Time To Chemotherapy Research Articles

Impact of delays in neoadjuvant chemotherapy initiation on pathologic complete response among patients with HER2-positive or triple negative breast cancer.

102 Background: Pathologic complete response (pCR) is used as a surrogate endpoint for overall survival (OS) in high-risk early-stage breast cancer (BC). pCR rates vary according to BC molecular subtype and have the highest association with OS in triple negative BC (TNBC) and HER2-positive (HER2+) BC. In these subgroups, neoadjuvant chemotherapy (NACT) is often the standard of care. We evaluated the association of delays in NACT initiation (NACTI) with pCR. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis cT2+ or lymph node positive HER2+ or TNBC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of BC diagnosis. Time to chemotherapy (TTC) was recorded in days. Patients were categorized by receptor status. We used AJCC 7 th and 8 th edition T and N staging to define pCR (pT0 or pTis and pN0 or pN0I-). Delay was defined as TTC > 60 days. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to calculate odds of pCR associated with delays. A sensitivity analysis defining delay >30 and >90 days was also conducted. Results: We identified 105,352 eligible patients, 73% were White, 19% were Black, 3% were Asian, and 4% were Other/Unknown. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180). There were 56,868 patients with HER2+ BC and 48,484 with TNBC; 9% of patients were delayed > 60 days in each group. Among all HER2+ patients, 39.1% achieved a pCR: 35.0% with delay compared to 39.5% without delay. Among TNBC patients, 30% achieved a pCR: 25% with delay compared to 31% without delay (p < 0.0001 for all). In multivariable analysis, patients with HER2+ disease (OR 0.85, 95%CI 0.79-0.92) and TNBC (OR 0.80, 95%CI 0.73-0.87) were less likely to achieve pCR if delayed > 60 days. In a sensitivity analysis, delay > 30 days was associated with lower likelihood of achieving pCR for all and delay > 90 days was associated with lower likelihood for TNBC (Table). Conclusions: Delays in NACTI >60 days among patients with HER2+ and TNBC BC was an independent predictor of not achieving pCR. Given the known association between socioeconomic factors and delays to initiation of treatment, interventions aimed at reducing delays may reduce disparities in BC outcomes. Future studies to identify causes of delays and the downstream impact are needed to ultimately develop interventions that mitigate these effects among patients with HER2+ or TNBC, where pCR rates are associated with OS. Association of pCR in patients who experience NACTI delay using multivariable logistic regression* n(complete case) = 77,690. Subgroup >30-day Delay in NACTIOR (95% CI) >60-day Delay in NACTIOR (95% CI) >90-day Delay in NACTIOR (95% CI) HER2+n =41,672 0.91 (0.87-0.95) 0.85 (0.79-0.92) 0.93 (0.80-1.07) TNBCn = 36,018 0.87 (0.83-0.92) 0.80 (0.73-0.87) 0.78 (0.65-0.92) *Adjusted for demographic, socioeconomic and tumor characteristics.

Factors associated with delays in receipt of neoadjuvant chemotherapy in patients with operable breast cancer.

