Hormone Receptor-positive Advanced Breast Cancer Research Articles

Targeting CDK4 and CDK6 in cancer.

Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.

Real-World First-Line Treatment Patterns and Outcomes in Hormone Receptor-Positive Advanced Breast Cancer Patients: A Multicenter, Retrospective Study in China.

BackgroundRecent data on first-line treatment patterns administered to hormone receptor-positive (HR+) advanced breast cancer (ABC) patients in the real-world setting are limited. This study aimed to report the first-line treatment patterns and outcomes of HR+ ABC patients in China.MethodsThis was a multicenter, noninterventional study. Eligible patients were cytologically or histologically confirmed to have HR+ ABC with ≥2 complete medical records and received first-line therapies between January 2015 and June 2019. Treatment patterns and outcomes were extracted from structured or unstructured electronic medical records. Progression-free survival (PFS) was analyzed with the Kaplan-Meier method.ResultsIn total, 1072 patients with HR+ ABC were enrolled at 6 treatment sites: 327 human epidermal growth factor receptor 2-positive (HER2+) patients, 696 HER2-negative (HER2-) patients and 49 HER2-unknown patients. Overall, 62.41% of patients received first-line chemotherapy (CT), 21.08% received targeted therapy (TT) and 15.49% received endocrine therapy (ET). For HR+/HER2+ patients, 65.14% received TT, 28.44% received CT, and 5.81% received ET. Compared with patients who received TT, patients who received CT alone, had a significantly worse median PFS (adjusted hazard ratio [HR] =2.59, 95% confidence interval [CI], 1.64-4.10, p<0.001). For HR+/HER2- patients, 77.01% received CT, 20.69% received ET and 1.15% received TT. Compared with patients who received ET, patients who received CT with maintenance therapy had a significantly prolonged median PFS (adjusted HR =0.57, 95% CI, 0.44-0.76, p<0.001). Among HR+/HER2- patients who received CT with maintenance treatment, those with maintenance ET had a longer median PFS than those with maintenance CT, but the difference was not significant (adjusted HR=0.92, 95% CI, 0.64-1.33, p=0.66).ConclusionsThis real-world study demonstrates that CT remains the mainstream first-line treatment option for HR+ patients in China. Among patients with HR+/HER2+ ABC, the majority received first-line TT and experienced a PFS benefit. A high percentage of HR+/HER2- patients received CT as first-line therapy in clinical practice. PFS benefit was significantly longer in patients who received CT with maintenance therapy. Moreover, there was no obvious difference in PFS between maintenance ET and CT. Maintenance ET may be a better choice considering its lower toxicity and better quality of life.

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Abstract P5-16-11: Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC)

Abstract Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [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 P5-16-11.

