Visceral Crisis Research Articles

Can CDK 4/6 inhibitors be used in patients with visceral crises? Deviating from conventional teaching

Visceral crisis is a situation in which the vital organ function is impaired due to infiltration by cancer cells. It Is of particular importance in the subset of HR+/Her2- metastatic breast cancer.. Current guidelines that recommend cytotoxic chemotherapy for visceral crisis are based on historical data that indicate that chemotherapy has higher response rates than endocrine therapy. These trials included patients with advanced breast cancer who were not selected for the hormonal receptor or Her 2 receptor status. In addition, the comparator had a weak endocrine agent. Objective response rates with endocrine therapy in combination with any of the CDK 4/6 inhibitors in patients with measurable disease range from 50-59%. These response rates are higher than the chemotherapy rates found in the historical trials. Moreover, patients with visceral crisis have a compromised performance status and impaired organ functions. Therefore, it is unlikely that these patients would tolerate complete doses of the most active chemotherapeutic agents, including anthracycline and taxane. The retrospective analysis of the real-world data base clearly demonstrates that the combination of endocrine agents with a CDK 4/6 inhibitor is superior to chemotherapy with improvement in overall survival. In conclusion, it is time to redefine the guidelines and consider endocrine therapy with a CDK 4/6 combination as the preferred option in the initial management of the visceral crisis.

Impact of the COVID-19 Pandemic on Breast Cancer Management in Portugal: A Cross-Sectional Survey-Based Study of Medical Oncologists.

IntroductionCancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer.MethodsAn anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents’ regions, case volumes, and practice type were explored.ResultsOf 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents’ region and case volume were noted.ConclusionMedical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-022-00191-7.

Low social and family well-being is associated with greater RAGE ligand s100A8/A9 and interleukin-1 beta levels in metastatic breast cancer patients

Greater inflammatory signaling has been shown to promote breast cancer disease progression and poorer clinical outcomes. Lower social support and social well-being have been related to greater inflammatory signaling and poorer clinical outcomes in women with non-metastatic breast cancer, and this appears to be independent of depression. However, little is known about these associations in women with metastatic disease. s100A8/A9 and interleukin 1 beta (IL-1β) proteins are widely studied in breast cancer and are considered as biomarkers of cancer progression or as having a causal role in carcinogenesis and cancer progression and metastasis via inflammatory signaling. The aim of this study was to examine the associations between less social/family well-being (SWB) and S100A8/A9 and IL-1β levels in women diagnosed with metastatic breast cancer. Sixty women (Mean age 58.95 ​± ​1.49) with a diagnosis of metastatic breast cancer participated in the study. The Functional Assessment of Cancer Therapy (FACT) social and family well-being (SWB) subscale and the Hospital Anxiety Depression Scale (HADS) were administered to patients undergoing a first- or second-line endocrine or oral chemotherapy treatment and who were not experiencing brain metastasis or visceral crisis. Salivary s100A8/A9 and IL-1β levels were assessed at 5PM on two consecutive days and averaged. Multiple regression tested the independent contribution of SWB on s100 A8/A9 and IL-1b while controlling for depression. Lower levels of SWB were associated with greater S100A8/A9 (ß ​= ​−0.345, p ​= ​0.007) and IL-1β (ß ​= ​−0.286, p ​= ​0.027) levels and these associations remained significant after controlling for depression. This work provides new evidence for the role of decreased SWB and greater s100A8/A9 and IL-1b levels in patients diagnosed with metastatic breast cancer. Psychosocial interventions that promote social support and positive social interactions through interpersonal skills may help metastatic breast cancer patients to improve their SWB. This may have salutary effects on cancer-promoting processes, which could provide psychological and physical health benefits.

Abstract OT2-27-02: A prospective phase II study on efficacy and safety of anlotinib combined with fulvestrant in patients with HR-positive and HER2-negative, secondary endocrine-resistant, locally advanced or metastatic breast cancer