126 Background: Delays in neoadjuvant chemotherapy initiation (NACTI) after breast cancer (BC) diagnosis have been associated with worse outcomes. We evaluated incidence and predictors of delays of NACTI among high clinical risk patients treated with NACT on a national level. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of diagnosis. Patients who received neoadjuvant endocrine therapy were excluded. Time to chemotherapy (TTC) in days was recorded. Patients were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to identify characteristics associated with delays > 60 days from diagnosis to NACTI. Multiple imputation was used for missing data. Results: We identified 145,697 eligible patients, 74% were White, 18% were Black, 3.3% were Asian, and 4.6% were Other/Unknown. Across all racial categories, 9.2% were Hispanic. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180), and 10% had a delay > 60 days. There were 40,345 patients in the HR+/HER2- cohort, 56,868 in the HER2+ cohort, and 48,484 in the TNBC cohort; 12%, 9.0%, and 8.9% (p < 0.001) had a delay in NACTI, respectively. In multivariable analysis among the HR+/HER2- sub-cohort, characteristics associated with delays in NACTI included Black race (OR 1.71, 95%CI 1.57-1.86) and Hispanic ethnicity (OR 1.76, 95%CI 1.60-1.94) compared to White and non-Hispanic patients. Patients with Medicare, Medicaid, or who were uninsured were more likely to be delayed (OR 1.44 95%CI 1.30-1.58, 2.10, 95%CI 1.92-2.29, 2.28, 95%CI 1.99-2.61) compared to those with commercial insurance. Results were similar in the HER2+and TNBC cohorts, as seen (Table). Conclusions: Among patients with operable BC who received NACT, patients who were Black, Hispanic, had Medicaid or no insurance had as high as a twofold increase in odds of a delay in NACTI. Targeted interventions to address these racial and socioeconomic disparities are necessary to ensure equitable care. Multivariable logistic regression adjusted for demographic, socioeconomic, and tumor characteristics variables (n = 145,697). HR+/HER2-N= 40,345 HER2+N= 56,868 TNBCN= 48,484 OR 95%CI OR 95%CI OR 95%CI Black Race 1.71 1.57-1.86 1.89 1.74-2.04 1.90 1.76-2.06 Hispanic Ethnicity 1.76 1.60-1.94 2.18 2.00-2.36 2.00 1.80-2.21 Medicare 1.44 1.30-1.58 1.46 1.34-1.61 1.45 1.32-1.61 Medicaid 2.10 1.92-2.29 2.13 1.96-2.31 2.14 1.96-2.34 No Insurance 2.28 1.99-2.61 2.36 2.07-2.70 2.25 1.96-2.59

Comparative effectiveness analysis of survival with first-line palbociclib or ribociclib plus AI in HR + /HER2- advanced breast cancer (CEPRA study): preliminary analysis of real-world data from Thailand

BackgroundThe current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 −) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib.MethodsThis multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 − ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events.ResultsOf the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55–1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29–1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%).ConclusionThis preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 − ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.

Factors associated with delays in receipt of neoadjuvant chemotherapy in patients with operable breast cancer.

e13541 Background: Delays in neoadjuvant chemotherapy initiation (NACTI) after breast cancer (BC) diagnosis have been associated with worse outcomes. We evaluated incidence and predictors of delays of NACTI among high clinical risk patients treated with NACT on a national level. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of diagnosis. Patients who received neoadjuvant endocrine therapy were excluded. Time to chemotherapy (TTC) in days was recorded. Patients were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to identify characteristics associated with delays > 60 days from diagnosis to NACTI. Multiple imputation was used for missing data. Results: We identified 145,697 eligible patients, 74% were White, 18% were Black, 3.3% were Asian, and 4.6% were Other/Unknown. Across all racial categories, 9.2% were Hispanic. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180), and 10% had a delay > 60 days. There were 40,345 patients in the HR+/HER2- cohort, 56,868 in the HER2+ cohort, and 48,484 in the TNBC cohort; 12%, 9.0%, and 8.9% (p <0.001) had a delay in NACTI, respectively. In multivariable analysis among the HR+/HER2- sub-cohort, characteristics associated with delays in NACTI included Black race (OR 1.71, 95%CI 1.57-1.86) and Hispanic ethnicity (OR 1.76, 95%CI 1.60-1.94) compared to White and non-Hispanic patients. Patients with Medicare, Medicaid, or who were uninsured were more likely to be delayed (OR 1.44 95%CI 1.30-1.58, 2.10, 95%CI 1.92-2.29, 2.28, 95%CI 1.99-2.61) compared to those with commercial insurance. Results were similar in the HER2+ and TNBC cohorts, as seen in Table. Conclusions: Among patients with operable BC who received NACT, patients who were Black, Hispanic, had Medicaid or no insurance had as high as a twofold increase in odds of a delay in NACTI. Targeted interventions to address these racial and socioeconomic disparities are necessary to ensure equitable care. Multivariable logistic regression adjusted for demographic, socioeconomic and tumor characteristics variables (n= 145,697). [Table: see text]

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.

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

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

Fulvestrant with or without anti-HER2 therapy in patients in a postmenopausal hormonal state and with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG-C06).

The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear. We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes.

