Prolonging the lives of African-Americans with metastatic breast cancer by adding palbociclib to an aromatase inhibitor in routine clinical practice: a plain language summary of a real-world database study.

WHAT ARE THE KEY TAKEAWAYS?: This study used de-identified medical information from the Flatiron Database. This database contains healthcare information on people with cancer treated by doctors in the United States but personal information is removed to maintain privacy. Medical information for people who received certain treatments in routine clinical practice or real-world setting was included in the study. This study showed that in the real-world setting, African-Americans with HR+/HER2- MBC lived longer when receiving palbociclib with an AI than with an AI alone. Also, the study showed that African-Americans treated with palbociclib plus an AI lived longer without their cancer getting worse than those treated with an AI alone. WHAT WAS THE MAIN CONCLUSION REPORTED BY THE RESEARCHERS?: These results support the use of palbociclib with an AI as a first treatment for African-Americans with HR+/HER2- MBC. Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).

Treatment outcomes in older patients with metastatic breast cancer receiving palbociclib plus an aromatase inhibitor: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This summary describes an article published in the medical journal Frontiers in Oncology in September 2023. The article reports results from a study that looked at breast cancer treatments for older patients aged 75 years or older. The study focused on a type of cancer called HR+/HER2- metastatic breast cancer. HR+/HER2- stands for hormone receptorpositive/human epidermal growth factor receptor 2-negative. This study evaluated whether older patients with this type of cancer benefited from the combination of two medicines - palbociclib and an aromatase inhibitor - compared with taking an aromatase inhibitor alone. HOW WAS THE STUDY IN THIS SUMMARY CARRIED OUT?: The Flatiron database contains medical records for people with cancer in the US. This study used deidentified health care information from this database. 'Deidentified' means that all information that could identify an individual was removed to protect individuals' privacy. People in this study received treatment in routine care and not in a clinical trial. WHAT DO THE RESULTS MEAN?: Older patients who took palbociclib plus an aromatase inhibitor lived longer than those who took an aromatase inhibitor alone. Older patients who took palbociclib plus an aromatase inhibitor also lived longer without their cancer getting worse and started chemotherapy later than those who took an aromatase inhibitor alone. These results support using palbociclib plus an aromatase inhibitor as the first treatment for patients aged 75 years or older with HR+/HER2- metastatic breast cancer.

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.

BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. FUNDING: Pfizer and Celcuity.

Real-world treatment patterns for palbociclib plus an aromatase inhibitor, or an aromatase inhibitor alone, for patients with metastatic breast cancer in the Flatiron Database.

There are limited real-world comparative effectiveness data for palbociclib plus an aromatase inhibitor (AI) as a first-line (1L) treatment examining endpoints that require long term follow-up and post 1L progression. The Flatiron Health Analytic Database was used to characterize treatment and dosing patterns in patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) receiving palbociclib plus an AI vs an AI alone in routine US clinical practice. In addition, time to chemotherapy (TTC) and real-world progression-free survival (rwPFS) when combining 1L and second-line of therapy (rwPFS2) were assessed. Of 1324 patients who received palbociclib plus an AI between February 3, 2015 and March 31, 2020, 1110 (83.8%) started palbociclib at the recommended 125 mg/day dose. After stabilized inverse probability treatment-weighting (sIPTW), median TTC in patients treated with palbociclib plus an AI and AI alone was 37.4 months (95% confidence interval [CI], 33.7-40.7) and 29.2 months (95% CI, 26.8-33.5), respectively (hazard ratio [HR] = 0.77 [95% CI, 0.69-0.86], P < .0001); median rwPFS2 was 32.6 months (95% CI, 29.4-35.2) and 20.7 months (95% CI, 18.9-22.6), respectively (HR = 0.62 [95% CI, 0.54-0.70], P < .0001). Sensitivity analyses with propensity score matching showed similar results to sIPTW analyses. Results from this large real-world study examining additional effectiveness outcomes beyond 1L rwPFS and overall survival support the use of palbociclib plus an AI as a 1L treatment for patients with HR+/HER2- mBC.

A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer.

PURPOSE: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2- mBC. PATIENTS AND METHODS: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. RESULTS: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8-20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001). CONCLUSIONS: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

Efficacy of Single-Agent Chemotherapy in Endocrine Therapy-Refractory Metastatic Invasive Lobular Carcinoma.

