences in treatment allocation for these patients when compared with younger ones. MethodsWe included data from consecutive patients with early luminal HER2-negative breast cancer, treated between 2010 and 2022 at the University Hospital Basel and Cantonal Hospital Baselland, Switzerland. The older cohort included 63 (19%) patients aged ≥70, and the younger cohort 263 (81%) patients aged <70. ResultsOlder breast cancer patients had more co-morbidities (N = 36, 57% vs. N = 92, 35%, p = 0.002) and a higher clinical risk status (N = 49, 78% vs. N = 155, 59%; p = 0.01) when compared to younger patients. Histopathologic characteristics were significantly different between the two cohorts. Although older patients had a higher clinical risk status (78% vs. 59%) (p = 0.01), most of them (74%) received no CHT. Specifically, adjuvant CHT was administered less frequently in older than in younger patients (13% vs. 22%; p = 0.01). Moreover, older patients were less likely to complete CHT (>4 cycles: 78% vs. 97%). ConclusionBreast cancer patients aged ≥70 have higher clinical risk status, more co-morbidities, higher clinical stage (driven by larger tumor size), and more often RS ≥26. However, they receive fewer adjuvant RT and CHT than those aged <70. RS maintains its independent prognostic value in older patients. However, assessing the predictive value of additional CHT benefit remains challenging due to significant differences in CHT administration. Although therapy decision-making in older patients with breast cancer still follows RS-based guidelines, clinical practice indicates an individualized treatment approach.

Prognostic factors in Luminal B-like HER2-negative breast cancer tumors

BackgroundMolecular and genomic platforms can classify breast cancer intrinsic subtypeswith precision, however these are not widespread and immunohistochemical (IHC) classification is still used globally. This study aimed to evaluate the main clinical and pathologic prognostic factors for Luminal B-like HER2-negative breast cancer in our clinical setting. MethodsA retrospective review of early Luminal B-like HER2-negative breast cancer patients diagnosed in 2017 in our center was conducted. The main prognostic factors for relapse were evaluated, including patient's characteristics such as age, menopausal status, comorbidity index, personal and family history of breast cancer and obesity; tumor features such as size, histology and grade, oestrogen and progesterone receptor (PgR) status, HER2 status, Ki67 index and nodal involvement; and the given treatment. Cancer relapse during five years of follow-upwas considered the main outcome. ResultsFifty-six patients with early Luminal B-like HER2-negative breast cancer were included. Seven patients relapsed within five years of follow-up. Lymph node involvement at diagnosis and postoperatively were significantly associated with relapse (24,5% vs 71,43%p = 0.022; 38,8% vs 83,3%p = 0.004, respectively),although the number of pathologic positive lymph nodes was not associated with relapse occurrence (mean 1.5 in no-relapse group vs 0.8 in relapse group; p = 0.308).Other possible risk factors such as young age, premenopausal status, self-history of breast cancer, tumor size, histologic grade, PgR, or Ki 67 were not significantly associated with relapse. Additionally, the distribution of the number of positive nodes among relapse and no relapse groups(2,1 vs 1,8; p = 0.082) was not significant. ConclusionsLymph node involvement was the only prognostic factor in Luminal B-like HER2-negative breast cancer identified in this study, independently of the number of affected nodes.

Status and prognostic value of immunological biomarkers of breast cancer.

