Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this ...combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
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•Combination checkpoint blockade leads to impaired efficacy with low tumor burden•This impairment results from IFN-γ-mediated deletion of tumor-reactive T cells•AICD is an immune-intrinsic mechanism of therapeutic resistance to checkpoint blockade
Although immune checkpoint blockades are being combined to enhance anti-tumor efficacy, Pai et al. find that this approach can lead to therapy resistance in the low tumor burden setting. Potent immunotherapy in this setting overdrives tumor-reactive T cells, leading to their death. Optimal immunotherapy could therefore be disease-context dependent.
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Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant ...therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. Table: see text
Patients with breast cancer frequently experience escalation of anxiety after completing curative treatment.
This study evaluated the acceptability and psychological impact of a 1-day workshop to ...emphasize behavioral strategies involving intention and self-efficacy.
Breast cancer survivors who attended a 1-day Pathways for Survivors workshop provided feedback and completed electronic quality of life (QOL) questionnaires at baseline, 1 and 6 weeks, and 6 months after the workshop. Attendees' baseline QOL scores were compared to follow-up (FUP) scores. Scores from patients receiving routine FUP care were also compiled as a reference population.
In total, 77 patients attended 1 of 9 workshops. The mean satisfaction score was 9.7 out of 10 for the workshop and 9.96 out of 10 for the moderator. Participants' baseline mean Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scores were 57.8 (SD 6.9) and 55.3 (SD 7.5), respectively, which were significantly higher than those of patients receiving routine FUP care (49.1, SD 8.3 and 47.3 SD 8.0, respectively). PROMIS anxiety and depression scores decreased, and the Happiness Index Profile (HIP-10) score-measuring intention and resiliency-increased significantly at 1- and 6-week FUPs.
The Pathways for Survivors program was favorably received. Anxiety and depression decreased significantly at 1- and 6-weeks after the workshop and remained below baseline at 6 months. Increased HIP-10 scores suggest that patients acquired and implemented skills from the workshop. A 1-day workshop led by a lay moderator significantly improved several psychological measures, suggesting that it may be a useful and time-efficient strategy to improve QOL in breast cancer survivors. We are investigating whether an abbreviated "booster" of the intervention at a later date could further improve and maintain QOL gains.
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Background: Patients (pts) with metastatic breast cancer (MBC) and leptomeningeal disease (LMD) have a poor prognosis with limited therapeutic options. It is critical to better understand the ...risk factors and natural history of this condition, including pts in a modern cohort. Methods: In this single center retrospective cohort study, we identified pts with radiographic and/or cytologic evidence of LMD who received care at the University of California San Francisco (UCSF) from 2000-2023. To identify pts, we used the UCSF Pathology Database, the UCSF Radiation Oncology Database, and EMERSE, a searchable copy of the medical record. We conducted chart review to identify demographic and clinical characteristics, treatment history, and overall survival (OS). Results: 106 pts with MBC and radiographic and/or cytologic evidence of LMD were identified. All but one pt was female (n=105; 99.1%); most pts were non-Hispanic (n=93, 87.7%) and white (n=74, 69.8%). Median age at the time of MBC diagnosis was 51.9 years; 25 pts (20%) had de novo metastatic disease. Most pts had invasive ductal carcinoma (n=71, 66.9%), with invasive lobular carcinoma making up 21.7% (n=23) of cases. Pts presented with the following BC subtypes: Hormone receptor (HR) positive, HER2 negative (n=50, 47.1%), HR+/HER2+ (n=19, 17.9%), HR-/HER2+ (n=9, 8.5%), and triple negative (TNBC; n=23, 21.7%). Most pts had brain metastasis (n=78, 73.6%) in addition to LMD. Median time from diagnosis of MBC to LMD was 17.6 months (0-101.2 months). Pts received a median of 3.0 lines of therapy prior to the diagnosis of LMD (range 0-11.0) and 1.0 lines after the diagnosis of LMD (range 0-4.0). Many pts received intrathecal (IT) therapy (n=42, 39.6%) and/or whole brain radiation therapy or spinal radiation (n=49, 46.2%). Median OS from the diagnosis of LMD to death was 3.3 months. There was no significant difference in median OS by subtype: HR+/HER2- 3.5 months, HER2+ 4.7 months, and TNBC 2.2 months (p=0.45). There was no significant difference in median OS by histology: ductal (3.3 months) vs. lobular (4.7 months) (p=0.56). Pts who received IT therapy survived longer than those not treated with IT therapy (4.7 vs. 2.5 months, p=0.01). There was no significant difference in median OS among pts diagnosed with LMD between 2000-2015 (2.9 months) vs. 2016-2023 (3.6 months) (p=0.74). Conclusions: This study represents one of the largest reported case series of pts with MBC and LMD, including a more modern cohort. There appeared to be an over-representation of pts with lobular cancer and those with de novo metastatic disease. Most pts had brain metastases in addition to LMD. Survival was short in all pts, particularly those who did not receive IT therapy. There was no significant difference in median OS in pts diagnosed with LMD from 2000-2015 vs. 2016-2023; this remains an area of unmet clinical need.