Abstract Background: The management of HR-positive, HER2-negative metastatic breast cancer includes endocrine monotherapy or combination regimens, both with benefit diminishing as resistance develops. Nowadays, various studies have demonstrated that estrogen interacts with many angiogenic pathways and is an important mechanism for resistance leading to the question of whether combination with antiangiogenesis and antiestrogen therapies could be an appropriate therapeutic modality. Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, PDGFR, c-KIT, c-MET and RET. Previous studies have proven the efficacy of both anlotinib monotherapy and combination regimens in advanced breast cancer. This phase II study aims to preliminarily evaluate the efficacy and safety of anlotinib combined with endocrine therapy. Methods: This study is a prospective, single-arm, open-label, phase II clinical trial. Eligible patients were women aged 18 years or older of any menopausal status (the premenopausals had to receive luteinising-hormone-releasing-hormone agonist at least 4 weeks before randomisation) and with ECOG status 0-1, who had HR-positive (estrogen receptor- and/or progesterone receptor-positive) and HER2-negative, secondary endocrine-resistant (defined as disease relapse within 12 months after at least 24 months endocrine adjuvant therapy, or disease progress after at least 6 months endocrine salvage therapy), locally advanced or metastatic breast cancer. Mainly exclusive criteria included the previous use of angiogenic inhibitors or fulvestrant, prior more than one line of chemotherapy, visceral crisis, and uncontrolled CNS metastases. Eligible patients were treated with oral anlotinib (12 mg once daily on days 1-14, repeated every 21 days) plus intramuscular fulvestrant (500 mg on days 1 and 15 of cycle one, and then on day one of each subsequent 28 days cycle) till disease progression or intolerant toxicity. The primary endpoints is progression-free survival (PFS) and the secondary endpoints include overall response rate (ORR), Clinical Benefit Rate (CBR), overall survival (OS), and safety. In the part of statistical analysis, 40 patients are required to have a 80% power to detect significant improvement in median progression-free survival from 5.8 (fulvestrant alone) to 10 (fulvestrant combined with anlotinib) months, if tested at a two-sided significance level of α=0.05. This study is currently enrolling patients and planned completion in July, 2023. Registration information: ChiCTR2100047080. Results: The trial is in progress. Conclusion: The trial is in progress. Citation Format: Xiaojia Wang, Jian Huang. A prospective phase II study on efficacy and safety of anlotinib combined with fulvestrant in patients with HR-positive and HER2-negative, secondary endocrine-resistant, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-27-02.

Abstract OT2-19-06: Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL

Abstract Background: Endocrine therapy (ET) is the preferred therapy option for patients (pts) with hormone receptor-positive (HR[+]) advanced breast cancer (ABC), except for pts with visceral crisis who often receive chemotherapy to achieve rapid symptom control. Cyclin-dependent kinases 4/6 inhibitors have improved the effectiveness of ET across all subgroups of pts with ABC by targeting potential mechanisms of resistance. An exploratory analysis revealed that the addition of abemaciclib to ET conferred the largest benefit in pts with poor prognostic characteristics (liver metastases, high grade tumors, or progesterone receptor-negative status) [Di Leo, NPJ Breast Cancer 2018; 4: 41]. ABIGAIL aims to provide consistent evidence that abemaciclib plus ET is superior or non-inferior to paclitaxel in terms of early overall response as first-line regimen in HR[+], HER2-negative ABC pts with poor prognosis. Trial Design: This is a multicenter, randomized, open-label, phase 2 trial. Eligible participants are men and women of any menopausal status aged ≥18 years with HR[+], HER2-negative ABC who had no prior systemic therapy in the advanced setting and at least one of the following aggressive disease criteria: (i) Visceral disease; (ii) High histological grade and/or progesterone receptor-negative status; (iii) Lactate dehydrogenase >1.5 × the upper limit of normal; (iv) Relapse while on or within 36 months of completing adjuvant ET. Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease as per RECIST 1.1, and adequate organ function are also required. A total of 160 pts will be randomly assigned (1:1) to receive abemaciclib (300 mg/day orally during each 28-day cycle) plus ET as per investigator’s criteria (either letrozole [2.5 mg/day orally] or fulvestrant [500 mg intramuscularly on days 1, 15 of cycle 1, and on day 1 thereafter], or paclitaxel (90 mg/m² intravenously on days 1, 8, 15). Men and pre-/peri-menopausal women will receive a gonadotropin-releasing hormone agonist if randomized to abemaciclib plus ET. At investigator’s discretion, pts in the paclitaxel arm could receive abemaciclib plus ET at any point after the first 12 weeks or extend chemotherapy for a total of 6 cycles. Randomization will be stratified according to the presence of visceral disease and endocrine therapy. The primary endpoint is 12-week overall response rate (ORR) as per RECIST 1.1. Key secondary endpoints include ORR, clinical benefit rate, 12-week progression-free survival, progression-free survival, time to response, duration of response, overall survival, time to first subsequent therapy, time to second subsequent therapy, and time to first chemotherapy for pts in abemaciclib plus ET arm, patient-reported outcomes, and safety as per NCI-CTCAE 5.0. The sample size assumes the comparison of two proportions in an asymptotical normal test. We expect that 12-week ORR will be higher in the abemaciclib plus ET arm than paclitaxel arm (30% vs. 15%), with the assumption of a 5% non-inferiority margin. Based on a 10% dropout rate, a sample size of 160 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. We will test the superiority of abemaciclib plus ET as compared with paclitaxel if the non-inferiority is achieved. Both analyses, will be conducted with the Newcombe hybrid score method for confidence intervals. This trial was opened to accrual in May 2021. Citation Format: Antonio Llombart-Cussac, Joseph Gligorov, Serena Di Cosimo, Cinta Albacar, Patricia Cortez, Eduardo Martinez-De Dueñas, Ana López, Vicente Carañana, Jacques Medioni, Luigi Cavanna, Marina Elena Cazzaniga, Sofia Braga, Passos Coelho, Miguel Sampayo-Cordero, Andrea Malfettone, José Manuel Pérez-García, Javier Cortes. Phase 2 study of abemaciclib in combination with endocrine therapy with or without paclitaxel induction in patients with hormone receptor-positive, HER2-negative advanced breast cancer and aggressive disease criteria: ABIGAIL [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-06.

