Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for
mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover ...mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function
mutations in 25% of patients with resistance.
activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight
loss as a recurrent mechanism of resistance to PI3Kα inhibition.
Purpose
Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in
TP53
, have an over 50% risk of developing breast cancer by age 70. Patients with LFS ...are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy.
Methods
A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline
TP53
mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses.
Results
We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2–20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort.
Conclusions
We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.
Patients with cancer are often at elevated risk for cardiovascular disease due to overlapping risk factors and cardiotoxic anticancer treatments. Their cancer diagnoses may be the predominant focus ...of clinical care, with less of an emphasis on concurrent cardiovascular risk management. Widely adopted technology platforms, including electronic health records and mobile devices, can be leveraged to improve the cardiovascular outcomes of these patients. These technologies alone may be insufficient to change behavior and may have greater impact if combined with behavior change strategies. Behavioral economics is a scientific field that uses insights from economics and psychology to help explain why individuals are often predictably irrational. Combining insights from behavioral economics with these scalable technology platforms can positively impact medical decision-making and sustained healthy behaviors. This review focuses on the principles of behavioral economics and how “nudges” and scalable technology can be used to positively impact clinician and patient behaviors.
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•Patients with cancer are often at increased risk of cardiovascular disease.•Electronic health records and mobile devices are scalable technology platforms.•Insights from behavioral economics combined with scalable technology platforms can nudge clinician decisions and improve patient behaviors.•Combining technology with insights from behavioral economics can help address unmet needs of cardio-oncology patients.
Introduction
Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 ...negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT.
Case Report
Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine.
Management & Outcome
Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up.
Discussion
Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.
Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are ...unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials.
Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.
BACKGROUND18FFluorThanatrace (18FFTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a ...biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via 18FFTT PET before and after initiation of PARPi treatment and in vitro via 125IKX1 (an analog of 18FFTT) binding to surgically removed breast cancer.RESULTSThirteen patients had baseline 18FFTT PET. Nine of these then had resection and in vitro evaluation of 18FFTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had 18FFTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo 18FFTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, 18FFTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in 125IKX1 binding.CONCLUSION18FFTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test 18FFTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDINGMetavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.
Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of ...cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC.
Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro.
The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e'). Histological staining with Masson's trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells.
An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.
•Identification of TP53 pathogenic variants at lower-than-expected variant allele frequencies (VAF) for Li Fraumeni Syndrome (LFS) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis ...(CH).•Constitutional mosaic LFS and clonal hematopoiesis (CH) represent completely different entities with regards to cancer risk, family implications and management.•In a cancer genetics specialty clinic, approximately 17 % of TP53 genetic testing results were “mosaic”.•Ancillary tissue testing can help confirm a diagnosis of mosaic LFS.•Half of mosaic TP53 results may be postzygotic mosaicism (PZM) and half clonal hematopoiesis (CH).
Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.
Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.
Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of “mosaic”. A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.
Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.
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The σ
receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using
-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1
)-yl)butyl)-2-(2-
...F-fluoroethoxy)-5-methylbenzamide (
F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of
F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether
F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression.
Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of
F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of
F-ISO-1 was quantitated by SUV
and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67.
Tumor SUV
(median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUV
, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUV
greater than the low-Ki-67 (<20%) group (
= 0.02). SUV
exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46,
= 0.01,
= 29). Partial-volume-corrected SUV
was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51,
= 0.02,
= 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 (
> 0.05).
F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.
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