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Background: Immune checkpoint inhibitors (ICI) have improved outcomes in patients with breast cancer, however management of immune-related adverse events (irAE) remains a challenge. Delayed ...irAE after cessation of ICI have been observed. We sought to characterize delayed irAE occurring at our center. Methods: We identified patients with breast cancer who received ICI at UCSF using ICD codes specific to ICI administration between 2012-2018. After IRB approval, charts were reviewed for delayed irAE. Delayed irAE were defined as occurring >60 days after the last ICI dose; events were counted as irAE if provider notes indicated that the toxicity was/possibly was related to ICI. Data were securely stored using RedCap. Results: We reviewed 100 consecutive patients who underwent ICI (56 metastatic, 44 localized) of which 11 (2 (4%) with metastatic disease, 9 (20.5%) with localized disease) developed delayed irAE. Median age was 42. 3 patients had HR+ disease, 8 patients had triple negative disease. 10 patients received ICI on a clinical trial, including 9 on the neoadjuvant ISPY2 trial. 10 patients received pembrolizumab; 1 received durvalumab. Median number of ICI doses was 4, median follow-up time after last ICI infusion was 46 months. 14 incidences of delayed irAEs were identified (Table). 9 patients experienced both delayed and early irAE. 7 patients experienced 2 irAEs: 1) three dermatitis & delayed hypophysitis/adrenal insufficiency (AI) 2) one AI & delayed thyroiditis 3) one dermatitis and delayed colitis 4) one elevated transaminases & delayed colitis 5) one delayed elevated transaminases and delayed thyroiditis. One patient had 3 irAEs (thyroiditis, delayed AI & delayed arthralgia) and one patient had 4 irAE (colitis, dermatitis, delayed elevated transaminases & delayed neutropenia). Of the 9 patients with > 1 irAE, 3 experienced > 1 delayed irAE (thyroiditis + elevated transaminases; arthralgia + AI; elevated transaminases + neutropenia). All irAE either self-resolved, resolved with systemic steroids or indefinite hormone replacement. 6 irAEs required systemic steroids, not including hydrocortisone replacement for AI. Conclusions: Delayed irAE may occur months after ICI cessation and require awareness for identification. Patients who experience irAE may be more likely to develop additional irAE at either a delayed or earlier time point. Most patients with delayed irAE experienced an irAE at an early time point. Future directions include identifying risk factors for early and delayed irAEs to inform treatment decisions. Table: see text
To evaluate the efficacy of crofelemer, a first in class anti-secretory anti-diarrheal agent, to manage neratinib-induced diarrhea in patients with early-stage breast cancer taking adjuvant ...neratinib.
This single center, open label trial enrolled patients with Stage 2 to 3 HER2+ breast cancer taking adjuvant neratinib. One cohort took prophylactic crofelemer 125 mg bid and loperamide in the first 2 cycles, and as needed in subsequent cycles. The second cohort took dose-escalated neratinib with loperamide as needed (DE cohort). The primary endpoint was incidence of grade ≥ 3 diarrhea in the first 2 cycles.