Abstract P5-02-49: Efficacy of subsequent-abemaciclib treatment after disease progression on palbociclib combined with endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer

Abstract Purpose: Currently, CDK4/6i combined with endocrine therapy (ET) has become the standard of care as first- or second-line treatment for estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, at present, there are no guidelines for the selection of appropriate treatments after disease progression on prior CDK4/6i treatment combined with ET. Therefore, this retrospective study aimed to verify the efficacy and evaluate predictive factors of clinical outcomes in the patients with ER+/HER2- MBC during subsequent-abemaciclib treatment after disease progression on prior-palbociclib combined with ET. Methods: In total, 81 patients with ER+/HER2- MBC were treated with palbociclib and ET at our medical center between December 2017 and November 2020. Among them, 25 patients who received subsequent-abemaciclib after disease progression on prior-palbociclib were included. All patients provided informed consent for the indicated treatment. Clinicopathological variables were compared using Fisher’s exact test. The Mann–Whitney U test was used to compare categorical variables. PFS and time to chemotherapy (TTC) were estimated using Kaplan–Meier analysis with 95%CIs. Results: The median age was 69 years, and four women were premenopausal. Stage IV disease occurred in 28.0% (7/25) and visceral metastases were observed in 68.0% (17/25) of the patients. The treatment line of prior-palbociclib was the first-line in 3 (12.0%), second-line in 11 (44.0%), and third- and late-line in 11 patients (44.0%). The median PFS of prior-palbociclib plus ET was 6.3 months (95%CI=5.814–6.786). Subsequent-abemaciclib combined with fulvestrant after disease progression on prior-palbociclib was administered in 64.0% (16/25) of the patients. Median numbers of previous ET and chemotherapy of subsequent-abemaciclib were 2 and 0, respectively. Subsequent-abemaciclib after disease progression on prior-palbociclib resulted in an ORR and clinical benefit rate (CBR) of 16.0% (4/25) and 44.0% (11/25), respectively (Table 1). Kaplan–Meier curve analysis showed that the median PFS was 5.3 months (95%CI=3.082–7.518). Univariate analysis revealed that the best overall response (BOR) ≥PR and progression-free interval (PFI) ≥6 months in prior-palbociclib contributed to better clinical outcomes. Moreover, in multivariate analysis, BOR to prior-palbociclib was the only independent predictive factor for PFS (HR=0.190; 95%CI=0.050–0.722; p=0.015) (Table 2). With regard to grade ≥3 TRAEs in the subsequent-abemaciclib, neutropenia and diarrhea were observed in 16.0% (4/25); appetite loss and fatigue in 12.0% (3/25); leukopenia and anemia in 8.0% (2/25); and thrombocytopenia and liver dysfunction in 4.0% (1/25) of patients. Twelve patients (48.0%) required dose reduction due to TRAEs grade ≥3 in subsequent-abemaciclib. Of them, 10 patients required one dose-level reduction and 2 needed two dose-level reductions. Three patients (12.0%) required dose discontinuation: two had uncontrollable appetite loss and nausea and one had pneumonia. Of the 25 patients, 12 were not administered any prior chemotherapy and the median TTC in those treated with subsequent-abemaciclib was 33.9 months (95%CI=11.334–56.136). Next-line treatment after disease progression on subsequent-abemaciclib in the patients who were not administered prior chemotherapy was performed in 2 (8.0%) who were treated with ET and in 12 (48.0%) who were treated with chemotherapy (1 taxane-based, 7 eribulin, and 4 oral 5-fluorouracil). The median PFS in patients treated with chemotherapy after disease progression on subsequent-abemaciclib treatment was 6.2 months (95%CI=3.484–8.916). Table 1. Best overall response rate in patients with ER+/HER- MBC who were treated with subsequent-abemaciclib after disease progression on prior-palbociclib Table 2. Univariate and multivariate analyses of the progression-free survival in patients with ER+/HER2- MBC treated with subsequent-abemaciclib after progression on prior-palbociclib Citation Format: Hirohito Seki, Taketo Nakai, Ken Shimizu. Efficacy of subsequent-abemaciclib treatment after disease progression on palbociclib combined with endocrine therapy in patients with ER-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-49.

Cytoreductive Surgery for Primary Central Nervous System Lymphoma: Is it time to consider extent of resection?