BACKGROUND: Hormone receptor (HR)-positive, HER2-negative metastatic invasive lobular breast cancer (mILC) is distinct from invasive ductal cancer (IDC) in clinicopathologic and molecular characteristics, impacting its response to systemic therapy. While endocrine therapy (ET) combined with targeted therapies has shown efficacy in ET-sensitive mILC, data on chemotherapy in ET-refractory mILC remain limited. We investigated the efficacy of single-agent capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2-negative patients with mILC. MATERIALS AND METHODS: Using data from the MD Anderson prospectively collected breast cancer database, we identified patients with HR+ HER2-negative mILC who received prior ET and first-time chemotherapy in the metastatic setting. We compared outcomes between 173 CAP-treated and 96 TAX-treated patients. RESULTS: CAP-treated patients had significantly better median progression-free survival (PFS) than TAX-treated patients (8.8 vs 5.0 months, HR 0.63, P < .001). Overall survival (OS) did not differ significantly between the groups (42.7 vs 36.6 months for CAP vs TAX, respectively, HR 0.84, P = .241). Multivariate analyses for PFS and OS revealed better outcomes in subjects with fewer metastatic sites and those exposed to more lines of ET. Additionally, Black patients showed worse OS outcomes compared to White patients (HR 2.46; P = .001). CONCLUSION: In ET-refractory HR+ HER2-negative mILC, single-agent CAP demonstrated superior PFS compared to TAX. Our findings highlight the potential benefit of CAP in this patient subset, warranting further investigation through prospective trials.

Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.

PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.

Palbociclib Combined with an Aromatase Inhibitor in Patients with Breast Cancer with Lung or Liver Metastases in US Clinical Practice.

A cyclin-dependent kinase 4/6 inhibitor combined with endocrine therapy is the standard of care for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), but real-world effectiveness data for patients with lung or liver metastases are limited. This retrospective study included data from the US Flatiron Health database of patients with HR+/HER2- mBC and lung or liver metastases treated with first-line palbociclib (PAL) plus an aromatase inhibitor (AI) or an AI alone in routine clinical practice. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed. A total of 891 patients were included (622 with lung metastasis, 376 with liver metastasis, and 107 with both lung and liver metastasis). After stabilized inverse probability of treatment weighting to balance patient characteristics, PAL + AI versus AI alone was associated with significantly prolonged OS (HR = 0.62; p < 0.001) and rwPFS (HR = 0.55; p < 0.001) in patients with lung metastases and numerically longer OS (HR = 0.73; p = 0.056) and significantly longer rwPFS (HR = 0.57, p < 0.001) for those with liver metastases. Overall, PAL + AI versus AI alone was associated with prolonged OS and rwPFS in routine clinical practice, supporting the use of first-line PAL + AI for patients with HR+/HER2- mBC with lung and/or liver metastases.

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

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

Absence of lobular carcinoma in situ is a poor prognostic marker in invasive lobular carcinoma.

AIM: To determine if the outcomes of patients with ILC co-occurring with LCIS are similar to pure ILC and if the presence of LCIS is a prognostic factor for ILC. METHODS: In an observational, population-based investigation using data from the MD Anderson breast cancer prospectively collected electronic database, we analysed patients with a diagnosis of stage I-III ILC. Patients were divided into two groups: those with ILC with co-occurring ipsilateral LCIS (ILC + LCIS) and those with pure ILC without a histologically detected co-occurring ipsilateral LCIS (ILC alone). We obtained data on demographics, pathologic tumour size (pT), pathologic lymph node (pN) involvement, estrogen (ER), progesterone (PR) receptor status, HER2 status, Ki67, treatment received, distant recurrence-free and overall survival (DRFS, OS). RESULTS: We identified 4217 patients with stage I-III ILC treated at MD Anderson between 1966 and 2021. 45% of cases (n = 1881) had co-existing LCIS. Statistically and numerically, ILC alone tended to associate with pT4 and pN3 stage (P < 0.001), ER/PR negativity (P = 0.0002), HER2 positivity (P = 0.010), higher Ki67 (P = 0.005), non-classical ILC subtype (P = 0.04) and more exposure to neoadjuvant chemotherapy (P = 0.0002) compared to the ILC + LCIS group. The median follow-up time was 6.5 years. Patients with ILC + LCIS had better median DRFS (16.8 versus 10.1 years, Hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50-0.60, P < 0.0001) and better median OS (18.9 versus 13.7 years, HR 0.62, 95% CI 0.56-0.69; P < 0.0001). Multivariate analysis showed the absence of LCIS to be an independent poor prognostic factor along with a higher pT stage and higher pN stage for DRFS and OS. CONCLUSION: The findings of this study suggests that the absence of ipsilateral LCIS with ILC is an independent poor prognostic factor and that further studies are warranted to understand this phenomenon.