Abstract OT1-18-01: A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study

Abstract Background: Hormone receptor (HR)-positive HER2-negative breast cancers have a lower tumor mutation burden than other types of cancer and triple-negative breast cancer, resulting in relatively low immunogenicity. It is also known that estrogen suppressively regulates immunity through regulatory T cells in the tumor microenvironment. Therefore, the development of immunotherapy in HR-positive and HER2-negative breast cancer is a challenging issues. Anti-VEGF therapy has been shown to improve antigen presentation, local migration of cytotoxic T lymphocytes, and suppressive tumor microenvironment in preclinical and clinical studies of various cancers. Anti-VEGF therapy can be hypothesized to modulate immunotherapy. Methods: JCOG1919E (AMBITION) is a randomized, multicenter, open-label, phase III trial to evaluate efficacy and safety of bevacizumab and paclitaxel in combination with atezolizumab (BEV+PTX+ATZ) comparing to bevacizumab and paclitaxel (BEV+PTX) in patients with HR-positive HER2 negative locally advanced or metastatic breast cancer. The key eligibility criteria are as follows: 1) ECOG PS 0-2, 2) ER and/or PgR positive and HER2-negative breast cancer, 3) endocrine resistance or life-threatening disease, 4) measurable disease, 5) centrally confirmed programmed death-ligand 1 (PD-L1) status on tumor-infiltrating immune cells, 6) no prior chemotherapy for locally advanced or metastatic breast cancer, 7) adequate organ function. Patients will be randomized (staratified by recurrence/de novo, liver metastasis, or PD-L1 status) in a 1:1 ratio, to BEV+PTX arm or BEV+PTX+ATZ arm. Patients in arm A receive PTX (90 mg/m2/day, days 1, 8 and 15, iv) and BEV (10 mg/kg/day, days 1 and 15, iv) on a 28-day cycle. Patients in arm B receive PTX and BEV plus ATZ (840 mg/body/day, days 1 and 15, iv). Treatment in both arms is continued until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by investigators. The secondary endpoints include overall survival, PFS assessed by blinded independent central review, response rate, adverse events, PFS (PD-L1 positive), and OS (PD-L1 positive). We assumed a median PFS of 16 months in BEV+PTX+ATZ arm and 11 months in BEV+PTX arm. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 2.5%, power of 80%, an accrual period of 2.5 years, and a follow-up period of 2 years. Translational research also will be conducted accompanying with this trial. Patient accrual was started in January 29, 2021 and 37 patients were enrolled by June 18, 2021. Safety of patients in this study is being monitored by IDMC. For further information on this trial, visit ClinicalTrials.gov (NCT04732598). Citation Format: Fumikata Hara, Makiko Ono, Shigehisa Kitano, Shigehira Saji, Akihiko Shimomura, Takashi Yamanaka, Takayuki Kadoya, Mitsuya Ito, Hiroko Bando, Hiroyuki Yasojima, Keita Sasaki, Tomoko Kataoka, Tadahiko Shien, Kan Yonemori, Hiroji Iwata. A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION 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 OT1-18-01.

The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer.

Breast cancer is the most frequently diagnosed cancer in women worldwide. Aromatase inhibitors (AIs) are effective treatment options for both early-stage and advanced hormone receptor-positive breast cancer. Because of AIs are used long term in adjuvant therapy, side effects are also very important. It is considered that AIs may affect cognitive functions by decreasing the level of estrogen in the brain. The purpose of our study is that evaluate the relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy. Two-hundred patients diagnosed with breast cancer who were treated with AIs as adjuvant treatment were included. The patients were surveyed for demographic characteristics. Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were performed to evaluate patients' cognitive functions. The total scores of the tests and the orientation, short-time memory, visuospatial functions, attention, language, executive functions which are the MoCA subscales were evaluated separately. Patients were grouped as 0-6, 6-12, 12-24, 24-36, 36, and more months according to the duration of AIs using time. The total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. There was no relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy (P > 0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (P > 0.05). Prolonged adjuvant treatment with AIs does not affect cognitive functions in hormone receptor-positive breast cancer patients.

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 &amp;gt;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 P2-01-18: Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology

Abstract Background: Indentification of actionable or therapy resistance-associated mutations may guide sequential treatments in Hormone Receptor-positive and HER2-negative (HR+/HER2-) Advanced Breast Cancer (ABC) patients with resistance to prior endocrine therapies. Molecular profiling from cell-free DNA (cfDNA) is progressively permeating the clinical setting as an alternative or adjunct to tissue biopsies. Digital PCR (dPCR) assays permit the detection of genomic alterations with high sensitivity but are associated with cumbersome workflows and limited genomic coverage. NGS-based cfDNA assays are being increasingly adopted, as they can offer broader coverage while maintaining competitive sensitivity. Methods:Mutation testing was performed on plasma samples obtained from patients with HR+/HER2- ABC who had recurred or progressed after receiving an aromatase inhibitor. Samples were collected at the start of new treatment, during therapy, and at progression. dPCR tests were carried out using QuantStudio3D Digital PCR at the Molecular Oncology Laboratory at Clínico San Carlos Hospital. dPCR targets included PIK3CA E542K, E545K, and H1047R, and ESR1 Y537S and D538G. Samples[CdS1] were also tested with the SafeSEQ Breast Cancer Panel to assess clinically relevant genomic regions across PIK3CA, ESR1, AKT1, TP53, KRAS, and ERBB2. SafeSEQ testing was performed in Sysmex Inostics’ CLIA-certified, CAP-accredited laboratory. Results: Mutational data obtained from both dPCR and SafeSEQ testing were available for concordance analysis in 107 samples from 50 patients for PIK3CA, and 86 samples from 41 patients for ESR1. Combined results showed PIK3CA mutations in 47 samples (43.9%), with H1047R (14%), E545K (11.2%), and E542K (9.3%) being the most frequent mutations detected. ESR1 mutations were present in 35 samples (32.7%), where D538G (19.6%) and Y537S (9.3%) were most commonly observed. Among samples with no mutations detected by dPCR, the expanded coverage of SafeSEQ enabled the detection of clinically relevant mutations in PIK3CA and ESR1 in 10 (9.3%) and 3 (2.8%) samples, respectively. The concordance rates for dPCR and SafeSEQ were 93.1% and 88.9% for PIK3CA and ESR1, with positive percent agreements (PPA) of 93.8% and 84.6%, and negative percent agreements (NPA) of 92.8% and 90.9% for PIK3CA and ESR1, respectively. A strong correlation was observed between MAF levels (Spearman's ρ = 0.87 [95% CI 0.79-0.93], p&amp;lt;0.001) as well as number of mutant molecules per mL of plasma (ρ = 0.79 [95% CI 0.66-0.88], p&amp;lt;0.001). When samples with MAFs&amp;lt;0.1% were evaluated, lower concordance rate was detected (38.5%; N=13; 46.2% detected by SafeSEQ and 92.3% by dPCR). Finally, no significant difference between assays was found when comparing concordance rates among samples at different timepoints. Regarding longitudinal ctDNA data, 18 and 16 patients showed mutations in PIK3CA and/or ESR1 in plasma at least in one timepoint. Monitoring results were concordant in 50%/56.3% of patients for PIK3CA/ESR1 (during therapy and/or at progression time, 5.6%/18.8% of patients showed decrease or clearance of ctDNA and 38.9%/25% showed increase of ctDNA).Conclusion:In this cohort of AI-progressing HR+/HER2- ABC patients, dPCR and SafeSEQ methods showed high overall agreement for the detection of mutations in PIK3CA and ESR1, key genes for clinical decision-making and enrollment in clinical trials. The expanded coverage of SafeSEQ makes it a powerful tool to inform patient management considering the growing pool of clinically relevant genomic alterations in this type of patients. Efforts are ongoing to expand the analysis to a larger cohort and incorporate long-term outcomes and multivariate adjustment. Supported by AstraZeneca. Citation Format: Jesus Fuentes Antras, Vanesa García-Barberán, Fernando Moreno, Hillary Sloane, Igor López-Cade, Alicia De Luna, Alejandro Pascual, Carmen Ramirez-Ruda, Victor Lorca, Paloma Flores, Pedro Perez-Segura, Alberto Ocaña, Jennifer Preston, Hannah Quinn, Frederick Jones, Jose Angel Garcia-Saenz. Orthogonal assessment of PIK3CA and ESR1 mutation detection in longitudinal cfDNA samples from endocrine-resistant HR+/HER2- advanced breast cancer patients using dPCR and NGS-based SafeSEQ technology [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 P2-01-18.

Abstract P5-13-16: A real-world assessment of PIK3CA testing and alpelisib treatment patterns among metastatic breast cancer patients in a community oncology setting