The immune response to cancer serves an important role in disease progression and patient prognosis. For triple-negative breast cancer showing aggressive behavior, immunotherapy has a good efficacy because of the potent immunogenicity of this type of cancer. However, the dominant subtype, luminal human epidermal growth factor receptor-2 (HER2)-negative breast cancer, is less immunogenic. To determine whether luminal HER2-negative cancer reacts to the anticancer immune response, the present study analyzed the status and prognostic value of the principal immunological biomarkers of breast cancer, including tumor-infiltrating lymphocytes (TILs), CD8+ T lymphocytes, the major histocompatibility complex and programmed cell death ligand-1 (PD-L1). The biomarkers were compared between patients with luminal HER2-negative breast cancer and those with immunogenic subtypes including triple-negative and HER2-overexpressed breast cancer. A total of 71 patients with primary breast cancer were classified into the immunogenic non-luminal (n=23) and less immunogenic luminal HER2-negative groups (n=48) based on immunogenicity. In the luminal HER2-negative group, compared with patients with low TIL levels, those with high TIL levels were at an advanced stage of cancer (P=0.024) and showed worse relapse-free survival (P=0.057); however, the remaining biomarkers exhibited no association with cancer progression or prognosis. In the non-luminal group, patients with high TIL levels showed significantly better RFS than those with low TIL levels (P=0.014). Compared with non-luminal patients negative for PD-L1, those positive for PD-L1 exhibited better overall survival (P=0.064). Notably, TIL status was found to exhibit contrasting prognostic predictions based on immunogenicity. In conclusion, TILs are a strong candidate for prognostic prediction in breast cancer, regardless of the subtype. PD-L1 is a potential candidate for prognostic prediction in immunogenic breast cancers, but not in the luminal HER2-negative subtype.

The efficacy of alpelisib in luminal HER2-negative breast cancer with brain metastases: clinical cases

Активирующие мутации в гене PIK3CA при гормонозависимом HER2-негативном (HR+ HER2–) метастатическом раке молочной железы (РМЖ) ассоциированы с повышенной частотой метастазирования в головной мозг (ГМ). Данные об эффективности таргетных препаратов при метастатическом поражении головного мозга, особенно при активных симптомных метастазах, ограничены, поскольку в клинические исследования включают, как правило, пациентов со стабильными метастазами после проведённой ранее лучевой терапии на метастазы в ГМ.&#x0D; В данной статье представлены два клинических наблюдения применения комбинации алпелисиба с фулвестрантом у пациенток с HR+ HER2– мРМЖ с мутациями в гене PIK3CA с метастазами в ГМ.&#x0D; В первом клиническом наблюдении пациентка с множественными метастазами в головном мозге, легких, печени и костях скелета получала алпелисиб в комбинации с фулвестрантом в 5 линии лечения в течение 9 месяцев. Отмечено исчезновение метастаза в лобной доле, стабилизация других очагов в ГМ без проведения лучевой терапии и со стабилизацией болезни по экстракраниальным проявлениям заболевания.&#x0D; Во втором случае пациентка с множественными метастазами в ГМ, легких и костях скелета получала алпелисиб в комбинации с фулвестрантом в 9 линии терапии в течение 18+ месяцев со стабилизацией метастазов в ГМ и частичной регрессией по экстракраниальным проявлениям заболевания. До проведения лекарственной терапии пациентке была проведена дистанционная лучевая терапия на весь ГМ, однако длительное в течение 10 месяцев уменьшение метастазов в ГМ после проведения ДЛТ, может свидетельствовать о противоопухолевой активности алпелисиба в комбинации с фулвестрантом на метастазы в ГМ.&#x0D; Переносимость терапии в обоих случаях была удовлетворительной, у одной пациентки выполнено снижение дозы алпелисиба на один дозовый уровень в связи с тошнотой 2 степени, у второй - коррекции дозы не потребовалось.&#x0D; Представленные случаи демонстрируют эффективность алпелисиба при метастазах в головном мозге.

Abstract P5-14-13: Benefits of Oncotype DX genomic screening in a geriatric vs. non-geriatric cohort. Analyzing key factors in therapy decision making process