Abstract P4-12-13: Psychosocial aspects in relation to clinical status of breast cancer patients after prolonged COVID pandemic in south India: A observational survey study

Abstract BACKGROUND:The prolonged global threat imposed by covid 19 pandemic’s first and second wave has created immense stress among the breast cancer due to interruptions of standard oncological care. The frequent lockdown imposed had tremendous impact on the patients’ financial status and posed hinderance in transportation to oncological centre. In our hospital, majority of the treatment population are from distant places and below poverty line. We conducted a questionnaire based study to assess the psychological impact in this situation affecting their quality of life(QOL) and their perspective in this current situation. MATERIALS AND METHODS:Breast cancer patients who had been diagnosed and registered in our department from 1st January to 1stApril 2020 before the covid out break were tracked from the medical records. The patients details, disease status dates of follow up and the treatment details were collected.Defaulted patients were contacted.Post one year, in April 2021, these patients were assessed clinically and questioned regarding the treatment perspective. Psychological status and health related quality of life were analysed with GAD-7 (Generalised anxiety disorder questionnaire), PHQ-9 (patient health questionnaire) and EORTC QLQ-C30 questionnaire.RESULTS:A total of 202 breast cancer patients were included. 83 patients(41%) were diagnosed with early breast cancer of which 67(33%) patients were started on adjuvant chemotherapy after surgery,16 (8%)were registered for hormonal therapy. 54(27%) patients with locally advanced, were on neoadjuvant chemotherapy. 65(32%)had metastatic disease at presentation. 23 of 65 metastatic patients were in visceral crisis and were on supportive management for the same. 35 patients had been started on palliative chemotherapy. Out of the 156 patients who had been in initiated with various chemotherapy, only 62(31%) patients were able to review at correct interval for the scheduled chemotherapy. 45 patients(22%) reviewed in the day care irregularly. Among the 45, 28 patients had locally advanced breast cancer and 22 patients had clinical progression due to prolonged gap. 38 patients(19%) had defaulted completely.Of the 38,16 had advanced disease and presented with clinical progression of disease and switched to second line chemotherapy. 15 patients progressed to have distant metastases and are started on palliative chemotherapy or supportive care. 7 patients who were on adjuvant chemotherapy are kept under close follow up. 11 patients with metastatic breast cancer had died during the past one year. 3 patients had committed suicide.112(55 %) patients were within the city. 71 patients(35%) were from suburban areas. 19 patients(10%) were from adjacent rural areas. 113(56%) were educated.176 (87 %) were desperate to continue treatment inspite of pandemic, while remaining patients main concern was to avoid infection than to get oncological management. While the most common reason for defaulting was travel restrictions, few also documented financial issues and ignorance about progression of cancer. 46 (22%)of patients who had been visiting the day care had turned covid positive. Except for 2 patients who succumbed to the infection, none had major complications. 51%, 42%, 7% had mild, moderate and severe anxiety. 69%, 25%, 6% had mild, moderate and severe depression. The severe anxiety and depression was significant with metastatic breast cancer and educated patients. There were 3 suicides. The overall heath score had a mean of 4. The overall QOL had a mean score of 3 (1- very poor to 7- excellent).CONCLUSION: In patients who were already psychologically affected by onset of cancer, the chaos created by the pandemic added to it further. Hence the patients also need counseling appropriately during oncological treatment Citation Format: Chandralekha Krishnan. Psychosocial aspects in relation to clinical status of breast cancer patients after prolonged COVID pandemic in south India: A observational survey study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-13.