Abstract Background: Alpelisib (PIQRAY®) in combination with fulvestrant was approved by the US- FDA in May of 2019 for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) PIK3CA mutant advanced or metastatic breast cancer (aBC or mBC) following progression on aromatase inhibitors. Prior to the US-FDA approval of alpelisib, routine molecular profile testing for this patient population was not supported by NCCN guidelines. Thus, data on the natural history of HR+/HER2- mBC patients, particularly in terms of biomarker testing and treatment patterns in a real-world patient setting, are limited. To understand integration of alpelisib into clinical practice for this patient population, this retrospective non-interventional study assessed biomarker testing, treatment patterns, and patient characteristics for patients at Texas Oncology (TxO) from 2015 to 2020.Methods: The study index date was defined as the first date of a new diagnosis of advanced BC (de novo or recurred mBC) between January 2015 and June 2020 with a minimum follow-up opportunity of 6 months follow-up. Treatment patterns were assessed until December 2020, allowing assessment of alpelisib real-world utilization post the US-FDA approval. Databases curated included the EMR (iKM), the TxO Precision Medicine (PM) Molecular databases. Information mined included total number of mBC patients, HR and HER2 status, and the presence and classification of PIK3CA mutations. Treatment patterns were also examined. Results: Study cohort consisted of 1093 patients for whom PIK3CA, HR, HER2 status and systemic treatment were known. Of these, 768 (70%) were HR+/HER2-, 220 (20%) were HR-/Her2HER2-, 73 (7%) were HR+/Her2HER2+ and 32 (3%) were HR-/Her2HER2+. Among all subtypes, 410 (38%) were PIK3CA mutant, and within HR+/HER2- cohort, 333 (43%) were PIK3CA mutant. Of the 105 patients treated with alpelisib, 102 (97%) were treated after drug approval, and the remaining 3 patients (3%) received alpelisib via compassionate use program. Within the HR+/HER2-/PIK3CA mutant patient cohort (n=333), 97 (29%) were treated with alpelisib. The most frequent alpelisib-containing regimen is alpelisib+fulvestrant, given to 84 (87%) of patients. It is most frequently given as a second- (n=28, 29%), third- (n=16, 16%) and fourth-line (n=16, 16%) lines of therapy. Out of 97 patients, 69 (71%) were treated previously with a cyclin-dependent kinase 4/6 inhibitor. The median duration of alpelisib therapy was 4.6 months. As of December 30, 2020, 34 of the 97 patients had treatment with alpelisib ongoing, 24 expired, 14 were referred to hospice,18 completed last recorded line of therapy prior to study end date, and 7 patients progressed to the next line of therapy. There was no noteworthy difference in patients treated vs. not treated with alpelisib with respect to age (mean 61.5 vs. 59.3 yrs.) or performance status (Karnofsky) (29% vs. 25% at 100%, 42% vs. 49% at 90% respectively). In PIK3CA mutant cancers, the most frequent PIK3CA mutations were H1047R, E545K, E542K, N345K and H1047L, and 43 (10%) had 2 or more mutations. Patient outcomes including the median progression free survival was also determined for this cohort and will be reported. Conclusions: This retrospective study demonstrates that 38% of mBC patients’ cancers across all sub-types harbored a PIK3CA mutation where multiple testing platforms were utilized in the community setting. Approximately 30% of patients with HR+/HER2-/PIK3CA mutant status did receive alpelisib. Co-morbidities and other clinically relevant factors between PIK3CA mutant patients who did and did not receive alpelisib, such as those on oral diabetes medication, insulin or had elevated HgbA1c, should be studied further. Citation Format: Joyce O'Shaughnessy, MD, Steven Paulson, MD, Lorraine Brisbin, M.S, James Lindsey, Anna Williford, Ph.D, Monica Lisi, Rohan C. Parikh, Ph.D, Stacey Simmons, MD and Sanjeev Balu, Ph.D. A real-world assessment of PIK3CA testing and alpelisib treatment patterns among metastatic breast cancer patients in a community oncology setting [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 P5-13-16.

Abstract P1-18-18: Real-world natural history data among patients with PIK3CA-mutant and PIK3CA-wild-type advanced breast cancer