Abstract Introduction In early luminal HER2 negative breast cancer Oncotype DX® Recurrence-Score (RS) has been broadly validated in pre- and postmenopausal patients and can predict prognosis and benefit of chemotherapy. Its value in elderly breast cancer populations has not been deeply addressed. This study analyses clinical and pathologic factors, RS distribution and outcomes in an elderly vs. non-elderly breast cancer population with the purpose of establishing RS added value to the therapy decision-making process in a geriatric cohort. Methods This is a retrospective analysis of available data from patients with early luminal HER2 negative breast cancer treated at the University Hospital Basel and the Cantonal Hospital Baselland between 2010 and 2022. Cohort A (A) consists of patients &amp;lt; 70 years old and cohort B (B) of patients aged ≥70 years. At moment of decision for adjuvant treatment all patients had known RS result. Results A and B included 266 (81%) and 60 (19%) patients, respectively. The median age in A was 55.2 and in B, 74 years. The following clinical and pathologic factors were different in B vs. A: co-morbidities (55 % vs. 35%, p=0.005), BMI (BMI≥25 (overweight vs. normal, p=0.023), tumor size (31.3 mm vs 23.6 mm p=0.021). Geriatric patients also tended to have a clinically higher risk status (83% vs. 70%; p=0.05). There was a trend for a higher mastectomy rate in B vs. A (41.7% vs. 29%, p=0.065), significantly less radiotherapy use (65% vs. 81%, p=0.009) and more osteo-oncologic treatment (61% vs 43%, p=0.013). RS distribution was not significantly different between cohorts (A vs. B was: RS 1-15: 44.3% vs 41.7%, RS 16-25 41.2% vs 35% and RS≥26 14.5% vs 23.3%; p=0.234). Adjuvant chemotherapy was performed in 11.5% of B and 22.9% of A (p=0.116) and adjuvant endocrine therapy in 98.3% of B vs. 93.5% of A (p=p=0.214). Tumor board suggested systemic treatment was not implemented in 22% vs 15 %, (B vs. A; p =0.087). With a median follow-up of 36.6 months, recurrence rate was higher, but not statistically significant in B vs. A (10% vs 6%, p=0.259). Relapse rate was higher with RS≥26 vs. RS 0-25 (13.5% in B vs. 5.7% in A; p=0.043). Conclusions Older breast cancer patients tend to have higher clinical risk status, more co-morbidities and higher BMI. RS distribution was not significantly different between the two cohorts, however higher RS did pose a higher relapse rate for older patients in our cohort. Although RS based guidelines, still apply in therapy decision making in the case of geriatric breast cancer patients, clinical practice points to a rather individualized treatment in which all clinical and pathological factors are weighted. Citation Format: Elena D Chiru, Cvetka Grasic Kuhar, Anton Oseledchyk, Christian Kurzeder, Marcus Vetter. Benefits of Oncotype DX genomic screening in a geriatric vs. non-geriatric cohort. Analyzing key factors in therapy decision making process [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-13.

Real clinical practice patterns of palbociclib usage in Russian Federation

Introduction. Current treatment of metastatic luminal Her2-negative breast cancer includes combination of endocrine therapy (ET) with CDK4/6 inhibitors. This type of therapy demonstrated impressive efficacy over mono ET in early lines of treatment in phase III randomized clinical trials. Treatment patterns in real clinical practice (RCP) are of great interest. We represent the first available local data for all CDK 4/6 inhibitors in RCP in Russian Federation in accordance with the number of patients (pts).Aim. Analysis of the patterns of palbociclib administration in RCP.Materials and methods. One hundred and 5 pts from 12 regions of Russian Federation were included in this analysis and received palbociclib in combination with ET from 2017 to 2020. Median age was 57 years (29-75), 31/105 (29.5%) of pts were &lt; 50. De novo metastatic disease was observed in 16 (15.2%) pts, 89 pts progressed after radical treatment. Visceral metastases (mts) at palbociclib initiation had 61/105 (58.1%) of pts.Results. Only 22/105 (21%) of pts received palbociclib as 1st line treatment of metastatic disease. The majority of pts was treated with palbociclib in 2nd and 3rd lines (28.5% and 30.5% respectively). In 26/105 (24.8%) pts palbociclib was combined with aromatase inhibitors, in other cases - with fulvestrant. Median follow-up time was 6.5 (1.1-31.9) months, median progression free survival - 6.0 (1.0-28.0) months. Most common adverse events (AE) were leukopenia, neutropenia and thrombocytopenia. Only in 3 cases palbociclib was completely stopped due to toxicity.Conclusions. Our data indicates that there is a need to move palbociclib initiation in first two lines of treatment to get maximal improvement in survival and to increase its usage in young women.