BackgroundCytoreductive surgery for Primary Central Nervous System Lymphoma (PCNSL) is controversial and is not routinely practiced. Cumulative literature in recent years, however, suggests a potential survival benefit associated with a greater extent of resection. MethodsA retrospective single institution cohort analysis of 58 consecutive patients with PCNSL was conducted between January 2011 and December 2020. Demographic, clinical, and radiographic characteristics were compared between patients with and without cytoreductive surgery following diagnosis of PCNSL. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Secondary outcome measures included time to remission (TTR), time to chemotherapy (TTC) and response to initial chemotherapy (RIC). ResultsForty-six patients (79.3 %) received stereotactic biopsy and 12 (20.6 %) underwent cytoreductive surgery. There was a trend towards longer OS (29.8 vs 22.3 months, p = 0.672), shorter TTR (4.0 vs 4.7 months, p = 0.362), and greater complete or near-complete radiographic RIC (81.8 % vs 67.6 %, p = 0.367) for patients undergoing cytoreductive surgery. This correlated with a lesser need for whole brain radiotherapy (WBRT) (8.3 % vs 19.6 %, p = 0.359). ConclusionOur data suggests a potential benefit of cytoreductive surgery for selected patients diagnosed with PCNSL. Although not statistically significant, there was a trend towards improved OS, reduced TTR, greater RIC, and reduced WBRT requirement. Further studies with better randomization and statistical power are needed to validate this correlation.

Factors Predicting 30-Day Grade IIIa-V Clavien-Dindo Classification Complications and Delayed Chemotherapy Initiation after Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: A Prospective Cohort Study.

Simple SummaryBoth surgical outcome and timely initiation of chemotherapy are essential endpoints after cytoreductive surgery for advanced-stage epithelial ovarian cancer (AEOC). This was a multicenter prospective study of 300 primary AEOC patients who underwent cytoreductive surgery. We aimed to evaluate factors associated with 30-day severe postoperative complication as according to Clavien–Dindo classification (CDC) grade ≥IIIa and delayed initiation of chemotherapy defined as time to chemotherapy (TTC) >42 days after cytoreductive surgery for primary AEOC. The understanding of these risk factors and their consequences offers an opportunity to improve future perioperative care for AEOC. Our study highlights that patient with CDC grade ≥IIIa had a significant longer median TTC compared to patients without CDC grade ≥IIIa. Intraoperative upper-abdominal visceral injury was the strongest factor associated with both CDC grade ≥IIIa and TTC >42 days. In our analysis, patient performance status was the only preoperative modifiable risk factor for TTC >42 days.Objective: The aim of this study was to evaluate factors associated with 30-day postoperative Clavien–Dindo classification (CDC) grade IIIa or greater complications and delayed initiation of chemotherapy after cytoreductive surgery (CRS) for primary advanced-stage epithelial ovarian cancer (AEOC). Methods: This was a prospective study involving 300 patients who underwent primary or interval CRS for AEOC between February 2018 and September 2020. Postoperative complications were graded according to the CDC. Logistic regression analysis was used to evaluate factors predicting CDC grade ≥IIIa and time to chemotherapy (TTC) >42 days. Results: Interval CRS was performed in 255 (85%) patients. CDC grade ≥IIIa occurred in 51 (17%) patients. In multivariable analysis, age (p = 0.036), cardiovascular comorbidity (p < 0.001), diaphragmatic surgery (p < 0.001), intraoperative urinary tract injury (p = 0.017), and upper-abdominal visceral injury (e.g., pancreas, stomach, liver, or spleen) (p = 0.012) were associated with CDC grade ≥IIIa. In 26% of cases, TTC was >42 days (median (IQR) 39 (29–50) days) in patients with CDC grade ≥IIIa versus 33 (25–41) days in patients without CDC grade ≥ IIIa (p = 0.008). The adjusted odds ratio of developing TTC >42 days was significantly higher in patients associated with WHO performance grade ≥2 (p = 0.045), intraoperative bowel injury (p = 0.043), upper-abdominal visceral injury (p = 0.008), and postoperative CDC grade ≥IIIa (p = 0.032). Conclusions: Patients with advanced age, with cardiovascular comorbidity, and who required diaphragmatic surgery had an increased adjusted odds ratio of developing CDC grade ≥IIIa complications. CDC grade ≥IIIa complications were independently associated with TTC >42 days. Proper patient selection and prevention of intraoperative injury are essential in order to prevent postoperative complications and delayed initiation of chemotherapy.

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.