Seven patients in the crofelemer cohort and 4 in the DE cohort were enrolled. In the first 2 cycles, 2 patients (29%) in the crofelemer cohort and 2 patients (50%) in the DE cohort experienced grade 3 diarrhea lasting 1 day on average. After cycle 2, no additional patients in either cohort had grade 3 diarrhea. Five of 7 patients controlled diarrhea with crofelemer alone. There were no grade 4 diarrhea events in either cohort. Three patients in the crofelemer cohort dose-reduced neratinib due to diarrhea in the first 2 cycles. Patients in the crofelemer cohort had an average of 0.58 diarrhea episodes/day. 82% experienced constipation, all grade 1.
This is the first study to investigate crofelemer for neratinib-induced diarrhea and demonstrates crofelemer activity in this setting. Further investigation of crofelemer for diarrhea secondary to cancer treatment is needed.
Neratinib in patients with early stage HER2 breast cancer has been shown to improve survival but diarrhea remains a challenging toxicity. We evaluated the use of prophylactic crofelemer, a anti-secretory diarrheal, in the treatment of neratinibinduced diarrhea. 7 patients underwent treatment with crofelemer and loperamide, 5 of which were able to control diarrhea with crofelemer alone. This study shows activity of crofelemer in the treatment of neratinib-induced diarrhea.
Abstract Background The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers ...who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. Materials and Methods This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. Results Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. Conclusion Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.
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Background: Pseudocirrhosis is a term used to describe changes in hepatic contour that mimic cirrhosis radiographically, but lack the classic pathologic features of cirrhosis. This radiographic ...finding is frequently found in patients with metastatic breast cancer (MBC); the pathophysiology and clinical consequences are poorly understood. The objective of this study is to describe the patient, tumor, and treatment characteristics associated with pseudocirrhosis, and to assess associated clinical outcomes. Methods: In this retrospective study, we identified patients with MBC and imaging findings consistent with pseudocirrhosis (diffuse liver contour abnormalities) who were treated at the University of California San Francisco from 2002-2021. We used chart extraction and radiology review to determine demographic characteristics, treatment history, response to treatment, imaging features, and complications of pseudocirrhosis. Comparisons between groups were made using the unpaired t-test or two-sided Fisher’s exact test. Results: 120 patients with MBC and radiographic evidence of pseudocirrhosis were identified with the following BC subtypes: Hormone receptor (HR) positive, HER2 negative (n = 99, 82.5%), HR+/HER2+ (n = 14, 11.7%), HR-/HER2+ (n = 3, 2.5%), and triple negative (TNBC; n = 4, 3.3%). All patients with pseudocirrhosis had liver metastases (n = 120, 100.0%) and 82.5% (n = 99) had > 15 lesions. Median time from diagnosis of MBC to radiographic evidence of pseudocirrhosis was 29.2 months. Most patients received chemotherapy for MBC prior to the finding of pseudocirrhosis (n = 111, 92.5%) with median 2.0 lines. Pseudocirrhosis was observed in the setting of stable or responding disease in 50% of patients (n = 60). Patients received a median of 1.0 line of additional therapy after pseudocirrhosis diagnosis, with a median overall survival of 7.9 months from pseudocirrhosis to death. Sequelae of pseudocirrhosis included the radiographic finding of ascites (n = 97, 80.8%), gastric/esophageal varices (n = 68, 56.7%), splenomegaly (n = 26, 21.7%), GI bleeding (n = 12, 10.0%), or hepatic encephalopathy (n = 11, 9.2%). Radiographic evidence of ascites was associated with a shorter survival from MBC diagnosis compared to no ascites (42.8 vs. 76.2 months, p = < 0.001). GI/Hepatology consultation was uncommon (n = 9, 7.5%). Conclusions: To our knowledge, this is the largest reported case series of patients with MBC and pseudocirrhosis. Nearly all patients had HR+ disease and extensive liver metastases. Pseudocirrhosis was frequently observed in the setting of responding or stable disease, creating complexity in management. Survival was short in all patients, particularly patients with radiographic evidence of ascites. Further understanding of the pathogenesis of and risk factors for pseudocirrhosis could help improve outcomes for this condition.
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