Liver metastasis in estrogen receptor-positive HER 2-negative breast cancer. Ribociclib as prognosis-changing therapy

The life expectancy of patients with metastatic luminal HER 2-negative breast cancer has stagnated at the level of 40 months for many years. The introduction of CDK4/6 inhibitors into practice has changed the standards of therapy, providing not only a significant increase in the time without progression while maintaining a high quality of life, but also significantly increasing overall survival. The presence of liver metastases determines an extremely unfavorable prognosis, with GH+HER 2-mBC reducing life expectancy to a median of 21 months. Endocrine therapy combined with ribociclib significantly increased overall survival rates on average per year, reaching medians of 36.1 and 46.5 months, depending on the line of treatment. This publication is devoted to liver metastases in breast cancer, in particular in the luminal HER 2-negative subtype. Epidemiological aspects are considered, the possibilities of modern systemic therapy are evaluated. A clinical case of successful therapy with ribociclib in a young patient with liver damage is presented.

Comparison of endocrine therapy and chemotherapy as different systemic treatment modes for metastatic luminal HER2-negative breast cancer patients -A retrospective study.

PurposeThe purpose of this study was to evaluate endocrine therapy and chemotherapy for first-line, maintenance, and second-line treatment of hormone receptor-positive HER-2-negative metastatic breast cancer (HR+HER-2-MBC) and the relationship between different treatment options and survival.Patients and methodsThe patients included in this study were all diagnosed with metastatic breast cancer (MBC) at Shandong Cancer Hospital from January 2013 to June 2017. Of the 951 patients with MBC, 307 patients with HR+HER-2-MBC were included in the analysis. The progression-free survival (PFS) and overall survival (OS) of the various treatment modes were evaluated using Kaplan–Meier analysis and the log-rank test. Because of the imbalance in data, we used the synthetic minority oversampling technique (SMOTE) algorithm to oversample the data to increase the balanced amount of data.ResultsThis retrospective study included 307 patients with HR+HER-2-MBC; 246 patients (80.13%) and 61 patients (19.87%) were treated with first-line chemotherapy and first-line endocrine therapy, respectively. First-line endocrine therapy was better than first-line chemotherapy in terms of PFS and OS. After adjusting for known prognostic factors, patients receiving first-line chemotherapy had poorer PFS and OS outcomes than patients receiving first-line endocrine therapy. In terms of maintenance treatment, the endocrine therapy-endocrine therapy maintenance mode achieved the best prognosis, followed by the chemotherapy-endocrine therapy maintenance mode and chemotherapy-chemotherapy maintenance mode, and the no-maintenance mode has resulted in the worst prognosis. In terms of first-line/second-line treatment, the endocrine therapy/endocrine therapy mode achieved the best prognosis, while the chemotherapy/chemotherapy mode resulted in the worst prognosis. The chemotherapy/endocrine therapy mode achieved a better prognosis than the endocrine therapy/chemotherapy mode. There were no significant differences in the KI-67 index (<15%/15-30%/≥30%) among the patients receiving first-line treatment modes, maintenance treatment modes, and first-line/second-line treatment modes. There was no statistical evidence in this study to support that the KI-67 index affected survival. However, in the first-line/second-line model, after SMOTE, we could see that KI-67 ≥ 30% had a poor prognosis.ConclusionsDifferent treatment modes for HR+HER-2-MBC were analyzed. Endocrine therapy achieved better PFS and OS outcomes than chemotherapy. Endocrine therapy should be the first choice for first-line, maintenance, and second-line treatment of HR+HER-2-MBC.