Prognostic influence of an early time to chemotherapy following primary cytoreductive surgery for advanced epithelial ovarian cancer.

The current investigation analyzes the prognostic role of the time to chemotherapy (TTC) interval following primary cytoreductive surgery for patients with advanced epithelial ovarian cancer. Characteristics and outcome data for 509 consecutive patients with stage IIIB-IVB ovarian, fallopian tube, and peritoneal cancer who had primary cytoreductive surgery between January 2000 and December 2019 are utilized. A univariate Cox regression determined the association of categorical variables with progression-free survival (PFS) and overall survival (OS). Significant variables (p≤0.05) on univariate analysis were applied to Cox proportional hazard regression. The median TTC was 19 days and overall follow-up was 62.2 months. The PFS and OS were 25.5 months and 78.4 months for the study cohort plus 28.4 months and OS 84.5 months for patients rendered grossly disease-free. An early TTC (7-14 vs. 15-21 vs. 22-28 vs. >28 days) was associated with an improved PFS (41.7 vs. 30.6 vs. 18.9 vs. 17.9 months; p<0.001) and OS (132.7 vs. 104.6 vs. 56.5 vs. 48.0 months; p<0.001). The performance status, histology, disease distribution, dimension of residual disease, and categorical plus continuous TTC were predictors of PFS and OS. The use of maintenance therapy was also a predictor of PFS, and the route of chemotherapy administration was a predictor of OS. For advanced epithelial ovarian cancer, a TTC of less than 21-days was observed to independently improve the PFS and OS. A 7-14 days TTC trended towards a further extension of the OS.

Prognosis factors of Mitotane and loco-regional treatments combination in low-volume metastatic adrenocortical carcinoma

Recommended first line treatment for low burden IV ACC not amenable for radical resection is mitotane in association with multiple local treatments (M + LT). The aim of this study was to evaluate the efficacy, safety and prognostic factors of M + LT to determine patient population that might benefit the most of this strategy. This retrospective monocentric study performed from 2008 to 2020 included stage IVA patients with ≤ 2 tumoral organs who were treated with M + LT. Primary endpoint was time to chemotherapy (TTC) from mitotane initiation and secondary endpoint were overall survival (OS) and controlled disease (CD) rate. Prognosis factors were analyzed using Kaplan-Meier survival analysis and Cox's proportional hazards regression model. Thirty-four women and 26 men (60/79, 75.9%) with a median age of 48.1 years old (IQR: 38.3-59.8) were included. One hundred and nine LT were performed with a median of 2 (IQR: 1- 3). CDR was 66.6% (40/60). Median TTC was 42 [95%IC: 15 - 100] months. Oligometastatic and CD patients had significantly longer TTC (HR: 0.35, [95%IC 0.18 - 0.68]; HR: 0.27, [95%IC 0.13 - 0.54]). Oligometastatic and patients with only one metastatic organ had significantly longer OS (HR: 0.37, [95%IC 0.18 - 0.77]; HR: 0.30, [95%IC 0.14 - 0.65]). This study supports multiple and combined M + LT to achieve CD. It appears to be particularly efficient in pauci-metastatic ACC as defined by patients with less or equal to 5 metastasis and less than two metastatic organs.

234P Effect of palbociclib (PAL) + endocrine therapy (ET) on time to chemotherapy (TTC) across subgroups of patients (pts) with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC): Post hoc analyses from PALOMA-2 (P2) and PALOMA-3 (P3)

234P Effect of palbociclib (PAL) + endocrine therapy (ET) on time to chemotherapy (TTC) across subgroups of patients (pts) with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC): Post hoc analyses from PALOMA-2 (P2) and PALOMA-3 (P3)

A Cohort Study on Prognostic Factors for Laser Interstitial Thermal Therapy Success in Newly Diagnosed Glioblastoma.