CDK4/6 Inhibitors after Chemotherapy for Patient with HR+ve, HER2-ve Metastatic Breast Cancer Presented with Visceral Crisis: A Case Report

CDK4/6 Inhibitors after Chemotherapy for Patient with HR+ve, HER2-ve Metastatic Breast Cancer Presented with Visceral Crisis: A Case Report

Comparison of the Efficacy between First-Line Treatment Regimens for Patients with Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer

Purpose: Endocrine therapy is the first-line treatment recommended for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer without visceral crisis. However, this recommendation has not been followed clinically because of efficacy issues. In this study, the survival of patients with HR-positive/HER2-negative metastatic breast cancer was evaluated based on the following first-line treatment regimens: the combination of palbociclib plus letrozole, conventional endocrine therapy, or chemotherapy.Methods: Medical records were reviewed for this retrospective analysis. Patients with HR-positive/HER2-negative metastatic breast cancer were included. Progression-free survival (PFS) and overall survival (OS) were compared based on first-line treatment regimens.Results: A total of 184 patients were included in the analysis. The first-line treatments were palbociclib plus letrozole in 46 patients (25.0%), endocrine therapy in 40 patients (21.7%), and chemotherapy in 98 patients (53.3%). The PFS of the palbociclib plus letrozole group was significantly longer than that of the endocrine therapy (hazard ratio=3.43, p<0.001) and chemotherapy (hazard ratio=2.88, p=0.001) groups. No significant difference was observed between the endocrine therapy and chemotherapy groups (p=0.430). The OS of the palbociclib plus letrozole group was significantly longer than that of the endocrine therapy (hazard ratio=5.34, p=0.009) and chemotherapy (hazard ratio 4.23, p=0.043) groups. No significant difference was observed between the endocrine therapy and chemotherapy groups (p=0.451).Conclusion: The combination regimen of palbociclib and letrozole could be recommended as the first-line treatment of choice in patients with HR-positive/HER2-negative metastatic breast cancer.

Trends in incidence, molecular diagnostics, and treatment of patients with breast cancer in Kazakhstan, 2014-2019

Relevance: Globocan reported 4,390 new breast cancer cases and 1,654 deaths from breast cancer in the Republic of Kazakhstan (RK) in 2020. Molecular diagnostics of breast cancer includes the determination of Hormone Receptor (HR), HER2, and Ki-67 status to detect patients
 with HR-positive tumors and administer effective treatment.
 Methods: This observational study included a retrospective analysis of incidence, molecular diagnostics, and treatment regimens in women with a confirmed breast cancer diagnosis aged 18 years old and older, registered in the RK Electronic Registry of Cancer Patients (ERCP) from 1 January 2014 till 31 December 2019.
 Results: In the study period (2014 to 2019), the number of breast cancer cases registered annually has doubled. The incidence increased by 46.9%. The share of locally advanced and advanced forms of breast cancer has decreased. The proportion of Luminal type A (HR+/HER2-)
 among newly diagnosed patients ranged from 17.9% to 30%. Chemotherapy and endocrine therapy with goserelin, buserelin, leuprorelin, and fulvestrant are standard first- and second-line treatments for HR+ breast cancer. Since fulvestrant indications have been expanded, more
 than 50% of patients with HR-positive advanced breast cancer receive fulvestrant as the first-line therapy.
 Conclusion: Breast cancer incidence growth and a decrease in the share of locally advanced and advanced breast cancer cases in the RK could be attributed to increased coverage of eligible women aged 40 to 70 with breast cancer mammographic screening. Although international guidelines support the administration of hormone therapy with or without targeted therapy in women with HR-positive, HER2-metastatic breast cancer, upfront use of chemotherapy remains common in the RK even in the absence of visceral crisis. The use of CDK4/6 inhibitor palbociclib in combination with hormone therapy has become routinely available since 2019

Trends in incidence, molecular diagnostics, and treatment of patients with breast cancer in Kazakhstan, 2014-2019

Relevance: Globocan reported 4,390 new breast cancer cases and 1,654 deaths from breast cancer in the Republic of Kazakhstan (RK) in
 2020. Molecular diagnostics of breast cancer includes the determination of Hormone Receptor (HR), HER2, and Ki-67 status to detect patients
 with HR-positive tumors and administer effective treatment.
 Methods: This observational study included a retrospective analysis of incidence, molecular diagnostics, and treatment regimens in
 women with a confirmed breast cancer diagnosis aged 18 years old and older, registered in the RK Electronic Registry of Cancer Patients
 (ERCP) from 1 January 2014 till 31 December 2019.
 Results: In the study period (2014 to 2019), the number of breast cancer cases registered annually has doubled. The incidence increased
 by 46.9%. The share of locally advanced and advanced forms of breast cancer has decreased. The proportion of Luminal type A (HR+/HER2-)
 among newly diagnosed patients ranged from 17.9% to 30%. Chemotherapy and endocrine therapy with goserelin, buserelin, leuprorelin,
 and fulvestrant are standard first- and second-line treatments for HR+ breast cancer. Since fulvestrant indications have been expanded, more
 than 50% of patients with HR-positive advanced breast cancer receive fulvestrant as the first-line therapy.
 Conclusion: Breast cancer incidence growth and a decrease in the share of locally advanced and advanced breast cancer cases in the RK
 could be attributed to increased coverage of eligible women aged 40 to 70 with breast cancer mammographic screening. Although international guidelines support the administration of hormone therapy with or without targeted therapy in women with HR-positive, HER2-metastatic breast cancer, upfront use of chemotherapy remains common in the RK even in the absence of visceral crisis. The use of CDK4/6 inhibitor
 palbociclib in combination with hormone therapy has become routinely available since 2019.