Alpelisib therapy: from theory to practice

Before the development and implementation of the first PI3K inhibitor (alpelisib), the presence of a mutation in the PIK3CA gene had only prognostic value: it determined the unfavorable course of luminal HER2-negative metastatic breast cancer (testing for mutations was not part of routine screening methods). Achievements in the treatment of HR+HER2- mBC are primarily associated with the use of CDK4/6 inhibitors, which allowed not only a significant increase in the median progression-free survival while maintaining high quality of life, but also significantly increased overall survival of patients with luminal HER2-negative metastatic breast cancer. However, subgroup analyses demonstrate that the presence of the PIK3CA mutation is an independent factor in decreasing progression-free time and overall survival, even in patients treated with CDK4/6 inhibitors. Mutations of the PIK3CA gene are diagnosed in 30-40% of luminal metastatic breast cancer patients, they are associated with an increased risk of relapse and disease progression, are associated with a significant reduction in survival rates and treatment effectiveness, and determine the development of primary and secondary resistance to endocrine therapy. Standard endocrine therapy with fulvestrant combined with alpelisib has significantly improved treatment outcomes in patients with HR+HER2-metastatic breast cancer with the PIK3CA mutation who previously received treatment for advanced disease or had progression during adjuvant therapy. This combination is now included in all major international guidelines and is a priority therapy option. Testing for PIK3CA mutations is the current diagnostic standard in luminal HER2-negative mBC. The review presents an update of the main clinical trials with alpelisib, treatment results from real clinical practice, and also considers aspects of use in pretreated patients with different medical history. The article outlines the main recommendations for the prevention and correction of adverse events, and presents our own experience of using alpelisib in a patient with a classic course of breast cancer with a PIK3CA mutation.

82P Clinical application of a genomic tool for decision support in breast cancer patients in Scotland

There is growing evidence for incorporating genomic assays into the individualised management of early stage luminal HER2-negative breast cancer. TAILORx showed the effectiveness of the Recurrence Score (RS) in this group. RxPONDER evaluated its use in the node-positive setting. Genomic assays should enable accurate assessment of a tumour’s risk of distant recurrence and benefit from chemotherapy. The Oncotype DX Breast RS test has been adopted in Scotland, and has been the subject of a large population based study by the Scottish Consensus Group to assess the uptake of the RS value, and to analyse the effect it has had on clinical practice.

Validation of the Prognostic Stage from the American Joint Committee on Cancer 8th Staging Manual in Luminal B-Like Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

PurposeThe 8th edition American Joint Committee on Cancer (AJCC) prognostic staging system (PS) has been validated numerous times; however, the prognostic value of PS for breast cancer based on molecular subtype has rarely been explored. This study aimed to investigate the prognostic value of PS in Chinese patients with luminal B-like human epidermal growth factor receptor 2 (HER2)-negative breast cancer.MethodsA total of 407 eligible cases were included in the study. All of the cases were restaged using the 8th edition AJCC Anatomic Staging System (AS) and PS. The Kaplan–Meier method was used to calculate estimated survival and the Log rank test was used to compare the survival differences between groups.ResultsThe 5-year disease-specific survival (DSS) and overall survival (OS) rates were 90.3% and 93.5%, respectively, and there were statistically significant differences in the 5-year DSS and 5-year OS rates among the different anatomic and prognostic stage groups. The application of the PS resulted in the assignment of 215 (52.8%) patients to a different group. Different prognostic stage groups restaged from anatomic Stage III had significant differences in both DSS (χ2 = 4.366, p = 0.037) and OS (χ2 = 7.549, p = 0.006); additionally, different prognostic stage groups from the anatomic Stage II group had significant differences in DSS (χ2 = 7.724, p = 0.021) but no significant differences in OS (χ2 = 5.182, p = 0.075). However, different prognostic stage groups from anatomic Stage I had no significant differences in either DSS (χ2= 0.159, p = 0.690) or OS (χ2 = 0.099, p = 0.753).ConclusionThe 8th edition AJCC PS refined the anatomic stage grouping in luminal B-like HER2-negative breast cancer and could lead to a more personalized approach to breast cancer treatment.

Clinical and morphological aspects of neoadjuvant chemotherapy efficacy in patients with aggressive luminal HER2-negative breast cancer