Abstract Background: Oncogenic mutations involving PIK3CA gene (PI3Kα) are observed in over 40% of patients with hormone receptor-positive (HR+) advanced breast cancer (ABC). Clinical efficacy of PI3K inhibition was demonstrated in a recent trial, but data on the natural history of disease by PIK3CA status are limited in ABC. We assessed patient and disease characteristics, treatment patterns, and clinical outcomes among patients with ABC treated at the Memorial Sloan Kettering Cancer Center in the United States, prior to the clinical availability of alpelisib (a PI3Kα inhibitor). Methods: A retrospective medical record review of adult patients diagnosed with HR+ and human epidermal growth factor receptor 2-negative (HER2-) ABC between January 2014 and December 2018 was conducted. Data collection is ongoing and updated results will be presented. Cohorts were determined by eligible patients’ PIK3CA gene status (i.e., mutant or wild-type [WT]), and were frequency matched to have an equal distribution of the year of ABC diagnosis between cohorts. Study measures were descriptively summarized, and the Kaplan-Meier method was used to estimate progression-free survival (PFS) and left truncation-adjusted overall survival (OS), in months. To assess the association of PIK3CA mutation status on OS, a multivariate Cox proportional hazard model adjusted for age, race, stage at diagnosis, menopausal status, visceral disease, bone only disease, and Charlson Comorbidity Index score was computed. Additional adjustment on treatment modalities is planned. Results: Data for 249 PIK3CA-mutant and 143 PIK3CA-WT patients was analyzed. For the mutant cohort, the mean (SD) age was 59.0 (11.2) years, 80.7% were White, 30.9% were diagnosed with de novo ABC, and 54.6% were postmenopausal at initial BC diagnosis. Visceral- and bone only-disease were observed among 41.4% and 21.7% of patients, respectively. Among patients with a single PIK3CA mutation (n=220, 88.4%), the most common mutations were H1047R (37.3%), E545K (20.5%), and E542K (12.7%). Multiple PIK3CA mutations were observed in 29 (11.6%) patients. For the WT cohort, the mean (SD) age was 56.3 (12.1) years, 77.6% were White, 39.9% were diagnosed with de novo ABC, and 45.5% were postmenopausal at initial BC diagnosis. Visceral- and bone-only disease were observed among 51.8% and 16.8% of patients, respectively. Most common 1st-line treatments for ABC were cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) + aromatase inhibitor (AI) (mutant: 38.6%; WT: 40.6%), AI only (mutant: 21.3%; WT:22.4%), CDK4/6i + fulvestrant (mutant: 15.7%; WT: 7.7%), and chemotherapy-based regimens (mutant: 9.6%; WT: 11.2%). Chemotherapy-based regimens were the most common 2nd- (mutant: 25.6%; WT: 21.3%) and 3rd-line (mutant: 41.4%; WT: 33.9%) therapies for both cohorts. Results for PFS and OS are presented in Table 1, and the survival risk was similar for both cohorts (adjusted HR: 1.18, 95% CI: 0.88-1.60). Conclusion: In this preliminary analysis of HR+/HER2- ABC, CDK4/6i-based regimens were the most common 1st-line therapy, and PFS to 1st-3rd line therapies and OS were not statistically significantly different. The recent availability of PI3K inhibitor therapy may improve clinical outcomes among patients with PIK3CA-mutant tumors. Table 1.Progression-free Survival and Overall Survival Among Patients with HR+/HER2- ABC.PIK3CA MutantPIK3CA Wild-typeProgression-free Survival (months)1st line – all patients (n)249143Median (95% CI)12.4 (10.4-15.2)13.5 (10.3-16.0)1st line – CDK4/6i + AI (n)9658Median (95% CI)21.0 (17.0-27.9)19.1 (9.4-28.6)2nd line – all patients (n)211127Median (95% CI)7.3 (6.3-10.4)6.8 (5.4-8.8)2nd line – chemotherapy-based regimens (n)5427Median (95% CI)5.1 (3.7-6.3)5.2 (3.3-6.3)3rd line – all patients (n)186115Median (95% CI)4.5 (3.7-5.4)5.7 (4.7-8.9)3rd line – chemotherapy-based regimens (n)7739Median (95% CI)4.3 (3.0-5.1)4.7 (3.0-7.7)Overall Survival (months)Median (95% CI)47.4 (42.8-52.4)55.5 (44.9-61.9) Citation Format: Pedram Razavi, Rohan C Parikh, Barbara Acevedo, Abigail Hitchens, Mehnaj Ahmed, Anton Safonov, Emanuela Ferraro, Komal Jhaveri, Michelle Sidel, Stacey Simmons, Mark Robson, Sarat Chandarlapaty, Sanjeev Balu. Real-world natural history data among patients with PIK3CA-mutant and PIK3CA-wild-type advanced 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 P1-18-18.

Abstract P1-18-14: Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study

Abstract Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had &amp;gt;3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations. Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II 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 P1-18-14.

Pharmacoeconomic evaluations of CDK4/6 inhibitors plus endocrine therapy for advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer: a systematic review.

BackgroundHormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2−) breast cancer is the most common molecular subtype of breast cancer in many countries, and endocrine therapy remains a mainstay in its treatment. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of targeted agents administered orally that are recommended being used in combination with endocrine therapy as first and second line treatments for advanced HR+/HER2− breast cancer. However, their high prices largely hinder using these drugs in real world settings. To offer a new basis for future research, we investigated the cost-effectiveness of combinations of CDK4/6 inhibitors with endocrine therapy in the treatment of advanced HR+/HER2− breast cancer.MethodsWe systematically searched several frequently used databases and identified economic evaluations published from February 2015 to April 2021. The systematic review was performed after retrieving the literatures and extracting data based on inclusion and exclusion criteria. The quality of each selected economic evaluation was assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS).ResultsThe literature search yielded 161 articles, among which fourteen studies (15 articles) with CHEER scores ranging from 58.33% to 87.50% entered the final analysis. Markov models were used in most studies. Based on the currently available data, CDK4/6 inhibitors plus endocrine therapy were less cost-effective in first- or second-line treatment of patients with HR+/HER2− advanced breast cancer. However, ribociclib plus letrozole was more cost-effective than palbociclib plus letrozole in the first-line treatment of postmenopausal women. The economic impacts of CDK4/6 inhibitors plus endocrine therapy in non-postmenopausal patients or second-line therapy cannot be fully evaluated due to the limited number of studies. The three most common factors affecting economic outcomes were the prices of CDK4/6 inhibitors, hazard ratios for progression-free survival and overall survival, and health status utility values.DiscussionCDK4/6 inhibitors plus endocrine therapy have shown significantly improved efficacy outcomes in HR+/HER2− metastatic breast cancer (mBC)/advancer breast cancer (ABC) first-line and second-line treatment for endocrine-sensitive and endocrine-resistant populations, while more potential fields including neoadjuvant and adjuvant settings are being identified to benefit a wider range of breast cancer patients. Meanwhile, risk of severe adverse events that more likely to happen in patients treated with CDK4/6 inhibitors can lead to reduced life quality and higher medical costs patients need to afford. The adverse drug reaction related cost in several economic burden studies were explored to be primarily driven by hospitalizations and outpatient, and assessment of cost associated with CDK4/6 inhibitors adverse events is worth further developing. Drug wastage costs were found higher in palbociclib regimen than ribociclib regimen due to different dosing patterns. Moreover, current economic evaluations showed that ribociclib plus letrozole had better economic benefits than palbociclib plus letrozole for first-line treatment of postmenopausal women with HR+/HER2− ABC.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer

AimsFulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. Materials and methodsMedical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. ResultsData from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21–95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0–1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0–5) prior lines of endocrine therapy and median 0 (range 0–6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1–88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0–88). ConclusionsThis is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Time to Chemotherapy for Patients With Estrogen Receptor-Positive Breast Cancer and Cyclin-Dependent Kinase 4 and 6 Inhibitor Use.

PurposeSafely postponing the use of chemotherapy is important for quality of life maintenance in patients with hormone receptor-positive advanced breast cancer. In previous studies, a combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and fulvestrant prolonged the time to chemotherapy (TTC). In this study, we used real-world data to evaluate TTC in the context of CDK4/6i therapy.MethodsWe performed a retrospective chart review of women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated at the Aichi Cancer Center Hospital. The patients were categorized into having received CDK4/6i therapy first (n = 41), second (n = 33), and none at all (n = 67). The change in TTC among the groups was examined.ResultsThe median follow-up time was 13.8, 27.5, and 30.3 months in the CDK4/6i (first), CDK4/6i (second), and non-CDK4/6i groups, respectively. The median progression-free survival (PFS) with first-line therapy for metastasis was 30.0, 11.9, and 13.0 months, respectively (CDK4/6i [first] vs. non-CDK4/6i; p = 0.018, CDK4/6i [second] vs. non-CDK4/6i; p = 0.383). The median TTC was not reached in the CDK4/6i (first) group, was 39.1 months in the CDK4/6i (second) group, and was 44.2 months in the non-CDK4/6i group (CDK4/6i [first] vs. non-CDK4/6i; p = 0.880; CDK4/6i [second] vs. non-CDK4/6i; p = 0.407). The non-CDK4/6i group with TTC ≥ 60 months included more cases of secondary endocrine therapy resistance (p = 0.017), no perioperative chemotherapy (p = 0.021), and a longer disease-free interval (p = 0.093).ConclusionAlthough PFS was significantly longer in the CDK4/6i (first) group than in the non-CDK4/6i group, TTC did not significantly differ among the three groups in real-world data. The non-CDK4/6i group showed a long TTC in patients with late recurrence and low risk at the primary lesion site, who benefited greatly from hormone monotherapy.