Real-World Effectiveness of Palbociclib Plus Aromatase Inhibitors in African American Patients With Metastatic Breast Cancer.

BACKGROUND: Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have not been well represented in randomized clinical trials of CDK4/6 inhibitors. Real-world studies can provide evidence for effective treatment strategies for underreported patient populations. PATIENTS AND METHODS: This retrospective analysis of African American patients with HR+/HER2- metastatic breast cancer (mBC) from the Flatiron Health longitudinal database evaluated treatments for patients with BC in routine clinical practice in the US. Patients initiated first-line therapy with palbociclib plus an aromatase inhibitor (AI) or AI alone between February 2015 and March 2020. Outcomes assessed included overall survival (OS) and real-world progression-free survival (rwPFS) until September 2020. RESULTS: Of 270 eligible patients, 127 (median age 64 years) were treated with palbociclib + AI, and 143 (median age 68 years) were treated with an AI. Median follow-up was 24.0 months for palbociclib + AI and 18.2 months for AI-treated patients. Median OS was not reached (NR; 95% CI, 38.2-NR) in the palbociclib + AI group versus 28.2 months (95% CI, 19.2-52.8) in the AI group (adjusted HR, 0.56; 95% CI, 0.36-0.89; P = .013). Median rwPFS was 18.0 months (95% CI, 12.4-26.7) in the palbociclib + AI group and 10.5 months (95% CI, 7.0-13.4) in the AI group (adjusted HR, 0.74; 95% CI, 0.47-1.17; P = .199). CONCLUSION: This comparative analysis of palbociclib + AI versus AI alone indicates that palbociclib combined with endocrine therapy in the first line is associated with improved effectiveness for African American patients with HR+/HER2- mBC in real-world settings. TRIAL NUMBER: NCT05361655.

Survival Outcomes in Patients With Hormone Receptor-Positive Metastatic Breast Cancer With Low or No ERBB2 Expression Treated With Targeted Therapies Plus Endocrine Therapy.

Importance: Approximately 45% to 60% of hormone receptor (HR)-positive metastatic breast cancer (mBC) shows a low-level expression of ERBB2. Low ERBB2 expression is defined as ERBB2 immunohistochemical expression of 1+ or 2+ with a negative ERBB2 amplification by in situ hybridization. The efficacy of the antibody-drug conjugate trastuzumab deruxtecan in low-ERBB2, HR-positive mBC has been practice changing. However, there are conflicting data on the prognostic value of low ERBB2 expression in HR-positive mBC and whether low ERBB2 expression is a separate entity. Objective: To examine whether outcomes differ by immunohistochemical analysis for patients with HR-positive mBC with low ERBB2 expression vs those without ERBB2 expression when treated with targeted therapy (TT) plus endocrine therapy (ET). Design, Setting, and Participants: This single-institution cohort study used prospectively collected electronic data from the MD Anderson Cancer Center for patients with a diagnosis of HR-positive mBC treated with ET in combination with a TT (cyclin-dependent kinase 4/6 inhibitors [CDK4/6is], everolimus, or alpelisib) between January 1, 2010, and December 31, 2021. Exposure: HR-positive mBC with either low or no ERBB2 expression. Main Outcome and Measures: The main outcomes were median progression-free survival and overall survival. Data on demographic characteristics, estrogen and progesterone receptor status, ERBB2 status, histologic subtype, menopausal status, treatment duration, and survival status were collected. Results: A total of 1585 women (median [range] age, 51 [24-92] years) were included in the study. Of these women, 1013 (63.9%) had mBC with low ERBB2 expression and 572 (36.1%) had mBC with no ERBB2 expression. A total of 1084 (68.4%) were treated with a CDK4/6i (912 patients were treated in the first line and 172 were treated in the second line); 475 (30.0%) received everolimus and 26 (1.6%) received alpelisib. In the patients who received a first-line CDK4/6i, 618 (67.8%) received an aromatase inhibitor as their ET backbone and 265 (29.1%) received fulvestrant. With a median follow-up time of 17.9 months (range, 1-111 months), progression-free survival and overall survival were not statistically different between the patients with low and no ERBB2 expression treated with TT plus ET. Conclusions and Relevance: In this cohort study of patients with HR-positive mBC treated with TT plus ET, low ERBB2 expression did not have a significant association with prognosis.

