Evaluation of the clinical impact of the differences between planned and delivered dose in prostate cancer radiotherapy based on CT-on-rails IGRT and patient-reported outcome scores.

PURPOSE: To estimate the clinical impact of differences between delivered and planned dose using dose metrics and normal tissue complication probability (NTCP) modeling. METHODS: Forty-six consecutive patients with prostate adenocarcinoma between 2010 and 2015 treated with intensity-modulated radiation therapy (IMRT) and who had undergone computed tomography on rails imaging were included. Delivered doses to bladder and rectum were estimated using a contour-based deformable image registration method. The bladder and rectum NTCP were calculated using dose-response parameters applied to planned and delivered dose distributions. Seven urinary and gastrointestinal symptoms were prospectively collected using the validated prostate cancer symptom indices patient reported outcome (PRO) at pre-treatment, weekly treatment, and post-treatment follow-up visits. Correlations between planned and delivered doses against PRO were evaluated in this study. RESULTS: Planned mean doses to bladder and rectum were 44.9 ± 13.6 Gy and 42.8 ± 7.3 Gy, while delivered doses were 46.1 ± 13.4 Gy and 41.3 ± 8.7 Gy, respectively. D10cc for rectum was 64.1 ± 7.6 Gy for planned and 60.1 ± 9.3 Gy for delivered doses. NTCP values of treatment plan were 22.3% ± 8.4% and 12.6% ± 5.9%, while those for delivered doses were 23.2% ± 8.4% and 9.9% ± 8.3% for bladder and rectum, respectively. Seven of 25 patients with follow-up data showed urinary complications (28%) and three had rectal complications (12%). Correlations of NTCP values of planned and delivered doses with PRO follow-up data were random for bladder and moderate for rectum (0.68 and 0.67, respectively). CONCLUSION: Sensitivity of bladder to clinical variations of dose accumulation indicates that an automated solution based on a DIR that considers inter-fractional organ deformation could recommend intervention. This is intended to achieve additional rectum sparing in cases that indicate higher than expected dose accumulation early during patient treatment in order to prevent acute severity of bowel symptoms.

Cancer in sub-Saharan Africa: a Lancet Oncology Commission.

In sub-Saharan Africa (SSA), urgent action is needed to curb a growing crisis in cancer incidence and mortality. Without rapid interventions, data estimates show a major increase in cancer mortality from 520 348 in 2020 to about 1 million deaths per year by 2030. Here, we detail the state of cancer in SSA, recommend key actions on the basis of analysis, and highlight case studies and successful models that can be emulated, adapted, or improved across the region to reduce the growing cancer crises. Recommended actions begin with the need to develop or update national cancer control plans in each country. Plans must include childhood cancer plans, managing comorbidities such as HIV and malnutrition, a reliable and predictable supply of medication, and the provision of psychosocial, supportive, and palliative care. Plans should also engage traditional, complementary, and alternative medical practices employed by more than 80% of SSA populations and pathways to reduce missed diagnoses and late referrals. More substantial investment is needed in developing cancer registries and cancer diagnostics for core cancer tests. We show that investments in, and increased adoption of, some approaches used during the COVID-19 pandemic, such as hypofractionated radiotherapy and telehealth, can substantially increase access to cancer care in Africa, accelerate cancer prevention and control efforts, increase survival, and save billions of US dollars over the next decade. The involvement of African First Ladies in cancer prevention efforts represents one practical approach that should be amplified across SSA. Moreover, investments in workforce training are crucial to prevent millions of avoidable deaths by 2030. We present a framework that can be used to strategically plan cancer research enhancement in SSA, with investments in research that can produce a return on investment and help drive policy and effective collaborations. Expansion of universal health coverage to incorporate cancer into essential benefits packages is also vital. Implementation of the recommended actions in this Commission will be crucial for reducing the growing cancer crises in SSA and achieving political commitments to the UN Sustainable Development Goals to reduce premature mortality from non-communicable diseases by a third by 2030.