Background. The role of neoadjuvant chemotherapy (NACT) in luminal HER2-negative breast cancer (BC) remains highly controversial due to the lack of reliable predictors of drug therapy efficacy.Objective: to evaluate the effectiveness of NACT in patients with aggressive luminal HER2-negative BC and to compare modern systems for assessing the pathomorphological response.Materials and methods. The tumor response to NACT regimens was assessed in 64 patients with aggressive luminal HER2-negative BC stage II–III. The median age of women was 46.5 years (range 31–76 years), 76.6 % had primary operable stages (cT1–3N0–1), locally advanced BC (cT4, cN2–3) – 23.4 % patients. The characteristics of BC were as follows: invasive ductal carcinoma (76.6 %), grade G2 and G3–54.7 % and 45.3 %, Ki-67 ranged from 20 % to 98 %, median 45 %. The ER expression level was low (1–10 %, ERlow) in 12.5 % and was more than 10 % in 87.5 % of cases. HER2 status corresponded to 0, 1+ and 2+ in the absence of gene amplification – in 50.0 %, 35.9 % and 14.1 % of patients, respectively. The rate of TILs &lt;10 %, 10–20 % and &gt;20 % was in 71.4 %, 10.7 % and 17.9 % of cases. After NACT with the inclusion of anthracyclines and taxanes ± platinum combinations (in BRCA mutated status), the patients underwent radical surgery (mastectomy or breast-conserving surgery) with an assessment of the pathological response.Results. 15.6 % of patients had a complete pathomorphological response (pCR) to treatment, which corresponded to the RCB-0 class and the pathomorphological stage ypT0N0. Residual tumor load with incomplete response was very significant – class RCB-I was noted in only 7.8 %, and RCB-II and RCB-III – in 39.1 % and 37.5 %, respectively. An increase in the size of the residual tumor and the number of affected lymph nodes were associated with an increase in the RCB class. Predictors of pCR achievement in luminal HER2-negative cancer were: grade G3, rare histological forms of BC (medullary, metaplastic), rate of TILs ≥30 %, low ER expression, and HER2 0 status.Conclusion. Assessment of Ki-67, tumor grade, ER and HER2 rate, and TILs before starting NACT will help identify a group of high sensitivity to chemotherapy and optimize the treatment strategy in aggressive luminal HER2-negative BC.

Target therapy of luminal HER2-negative advanced breast cancer with PIK3CA mutation: combination of alpelisib plus fulvestrant in real clinical practice

Introduction. Сombination of alpelisib plus fulvestrant is approved in patients with hormone receptor positive, HER2-negative, PIK3CA-mutated advanced breast cancer (ABC) after progression on hormonotherapy. Efficacy data of alpelisib in heavily pretreated patients with HR+/HER-2-, PIK3CA-mutated advanced breast cancer are limited, only results from phase I trial are available. Here we report our results of alpelisib efficacy in 19 heavily pretreated patients.Object: to evaluate efficacy and safety of combination alpelisib plus fulvestrant in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer in initial and later lines of therapy in real clinical practice.Materials and methods. Combination of alpelisib plus fulvestrant was investigated in 19 patients with HR+/HER2-, PIK3CAmutated ABC, alpelisib at a dose of 300 mg per day plus fulvestrant at a dose of 500 mg i.m. every 28 days and once on day 15. Treatment continued until disease progression or unacceptable toxicity.Results. From February 2021 19 patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer were treated with alpelisib plus fulvestrant. The data cut off is October 2021. Median lines of treatment in advanced disease was five, including 19 (100%) patients received CDK4/6, 14 (74%) – fulvestrant and/or everolimus and 15 (79%) – chemotherapy. 4 (21%) received alpelisib in a second line, 15 (79%) – in subsequent lines. Median progression-free survival was 7 months. The response was evaluated in 18 patients: partial response was achieved in 5 (28%) patients, stable disease – in 9 (50%), disease progression – 4 (22%). The most frequent adverse events were hyperglycemia – 74% (grade 3 – 22%), creatinine increased – 42% and rash – 37% (grade 3 – 22%). Only one patient has discontinued the treatment due to Quincke`s edema.Conclusions. Combination of alpelisib with fulvestrant is an effective option both in initial and later lines of therapy in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer including fulvestrant, CDK4/6 inhibitors and/or everolimus – pretreated patients.

178P Age-related mutational landscape of luminal breast cancers

Breast cancer has afflicted more than 576000 women in 2020, one quarter of whom were younger than 50 years. A worse outcome has been associated with breast cancer at a younger age. In the luminal HER2 negative breast cancer subtype, an interaction between age and chemotherapy has been observed in younger women, consistently across the prospective trials MINDACT, TAILORx, and RxPONDER. The hypothesis that this benefit is due to an indirect effect of chemotherapy on ovarian suppression is debated.