Real-world comparative effectiveness of palbociclib plus letrozole versus letrozole in older patients with metastatic breast cancer.

BACKGROUND: Palbociclib, the first available cyclin-dependent kinase 4/6 inhibitor, plus endocrine therapy is approved for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). This study compared real-world effectiveness of palbociclib plus letrozole versus letrozole in older patients with MBC in US clinical practice. METHODS: This retrospective analysis included patients from the Flatiron Health longitudinal database. Overall, 796 women with HR+/HER2- MBC aged ≥65 years starting palbociclib plus letrozole or letrozole as first-line therapy between February 2015 and September 2018 were included. Patients were evaluated from treatment start until December 2018, death, or last visit, whichever came first. Real-world progression-free survival (rwPFS), overall survival (OS), and real-world best tumor responses (rwBTR) were endpoints. Stabilized inverse probability treatment weighting (sIPTW) balanced patient characteristics. RESULTS: After sIPTW, 450 patients treated with palbociclib plus letrozole and 335 treated with letrozole were included; median age was 74.0 years. Median rwPFS was 22.2 (95% CI, 20.0-30.4) months for palbociclib plus letrozole versus 15.8 (12.9-18.9) months for letrozole (hazard ratio, 0.59 [0.47-0.74]; P<0.001). Median OS was not reached for palbociclib plus letrozole versus 43.4 months (30.0-not estimable) with letrozole (hazard ratio, 0.55 [0.42-0.72]; P<0.001). No interactions between age groups (65-74 and ≥75 years) and treatment groups were observed for rwPFS or OS. Rate of rwBTR was significantly higher for palbociclib plus letrozole (52.4%) versus letrozole (22.1%; odds ratio, 2.0 [1.4-2.7]; P<0.001). CONCLUSION: This analysis demonstrates the effectiveness of palbociclib combination therapy as standard-of-care for older patients with HR+/HER2- MBC in the first-line setting.

A phase II study of neoadjuvant atezolizumab and nab-paclitaxel in patients with anthracycline-resistant early-stage triple-negative breast cancer.

PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.

Prolonging the life of people with metastatic breast cancer in routine clinical practice by adding palbociclib to an aromatase inhibitor from a real-world database analysis: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about a study called "P-REALITY X" that was published in the medical journal npj Breast Cancer in October 2022. "P-REALITY X" stands for Palbociclib REAl-world first-LIne comparaTive effectiveness studY eXtended. This study used information from a database to look at whether adding a second treatment (palbociclib) to an aromatase inhibitor (AI) helped people with a certain type of breast cancer to live longer. The type of breast cancer is metastatic hormone receptor-positive/human epidermal growth factor-negative breast cancer, also called HR-positive (or HR+)/HER2-negative (or HER2-) breast cancer. The study used information from the Flatiron Database. This database contains unidentified health care information collected from people seen by doctors in the USA. Only data from people who did not participate in a clinical trial were used. When people are treated outside of a clinical trial, this is called the real-world setting, or routine clinical practice. In clinical trials, people lived longer without their disease worsening if they were treated with palbociclib plus an AI versus being treated with an AI only. Based on the results of clinical trials, treatment with palbociclib plus an AI is already approved and recommended for people with HR+/HER2- breast cancer. This study looked at whether people lived longer if they were treated with palbociclib plus an AI versus being treated with an AI only in routine clinical practice as well. WHAT WERE THE RESULTS?: This study showed that, in routine clinical practice, people treated with the medicine palbociclib plus an AI lived longer than people treated with only an AI. WHAT DO THE RESULTS MEAN?: These results support the continued use of palbociclib plus an AI as the standard first medicine to be given to people with metastatic HR+/HER2- breast cancer. Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).