Endocrine therapy leads the first- and second-line treatment options for hormone receptor-positive advanced breast cancer—comments on the Monarch plus study

Endocrine therapy leads the first- and second-line treatment options for hormone receptor-positive advanced breast cancer—comments on the Monarch plus study

Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer—findings from the RIBECCA trial

BackgroundInhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies. MethodsHere, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib. ResultsGene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients. ConclusionsWe show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer.

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.

A Randomized Trial of Fulvestrant, Everolimus, and Anastrozole for the Front-line Treatment of Patients with Advanced Hormone Receptor-positive Breast Cancer, SWOG S1222.

Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer. This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy. Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival. Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated.

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer

BackgroundEntinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients.MethodsThis phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points.ResultsTwelve patients were enrolled. No DLTs or grade 3–5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9–not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months.ConclusionsEntinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation.Trial registrationJAPIC Clinical Trial Information, JapicCTI-153066. Registered 12 November 2015. ClinicalTrials.gov, NCT02623751. Registered 8 December 2015.

Clinical practice patterns for advanced breast cancer patients on CDK4/6 inhibitors receiving palliative radiation therapy.

269 Background: Patients with hormone-receptor positive advanced breast cancer (ABC) often require palliative radiation therapy (RT) while receiving systemic treatment with CDK4/6 inhibitors (CDK4/6i). There are conflicting reports in the literature regarding whether concurrent administration of CDK4/6i and RT increases RT or hematologic toxicity and there are currently no formal guidelines for this realm. A Canadian national survey was conducted to evaluate local practice patterns of CDK4/6i management during palliative RT. Methods: An anonymized online survey was distributed to 162 Canadian breast cancer health care professionals between November 2020 and January 2021. The survey collected provider demographics and questions regarding practice, experiences and opinions on CDK4/6i management during palliative RT for ABC. Results: The survey was completed by 76 (47%) of the invited participants: 40% were medical oncologists, 26% radiation oncologists, 16% pharmacists and 18% nurses, physician assistants or radiation therapists. Nine provinces were represented. The respondents' clinical practice settings were predominantly at an academic/cancer centre (84%), while 16% of clinicians were based at a community setting. Interrupting the CDK4/6i during RT was recommended always by 21% of respondents, sometimes by 46% and never by 9%, while 24% had no opinion. The majority of opinions were based on personal experience (55%), colleagues’ practice (37%), medical literature (33%) and experience with chemotherapy agents (18%). Unexpected RT toxicity observed in patients on concomitant CDK4/6i was reported by 9% of respondents and prolonged cytopenias by 15%. Among responders who always or sometimes interrupt CDK4/6i during palliative RT, the timeframe to hold CDK4/6i prior to RT was 4-7 days 45%, 1-3 days 32%, 8-14 days 13% and 10% were unsure. Responses were similar for the timeframe used to resume the drug after RT. The majority (94%) thought that advising the patient on what to do with the CDK4/6i during RT was the role of the Medical Oncologist, while 48% also thought it was the role of the Radiation Oncologist. 23% of respondents though the patient should always be reassessed prior to restarting the CDK4/6i; 45% said sometimes, and 29% said not necessary. 82% of respondents indicated a standardized protocol or guideline would be valuable in this setting. Conclusions: Two thirds of Canadian breast cancer specialists sometimes or routinely interrupt CDK4/6i treatment during RT with 15% having observed increased toxicity with concurrent administration. Consensus guidelines for the management of CDK4/6i and RT are necessary to reduce treatment variability and improve the quality and safety of care for these patients.