Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a ...method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments.
The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov–Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov–Smirnov, Mann–Whitney, and Fisher’s exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test.
In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival.
TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.
•We developed a statistical tool to compare two RCB distributions giving a single metric named Treatment Efficacy Score (TES).•TES identifies a regimen with a higher pCR rate and also captures the downstaging effects of treatment on residual cancer.•TES correlates with event-free and distant recurrence-free survival better than pCR rate difference.•TES could serve as a better early surrogate for trial arm level survival than pCR rate difference.•We created a free web tool (http://dssoftware.aei.polsl.pl/TES/TES/) to plot RCB distributions and calculate TES statistic.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II ...trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer.
Eligible patients with HR+/HER2− stage II–III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025.
Overall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction.
Adjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population.
NCT02040857.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist ...conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts.
In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2−) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability.
A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate 13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124, and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients.
Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.
•Lasofoxifene showed antitumor activity in patients with ESR1-mutated mBC that progressed on an AI plus a CDK4/6i.•Lasofoxifene numerically improved PFS (5.6 versus 3.7 months) and clinical benefit rate (37% versus 22%) versus fulvestrant.•Lasofoxifene was well-tolerated with no unexpected safety signals.•Lasofoxifene reduced ESR1 MAF, including Y537S MAF, in more patients than fulvestrant, exhibiting target engagement.•Lasofoxifene may be a promising endocrine therapy backbone for ESR1-mutated mBC in a post-CDK4/6i setting.
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GEOZS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were ...undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMD
), and 5 patients are deemed not to have LMD based on similar criteria (LMD
). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45
cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8
T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of T
than patients without LMD. Interestingly, the frequency of partially exhausted CD8
T cells (CD38
TIM3
) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8
T cells, which may offer an important therapeutic target.
Radiotherapy had the strongest association with soft tissue sarcoma development in the KP cohort (relative risk RR 8·1 95% CI 1·1-60·4; p=0·0052), with additional risk factors, including chemotherapy ...(alkylating agents and other sarcomas, RR 7·7 1·2–150·8; p=0·026; anthracyclines and angiosarcoma, 3·6 1·0–13·3; p=0·058), and hypertension (4·8 1·3–17·6; p=0·017) and diabetes (5·3 1·4–20·8; p=0·036) for angiosarcoma. Modelling studies have predicted increased risks for secondary cancer with VMAT versus three-dimensional conformal radiotherapy (3D-CRT),2 but a 2020 National Cancer Database study of more than 450 000 patients,3 with a median follow-up of 5·1 years (range 2·0–13·8 years), found no excess risk in secondary cancers with IMRT versus 3D-CRT, but the study did find a reduction in risk (adjusted odds ratio 0·62 95% CI 0·41–0·95) with use of protons compared with IMRT in patients with breast cancer followed up for more than 5 years. Increased genetic screening and identification of inherited mutations also has the potential to tailor treatments for patients at high risk of secondary cancers from radiotherapy.9 In addition to the rare risk of soft tissue sarcoma highlighted in the current study,1 breast cancer radiotherapy carries short-term risks, such as fatigue and dermatitis, and long-term risks for cosmesis, as well as to the heart and other organs in the radiotherapy field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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