Laser interstitial thermal therapy (LITT) is a promising approach for cytoreduction of deep-seated gliomas. However, parameters contributing to treatment success remain unclear. To identify extent of ablation (EOA) and time to chemotherapy (TTC) as predictors of improved overall and progression-free survival (OS, PFS) and suggest laser parameters to achieve optimal EOA. Demographic, clinical, and survival data were collected retrospectively from 20 patients undergoing LITT for newly diagnosed glioblastoma (nGBM). EOA was calculated through magnetic resonance imaging-based volumetric analysis. Kaplan-Meier and multivariate Cox regression were used to examine the relationship between EOA with OS and PFS accounting for covariates (age, isocitrate dehydrogenase-1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase hypermethylation). The effect of laser thermodynamic parameters (power, energy, time) on EOA was identified through linear regression. Median OS and PFS for the entire cohort were 36.2 and 3.5mo respectively. Patient's with >70% EOA had significantly improved PFS compared to ≤70% EOA (5.2vs 2.3mo, P=.01) and trended toward improved OS (36.2vs 11mo, P=.07) on univariate and multivariate analysis. Total laser power was a significant predictor for increased EOA when accounting for preoperative lesion volume (P=.001). Chemotherapy within 16 d of surgery significantly predicted improved PFS compared to delaying chemotherapy (9.4vs 3.1mo, P=.009). Increased EOA was a predictor of improved PFS with evidence of a trend toward improved OS in LITT treatment of nGBM. A strategy favoring higher laser power during tumor ablation may achieve optimal EOA. Early transition to chemotherapy after LITT improves PFS.

Abemaciclib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in premenopausal women: subgroup analysis from the MONARCH 2 trial

BackgroundIn MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial.MethodsThe premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS).ResultsAt the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246–0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302–0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379–1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously.ConclusionsResults of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant.Clinical trial registration: NCT02107703. Registered April 08, 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703.

Survival outcomes in patients with IDC and ILC breast cancer: A well matched single institution study.

e13056 Background: Invasive lobular carcinoma (ILC) accounts for only 10-15% of all invasive breast cancers but has distinct clinicopathologic characteristics and genomic profiles. In particular, metastatic lobular cancers (mILC) have unique sites of metastasis and it is unclear if the response to initial endocrine therapy differs from metastatic ductal cancers (mIDC). Therefore we have undertaken a single-institution, retrospective analysis to compare overall outcomes and response to initial endocrine therapy (ET) in patients (pts) with metastatic ILC and IDC. Methods: An IRB approved retrospective review of medical records was conducted evaluating pts treated for metastatic IDC and ILC at The Ohio State University Comprehensive Cancer Center from January 1, 2004 to December 31, 2014. Pts diagnosed with mIDC were matched on age, year of diagnosis, estrogen receptor/progesterone receptor and HER2 status and site of metastasis 2:1 to patients diagnosed with mILC. Overall survival (OS) was defined as the time from metastasis to death or last known follow-up. Progression-free survival (PFS) was defined as time from metastasis to progression on first-line ET. Time to chemotherapy (TTC) was defined as time from starting ET for metastasis to initiation of chemotherapy. Kaplan Meier (KM) methods were used to calculate median OS, PFS and TTC. Results: A total of one hundred sixty one pts with metastatic breast cancer were included in this analysis. The demographic features between the two groups were well balanced and included in the table below. The median OS was 2.6 yrs (95% CI: 1.55, 3.22) for mILC and 2.2 yrs (95% CI: 1.95, 2.62) for mIDC. A subset of 111 patients who started on endocrine therapy were used in the PFS and TTC analyses. The median PFS following first-line ET was 2.2 yrs (95% CI: 0.1.0, 2.7) for mILC and 1.4 yrs (95% CI: 0.91, 1.90) for mIDC. Median TTC was 2.1 yrs (95% CI: 1.71, 4.92) for mILC and 2.4 yrs (95% CI: 1.90, 4.77) for mIDC. There was no statistically significant difference in outcomes between the two groups. Conclusions: Outcomes in patients with ILC and IDC have been varied, with several studies reporting that patients with ILC have worse outcomes and response to chemotherapy. Our retrospective study examining outcomes in mILC in comparison with mIDC showed no difference in OS. Given the concern of resistance to conventional therapies in patients with lobular cancers, it is reassuring to see that the median PFS on first line ET and TTC was similar to metastatic ductal cancers.[Table: see text]

LBA18 Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC)

Phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation due to PIK3CA mutations contributes to poor survival in patients (pts) with HR+, HER2– ABC (Mosele 2020). In the phase III SOLAR-1 trial of pts with progression on/after aromatase inhibitor (AI), the PI3Kα inhibitor ALP together with FUL significantly improved progression-free survival (PFS) in the PIK3CA-mutant (mut) cohort (HR 0.65; 95% CI 0.50-0.85; P<0.001; median [m] PFS 11.0 mo with ALP + FUL vs 5.7 mo with placebo [PBO] + FUL), a population with poor prognosis. At final PFS analysis, the first interim OS results were immature. Men/postmenopausal women (N=572) with HR+, HER2– ABC with no prior chemotherapy treatment (tx) and whose disease progressed on/after AI were randomized 1:1 to receive ALP (300 mg PO QD) or PBO, + FUL (500 mg IM on D1 and D15 of C1 then D1 of each 28-d cycle) and stratified by presence of lung and/or liver metastases and prior cyclin-dependent kinase 4/6 inhibitor. OS in the PIK3CA-mut cohort, a key secondary endpoint, was evaluated by Kaplan-Meier methodology; a 1-sided stratified log-rank test was performed with an O’Brien-Fleming efficacy boundary of P≤0.0161. With mOS follow-up of 30.8 mo, mOS was 39.3 mo (95% CI 34.1-44.9) with ALP + FUL and 31.4 mo (95% CI 26.8-41.3) with PBO + FUL (HR 0.86; 95% CI 0.64-1.15; P=0.15); OS did not cross the prespecified boundary. Median time to chemotherapy (TTC) was 23.3 mo (95% CI 15.2-28.4) with ALP + FUL and 14.8 mo (95% CI 10.5-22.6) with PBO + FUL (HR 0.72; 95% CI 0.54-0.95). In pts with lung and/or liver metastases, mOS was 37.2 mo (95% CI 28.7-43.6) with ALP + FUL and 22.8 mo (95% 19.0-26.8) with PBO + FUL (HR 0.68; 95% CI 0.46-1.00). No new safety signals were observed with longer follow-up. Though not statistically significant, OS was prolonged by a clinically relevant ≈8 mo with ALP when added to FUL in HR+, HER2−, PIK3CA-mut ABC. mTTC was also prolonged with ALP + FUL vs PBO + FUL. Coupled with the statistically and clinically significant PFS, these data further support ALP + FUL in this poorer prognostic population of pts with PIK3CA-mut ABC.

Abstract 766: Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant

Abstract BACKGROUND: Mutations (mt) in PIK3CA have been implicated in resistance to endocrine therapy (ET) in HR+ advanced breast cancer (ABC). In the MONARCH 2 study the addition of abemaciclib to fulvestrant (fulv) demonstrated a clinically meaningful and statistically significant median overall survival (OS) benefit of 9.4 months (mos) (HR 0.757, p=0.01), in addition to prolonging time to chemotherapy (TTC) (Sledge et al. JAMA Oncology 2019). We previously showed that abemaciclib plus fulv demonstrated improvement in progression-free survival (PFS) regardless of PIK3CA mt status, with a numerically larger magnitude of benefit for patients (pts) with PIK3CA mt in baseline circulating tumor DNA (ctDNA; Tolaney et al. AACR 2019). Here, we assessed the OS, TTC, and chemotherapy-free survival (CFS) in patients with and without PIK3CA mt in MONARCH 2. METHODS: MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib plus fulv or placebo plus fulv in pre-/perimenopausal (with ovarian suppression) and postmenopausal women with ET resistant HR+, HER2- ABC. Results of PIK3CA mt status (E542K; E545K; H1047L; H1047R) from baseline ctDNA were available for 238 patients. Exploratory analyses of OS, TTC, and CFS were assessed in pts with and without PIK3CA mt using the Cox Interaction Model including treatment, PIK3CA mt status and treatment by PIK3CA interaction term. RESULTS: Abemaciclib plus fulv demonstrated a similar OS benefit for pts with PIK3CA mt (HR: 0.57; 95% CI: 0.34, 0.96) and for pts with PIK3CA wild-type (HR: 0.56; 95% CI: 0.34, 0.91) compared with placebo plus fulv. Median TTC and CFS were longer in the abemaciclib plus fulv arm compared with the placebo plus fulv arm both in pts with detectable PIK3CA mt and in pts without PIK3CA mt, as shown in Table 1. Table 1.PIK3CA mutantPIK3CA wild-typeAbemaciclib +Fulvestrant (n=58)Placebo + Fulvestrant (n=38)Hazard Ratio (95% CI)Abemaciclib + Fulvestrant (n=91)Placebo + Fulvestrant (n=51)Hazard Ratio (95% CI)Interaction p-valueOverall Survival Median (95% CI)44.5 mos (31.0, NR)33.8 mos (24.2, 41.7)0.57 (0.34, 0.96)55.5 mos (47.7, 55.5)41.7 mos (29.4, 49.7)0.56 (0.34, 0.91)0.949Time to Chemotherapy Median (95% CI)39.2 mos (24.6, NR)19.2 mos (6.7, NR)0.65 (0.37, 1.18)NR (34.3, NR)19.2 mos (12.0, 31.1)0.50 (0.31, 0.78)0.463Chemotherapy-Free Survival Median (95% CI)25.8 mos (16.0, 42.1)12.8 mos (5.2, 33.2)0.63 (0.39, 1.03)36.9 mos (20.7, NR)19.2 mos (12.0, 29.4)0.53 (0.35, 0.80)0.588CI = confidence interval; NR = not reached; mos = months CONCLUSIONS: In this exploratory analysis of MONARCH 2, abemaciclib plus fulv demonstrated benefit in OS, TTC, and CFS in patients with and without PIK3CA mutations. Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Hatem Soliman, Lacey M. Litchfield, Hong Wang, Sameera R. Wijayawardana, Valerie M. Jansen, George W. Sledge. Clinical outcomes of patients with PIK3CA mutations in circulating tumor DNA: Update from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 766.