Clinical case of the treatment of metastatic luminal breast cancer

Hormone therapy currently open up the prospect of long-term, comfortable and relatively low-toxic treatment for patients with hormone receptor – positive advanced breast cancer. For a long time, the presence of visceral metastases prompted oncologists to abandon hormone therapy in favor of cytostatic agents. Now days, even in the presence of visceral metastases, clinical guidelines allow use of modern hormonal therapy in the absence of a visceral crisis. In particular, the so-called CDK 4/6 inhibitors, presented on the Russian market by drugs: palbociclib, ribociclib and abemacyclib, became the drugs that significantly improved the results of hormone therapy. Each of them has demonstrated its effectiveness in clinical trials; moreover, there are lots of clinical cases demonstrating the benefits of this therapy in real clinical practice. The article presents a clinical case of treatment of advanced hormone receptor-positive breast cancer. The effectiveness of treatment with CDK 4/6 inhibitors has been demonstrated, a comparatively analysed with the data obtained in the course of clinical trials. The analysis of the tactics of treatment of cytomegalovirus infection of the cornea during therapy with ribociclib was carried out.

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

PurposePI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC).MethodsCohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).ResultsOverall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%).ConclusionAdding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects.Trial registration NCT03337724.

Outcomes of Critically Ill Lung Cancer Patients Initiating Targeted Therapy or Immunotherapy in the Intensive Care Unit: A Single-Center Report.

Introduction: Targeted therapy and immune checkpoint inhibitors (ICI) have drastically improved outcomes of metastatic non-small cell lung cancer (NSCLC) patients in outpatient settings. Because trials on critically ill patients are improbable, little is known about their efficacy among patients admitted to intensive care units (ICU). Methods: We retrospectively analyzed the clinical outcomes of critically-ill NSCLC patients receiving either ICI or targeted therapy during ICU admission at the MD Anderson Cancer Center from April 2016 to August 2020. We collected data on ICU admission diagnoses, sequential organ failure assessment (SOFA), previous cancer therapies, tumor gene mutations or translocations, and PD-L1 expression. Overall survival (OS) was calculated from the date of drug initiation using the Kaplan-Meier method. Results: Of 9898 ICU admissions, 9 patients with metastatic NSCLC who received either targeted therapy (5) or PD-1 ICI (4) during ICU admission were included. The most common reasons for ICU admissions were tumor visceral crisis (3/9) and sepsis (3/9). The median (range) admission SOFA was 4 (2-11). Six patients were naïve to systemic therapy. Five patients required mechanical ventilation. The median OS was 77 days (95%CI, 36-NA), and 5 patients were discharged alive (all received targeted therapy). The median OS of patients who received ICI was 25.5 days (95%CI, 8-NA) and for those who received targeted therapy was 218 days (95%CI, 77-NA). At 6 and 12 months follow-up, 3 and 2 patients who received targeted therapy were still alive, respectively. Conclusions: Our exploratory findings indicate a possible benefit of targeted therapy but suggest a lack of clinical utility of PD-1 ICI for critically ill metastatic NSCLC patients. Because of the small sample size, further studies are needed to expand on this topic.

Ribociclib in the treatment of HR+ HER2-negative metastatic breast cancer: updated results from the randomized clinical trials and their role in the clinical practice

The luminal HER2-negative subtype is the dominant variant of metastatic breast cancer; modern combined endocrine therapy with CDK4/6 inhibitors due to significantly change the prognosis of the disease, not only for increasing progression free survival, but also for significantly prolonging the life expectancy of patients. This review presents the features of the mechanism of action of CDK4/6 inhibitors, the most significant and updated results of large, randomized trials with ribociclib (MONALEESA-2, MONALEESA-3, and MONALEESA-7) assessing the efficacy and safety of combined endocrine therapy with various endocrine partners in a population of premenopausal women and menopausal patients. The prospects for the use of CDK4/6 inhibitors for therapy patients with visceral crisis are shown.

Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial

BackgroundDespite endocrine therapy being the mainstay of treatment for hormone receptor positive (HR+)/HER2− metastatic breast cancer, patients at risk of visceral crisis or doubt for endocrine sensitivity are still offered first-line chemotherapy. Maintenance hormonal therapy is generally offered at the discontinuation of chemotherapy. The MAINtenance Afinitor study is a randomised, phase III trial comparing maintenance everolimus combined with aromatase inhibitors (AIs) versus AI monotherapy in patients with disease control after first-line chemotherapy. MethodsPatients with stable disease, partial response or complete response after first-line chemotherapy were randomised to everolimus plus AIs (exemestane or letrozole or anastrozole) or to AIs alone. Primary aim was progression-free survival (PFS). Secondary aims included response rate, safety and overall survival (OS). ResultsIn total, 110 patients were randomised to everolimus + AIs (n = 52) or to AIs (n = 58). Median PFS was 11.0 months (95% confidence interval [CI] 8.1–13.8) in the everolimus + AI arm and 7.2 months (95% CI 4.7–10.9) in the AI monotherapy arm (hazard ratio [HR] 0.71, 95% CI 0.47–1.06). Objective response rate was 22.4% in everolimus + AI arm and 19.2% in AI monotherapy arm. A higher proportion of disease progression as best response was reported in the AI monotherapy arm (28.8% versus 14.3%). Median OS was 35.7 months (95% CI 26.0–47.8) in the combination arm versus 33.5 (95% CI 26.4–42.7) in the AI alone arm (HR 1.0, 95% CI 0.61–1.62). ConclusionsEVE + AIs did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first-line chemotherapy. Also taking into account treatment tolerability, maintenance endocrine therapy remains the standard. Trial registrationEudraCT: 2013-004153-24.

Abstract CT189: Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial

Abstract Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). Cell-free DNA (cfDNA) ESR1 mutation (ESR1mut) status prior to treatment initiation may be associated with shorter progression-free survival (PFS) under first line Pal+AI; however, the impact of the exact type of ESR1mut, of their quantitative levels and clonality are unknown. In a subsidiary analysis of the first line PADA-1 phase 3 trial, cfDNA samples previously detected as positive by ddPCR were submitted to NGS; mutations types, level and clonality were correlated with patient outcomes under first line Pal+AI. Methods: PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection in the blood of patients treated with AI-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for &amp;gt;12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in cfDNA from up to 4ml of plasma by a single ddPCR assay targeting E380, L536, Y537 and D538 hotspots (i.e. &amp;gt;90% of known ESR1 activating mutations) with 0.1% sensitivity (Jeannot et al, Oncogene 2020). We sequenced the ddPCR positive cfDNA samples using a short amplicon-based NGS panel spanning 30 genes, including the full sequence of ESR1. We assessed for the correlation between PFS and ESR1mut type (NGS), absolute level (copy/ml, ddPCR) or variant allelic frequency (VAF, NGS &amp; ddPCR), and clonality (NGS, pending the detection of other driver mutations). Results: Among the 1,017 included patients, N=33 (3.2%) had an ESR1mut detected by ddPCR at inclusion (median VAF= 2.5%, range (0.09-46.6%). 26/33 left-over cfDNA samples were available for NGS. ESR1mut VAFs retrieved by NGS and ddPCR showed an excellent intraclass correlation coefficient (ICC= 0.98; 95% CI [0.89;0.99]). In N=3 samples with low VAF by ddPCR (&amp;lt;1%), NGS was not able to detect ESR1mut. ESR1 codons 380, 536, 537 and 538 were mutated in N=5, 6, 10 and 7 patients, respectively (5 patients (19.2%) having polyclonal mutations). Among evaluable patients, ESR1mut were found clonal and subclonal in 11 (47.8%) and 12 (52.2%) patients, respectively. After a median follow-up of 24.8 months (range 0-41.9 months) (485 PFS events among the 1,017 included patients), ESR1mut detection at inclusion was found to be a prognostic factor for PFS (median PFS = 11.6 months 95% CI [8.3; NR] vs 28.5 months 95% CI [23.3;30.2]; HR= 2.2 95% CI = [1.4;3.4]). ESR1mut type, clonality and baseline levels had no significant additional impact on PFS. Conclusion: Presence of ESR1mut detected in cfDNA at metastatic relapse are associated with a shorter PFS under first line AI and palbociclib. ddPCR and NGS yielded similar quantitative results, while supplementary information obtained by NGS (mutation type and clonality) did not add further prognostic information. Funding: Pfizer, French National Cancer Institute (Grant PRT-K 2020-041) Citation Format: Anne Pradines, Céline Callens, Aurélia Doussine, Ivan Bièche, Jérôme Lemonnier, Marjorie Mauduit, Thomas Bachelot, Florence Dalenc, Alain Lortholary, Barbara Pistilli, Thibault De La Motte Rouge, Renaud Sabatier, Jean-Marc Ferrero, Sylvain Ladoire, Frédérique Berger, François-Clément Bidard. Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT189.