Histology-based survival outcomes in hormone receptor-positive metastatic breast cancer treated with targeted therapies.

The addition of targeted therapies (TT) to endocrine therapy (ET) has improved the outcomes of patients with HR-positive, HER2-negative metastatic breast cancer (mBC). However, it is unknown whether patients with invasive lobular carcinoma (ILC) or mixed invasive ductal and lobular carcinoma (mixed) histologies experience the same magnitude of benefit from this therapy as those with invasive ductal carcinoma (IDC). We aim to determine whether patients with IDC, ILC, and mixed HR+/HER2- mBC derive similar benefit from the addition of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is), mammalian target of rapamycin inhibitor (mTORi), and phosphoinositide 3-kinase inhibitor (PI3Ki) to ET in HR+/HER2- mBC. We conducted an observational, population-based investigation using data from the MD Anderson prospectively collected database. We conducted a histology-based analysis of progression-free survival (PFS) and overall survival (OS) durations in 3784 patients with HR+/HER2- mBC who were treated with TT plus ET between January 1, 2010, and December 31, 2021. Out of the 3784 patients, 2975 were included in the final analysis. Of these, 2249 received CDK4/6is (81% IDC, 15% ILC, and 4% mixed), 1027 received everolimus (82% IDC, 14% ILC, and 4% mixed) and 49 received alpelisib (81% IDC and 19% ILC). The addition of targeted therapy to ET did not result in statistically significant differences in PFS or OS duration among patients with IDC, ILC, and mixed HR+/HER2- mBC. We concluded that for patients with HR+/HER2- mBC, the addition of TT to ET leads to a similar magnitude of benefit, irrespective of histology.

Inclusion of premenopausal women in breast cancer clinical trials.

BACKGROUND: Patients with premenopausal breast cancer (PMBC) have been historically excluded from some clinical trials because of the limitations of using endocrine therapy (ET) in this population. We analyzed breast cancer randomized clinical trials (RCTs) to determine the rates of and factors associated with inclusion of PMBC patients to provide a benchmark for PMBC inclusion in RCTs moving forward. METHODS: Using ClinicalTrials.Gov, we identified breast cancer phase III RCTs and extracted inclusion criteria and patient enrollment information. Multiple binary logistic regression modeling was used to assess trial-related factors that were associated with PMBC patient inclusion. RESULTS: Of 170 breast cancer RCTs identified, 131 (77.1%) included PMBC patients. Sixty-five (38.2%) trials analyzed patients with hormone-receptor-positive (HR+) and HER2-negative (HER2-) breast cancer, of which 31 (47.7%) allowed for enrollment of PMBC patients. Lower rates of PMBC inclusion were seen in trials that studied HR+/HER2-patients (47.7% PMBC inclusion in HR+/HER2-trials vs. 94.3% in non-HR+/HER2-trials, aOR 0.07 [95% CI: 0.02-0.19], p < 0.001) and in trials that randomized or mandated ET (44.4% in ET trials vs. 83.2% in non-ET trials, aOR 0.21 [95% CI: 0.10-0.83], p = 0.02). Trials studying chemotherapy (CT) were associated with inclusion of PMBC patients (100% in CT trials vs. 70.5% in non-CT trials, a OR 14.02 [95% CI: 1.54-127.91], p = 0.01). All surgical and radiation therapy clinical trials allowed for the inclusion of PMBC patients in their eligibility criteria. CONCLUSIONS: Breast cancer clinical trials should carefully select their enrollment criteria and consider inclusion of premenopausal patients when appropriate.

Real-world study of overall survival with palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer.

Data on real-world effectiveness of cyclin-dependent kinase 4/6 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015-March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 [45.2-57.7] versus 43.2 [37.6-48.0] months; hazard ratio, 0.76 [95% CI, 0.65-0.87]; P < 0.0001). Progression-free survival (95% CI) is 19.3 (17.5-20.7) versus 13.9 (12.5-15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62-0.78]; P < 0.0001). These data support first-line palbociclib plus an AI treatment for HR+/HER2- MBC.(Trial number NCT05361655).