Abstract P2-14-07: Association between initiation of adjuvant chemotherapy beyond 30 days following surgery and overall survival among patients with triple-negative breast cancer

Abstract Background: The optimal time between surgery and initiation of adjuvant chemotherapy is unknown, though delayed time to chemotherapy (TTC) is associated with decreased outcomes of breast cancer patients. Recently, studies have suggested that the association might be subtype-dependent and that TTC within 30 days should be warranted particularly in high-risk triple-negative breast cancer (TNBC) patients. Objective: To determine the extent to which TTC beyond 30 days is associated with reduced overall survival (OS) in TNBC patients. Methods: Using the population-based nationwide Netherlands Cancer Registry we identified TNBC patients diagnosed between 2006 and 2014 who received adjuvant chemotherapy. We distinguished between patients who underwent breast-conserving surgery (BCS) versus mastectomy given the difference in preoperative characteristics and outcomes. Median (95% confidence interval) follow-up was 82.9 (80.5-86.5) and 81.4 (79.5-83.9) months, respectively. Main outcomes and measures: The association between TTC beyond 30 days and OS was estimated with hazard ratios (HR) using propensity-score matched Cox proportional hazard analyses separately for patients who underwent BCS and mastectomy. Results: In total, 3016 patients were included, of whom 1079 (35.8%) underwent BCS and 1937 (64.2%) underwent a mastectomy. In matched patients who underwent BCS, 10-year OS was significantly better for patients with TTC within 30 days compared to patients with TTC beyond 30 days (84.4% vs. 76.9%, P=0.001). Patients with TTC beyond 30 days were more likely than those with TTC within 30 days to die within 10 years after surgery (HR 1.69 (95% CI 1.22-2.34), P=0.002). In matched patients who underwent mastectomy, there was no difference in 10-year OS between those with TTC within or beyond 30 days (74.5% vs. 74.7%, P=0.716), nor an increased risk of death for those with TTC beyond 30 days (HR 1.04 (95%-CI 0.84-1.28), P=0.716). In both populations, the associations were independent of adjuvant radiotherapy. Conclusions: The current results suggest that initiation of chemotherapy beyond 30 days is associated with decreased OS in TNBC patients who underwent BCS; no association was observed for patients who underwent a mastectomy. Therefore, timelier initiation of chemotherapy in TNBC patients undergoing BCS seems warranted. Citation Format: Erik Heeg, Perla J. Marang-van de Mheen, Marissa C. Van Maaren, Kay Schreuder, Rob A.E.M. Tollenaar, Sabine Siesling, Monique E.M.M. Bos, Marie-Jeanne T.F.D. Vrancken Peeters. Association between initiation of adjuvant chemotherapy beyond 30 days following surgery and overall survival among patients with triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-07.