Endocrine Therapy Versus Chemotherapy as First Line Treatment in Metastatic Hormone Receptor Positive Breast Cancer

Introduction: The standard treatment of hormone receptor positive Her2 negative metastatic breast cancer is endocrine therapy with or without targeted therapy (e.g.CDK4/6inhibitors and mTOR inhibitors). Chemotherapy is indicated only in visceral crisis and the presence of visceral metastases is not indication for chemotherapy Aim of study The retrospective study aimed to characterize treatment and outcomes for patients with hormone receptor positive metastatic breast cancer in Alexandria clinical oncology department to review change in treatment trend during the last 10 years. Physician questionnaire to determine their preferences in choosing treatment. Methods Retrospective study using patient files of adult female diagnosed and treated at Clinical Oncology and Nuclear Medicine Department, Alexandria Main University Hospitals during the period from January 2010 to December 2019. Physician questionnaire was done by physician recruitment via online survey &amp; scientific meetings. Results: The study identified 611 women with hormone receptor positive metastatic breast cancer, median age was 50years, 48.9% were postmenopausal, 56.7% of hormone receptor positive, Her2 negative patients received chemotherapy as first line systemic treatment, 69.5% of these patients received chemotherapy as first line treatment in the first 5years. But, 48.8% of these patients received chemotherapy as first line in the last 5years and the study showed that median overall survival for all studied patients was 34 months. In contrast, the physician questionnaire showed that 75% of physicians prefer endocrinal therapy as first line treatment for hormone receptor positive, Her2 negative metastatic breast cancer. Conclusion: There is significant change in practice pattern in choosing the first line treatment between the first and last 5 years. Also, there is a discrepancy between practice pattern and physician preferences in choosing the first line systemic treatment for hormone receptor positive, Her2 negative metastatic breast cancer. The reason is the unavailability of most targeted agents (e.g; CDK4/6 inhibitors and mTOR inhibitors) and some hormonal agents such as fulvestrant.

Efficacy of CDK4/6i in the visceral crisis setting: Result from a real-world database.

1047 Background: The combination of the CDK4/6 inhibitors(CDK4/6i) and endocrine therapy has improved overall survival(OS) in patients(pts) with either endocrine sensitive or resistant disease who are not in visceral crisis. The goal of this retrospective analysis of a real world database was to look at the efficacy of CDK4/6i among pts with hormone receptor positive (HR+ve)/HER2-ve metastatic breast cancer(MBC) who present with visceral crisis at diagnosis. Methods: For this analysis, we utilized a federated network of de-identified health data representing approximately 64 million patient lives available through the TriNetX Platform. We identified 5966 pts who had HR+ve/HER2-ve MBC diagnosed between 2015 and 2020. OS was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of survival. Visceral crisis was defined as either liver metastases with liver dysfunction, lymphangitis with dyspnea or the presence of pancytopenia. Results: 906(15%) pts received CDK4/6i. OS any time after treatment among pts who did and did not receive CDK4/6i was significantly different (p=0.0002) favoring the group receiving CDK4/6i, with median OS at 59.6 months and 46.2 months and 2-year OS at 71.6% and 61.4% respectively. Among pts who received CDK4/6i versus another treatment as first line therapy, OS was significantly different(HR 0.7, 95%CI 0.57 – 0.86, p&lt;0.0001), and median OS was 59.6 months and 41.5 months respectively. 336 pts with HR+ve mbc presented with visceral crisis at the time of diagnosis of whom 61(18%) received CDK4/6i therapy as first line therapy. Median OS among pts who did and did not have visceral crisis at diagnosis and received treatment was 8.1 months and 210 months respectively. OS any time after initial treatment was significantly different among pts with visceral crisis who did and did not receive CDK4/6i (p=0.01), with 2-year OS at 26.1% and 8.1% and median OS at 11 months and 6 months respectively Conclusions: The use of CDK4/6i in the presence of visceral crisis at diagnosis was associated with a 5 month improvement in OS compared to chemotherapy. Future clinical trials should explore the use of CDK4/6i in the setting of visceral crisis.

Single center observational study of the efficacy of chemotherapy in breast cancer patients treated before and after the widespread use age of CD4/6 inhibitors: Is there evidence that chemotherapy response is impacted by prior use of CD4/6 inhibitors?

e13019 Background: Recently CD4/6 inhibitors have radically changed treatment pathways, leading to a deferment of chemotherapy for advanced disease. Patients still relapse following this treatment; we wish to share our experience of chemotherapy both before and after this change and explore whether there is a change in efficacy. In England CD4/6 inhibitors are prescribed according to the guidelines set out by NHS England (NICE), and are generally utilised in the first line setting unless there is visceral crisis. Methods: This is a retrospective double cohort observational single centre study comparing the efficacy of a chemotherapy regimen (vinorelbine and capecitabine vin cap) before and after the incorporation of CD4/6 inhibitors into breast cancer treatment (Jan 2017- Nov 20). The doublet chemotherapy is widely used at our centre providing a well tolerated and effective alternative to intravenous treatments such as taxanes or single agent capecitabine. Data was collected contemporaneously using e prescribing software and audited retrospectively Results: In the audit period n=19 treated with cap, n= 97 with vin cap, n= 24 treated with CD4/6, (of whom 5 relapsed). 5 patients received abemaciclib first line, as initial therapy, all G3, stage 11A or above, median number of cycles 4.2, I received ribociclib, G2, stage 111A, 7 cycles and 17 received palbociclib, 10 first line, 4 following 1 course chemo, 2 after 2 courses and 1 and after 3 courses, 30% G3 and 70% G2, mean number of cycles 11.06. Patients who received first line cap progressed after a median of 3.5 cycles, with a range of 0-22 months (RR= 47%), for cape vin a median of 8.6, a range of 0-60 months (RR=77%), post CD4/6 mean of 8, median of 9, a range of 0-17 (RR=80%). Conclusions: Those post CD4/6 requiring chemo relapsed far short of the median TTP of around 26months and may have specific characteristics predicting poor response to CD4/6. Despite small numbers salvage chemotherapy remains effective with similar responses. First line vin cap is more efficacious and better tolerated than Cap.[Table: see text]

Alpelisib and fulvestrant efficacy in HR-positive HER2-negative PIK3CA-mutant advanced breast cancer: Data from the French early access program.

1064 Background: In 11.2018, the PIK3CA-inhibitor alpelisib was made available in France through an early access program (EAP), in combination with fulvestrant in pre-treated PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer (ABC) patients. Patients had to received two or more prior systemic treatments for ABC, including an aromatase inhibitor and a CDK4/6 inhibitor in the absence of contraindications. This retrospective real-life, EAP-based study aimed to assess the efficacy and safety of alpelisib/fulvestrant combination in the post CDK4/6 inhibitor setting. Methods: The IRB-approved protocol and call for data were sent on 10.2020 to the cancer centers which participated the most in the EAP prospective registry. Eligible patients were women who started alpelisib/fulvestrant between 11. 2018 and 10.2020 as part of the EAP (which excluded patients with visceral crisis or inflammatory BC). Alpelisib and fulvestrant were used at standard doses. Primary endpoint was PFS by local investigators using RECIST1.1. Secondary endpoints included objective response rate and safety (NCI CTCAE v5.0). Results: 10 centers provided individual data regarding 209 consecutive patients. Patients had received a median number of 4 (1-14) previous systemic treatments for ABC, including CDK4/6 inhibitors, chemotherapy, fulvestrant (alone or in combination) and everolimus for 206 (98.8%), 159 (76.1%), 163 (78%) and 123 (58.8%) patients, respectively. With a median FU of 7.0 months, median PFS was 4.0 months (95%CI [3.5;5.0]) and 35.4% of 164 evaluable patients had an objective response. After stratification on the number of prior lines of treatment, prior exposure to everolimus had no impact on PFS (mPFS in the 123 patients pretreated with everolimus: 4.0m, 95%CI [3.5-5.5]). Of note, this population was enriched in patients who had a long disease control by everolimus (median time spent on everolimus: 7.0m, range (6.5-9.0)). In multivariable analysis, characteristics significantly associated with longer PFS were PS &lt; 3 (HR = 0.03, 95%CI [0.02-0.29]) and prior treatment with fulvestrant (HR = 0.53, 95%CI [0.32-0.89]). N = 81(38.8%) patients discontinued alpelisib due to adverse events (AEs). Most frequent grade 3/4 AEs were hyperglycemia, skin rash, diarrhea and fatigue occurring in 13.4, 8.1, 4.8 and 1.9 % of patients, respectively. Conclusions: Despite heavy pre-treatments, alpelisib +fulvestrant had a clinically relevant efficacy in the French EAP population. Interestingly, prior treatment with either everolimus or fulvestrant did not overtly impair alpelisib-fulvestrant efficacy. The best treatment sequence for PI3KCA/mTOR inhibitors could be examined in future trials in PIK3CA-mutant ER+/HER2- ABC patients.