Clinical characteristics associated with racial disparities in endometrial cancer outcomes: A surveillance, epidemiology and end results analysis.

OBJECTIVES: Racial disparities exist for endometrial cancer. We examined patterns of care and factors associated with poor outcomes for Black women with endometrial cancer. METHODS: We studied 110,826 endometrial cancer patients diagnosed between 1980 and 2008 with minimum 5years follow-up in the Surveillance, Epidemiology, and End Results database. Trends over time in sociodemographics, disease characteristics and treatment factors were analyzed over four eras: 1980-1989, 1990-1999, 2000-2004, 2005-2008. Using sequential Cox proportional hazards and Fine-Gray competing risk models we determined the association between potential explanatory variables and racial disparities in all-cause mortality (ACM) and cancer-specific mortality (CSM), respectively. RESULTS: Clinical characteristics of Black and White women were relatively constant over time. The unadjusted hazard ratio (HR) among Black women for ACM and CSM were 1.91 (95% CI 1.86-1.97) and 2.35 (95% CI 2.26-2.43), respectively. Adjustment for sociodemographics, disease presentation and surgery decreased the ACM HR to 1.29 (95% CI 1.24-1.34) and CSM HR to 1.18 (95% CI 1.11-1.26) without further decrease from controlling for radiotherapy. Black women were less likely to undergo operative management even when prescribed. Total and radical hysterectomy, and vaginal brachytherapy (VBT) were associated with improved ACM and CSM. Combination VBT and external beam radiotherapy was associated with improved ACM. CONCLUSION: Racial disparities in endometrial cancer survival are predominantly attributable to increased advanced stage, high-grade and aggressive histologic subtype tumors and differential use of surgery in Black women. Intensified surgical and radiation treatment is associated with improved survival, raising questions about treatment adaptations that may potentially reduce survival disparities.

Poor Prognosis among Radiation-Associated Bladder Cancer Is Defined by Clinicogenomic Features.

Radiotherapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control patients (CTRL; n = 41) and patients with RT-associated bladder cancer (n = 41). RT- and CTRL-specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, whereas CTRL tumors were enriched for CDKN2A mutation. Globally, there were an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/smoking), and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include a short tumor latency, smoking status, the presence of the smoking and X-ray therapy mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest at least two potential pathways leading to RT-associated bladder cancer: The first occurs in the setting of field cancerization related to smoking or preexisting genetic alterations and leads to the development of more aggressive bladder tumors, and the second involves RT initiating the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease. SIGNIFICANCE: Clinicogenomic analysis of radiation-associated bladder cancer uncovered mutational signatures that, in addition to a short tumor latency, smoking, and CDKN2A loss, are associated with a poor outcome. These clinical and genomic features provide a potential method to identify patients with prostate cancer who are at an increased risk for the development of aggressive bladder cancer following prostate RT.

Prospective Characterization of Circulating Tumor Cell Kinetics in Patients With Oligometastatic Disease Receiving Definitive Intent Radiation Therapy.

PURPOSE: There are currently no predictive molecular biomarkers to identify patients with oligometastatic disease (OMD) who will benefit from definitive-intent radiation therapy (RT). We prospectively characterized circulating tumor cell (CTC) kinetics in patients with OMD undergoing definitive-intent RT. METHODS: This prospective correlative biomarker study included patients with any solid malignancy ≤5 metastatic sites in ≤3 anatomic organ systems undergoing definitive-intent RT to all disease sites. Circulating tumor cells (CTCs) were captured and enumerated using a biomimetic cell rolling and nanotechnology-based assay functionalized with antibodies against epithelial cell adhesion molecule, against human epidermal growth factor receptor 2, and against epidermal growth factor receptor before and during RT and at follow-up visits up to 2 years post-RT. RESULTS: We enrolled 43 patients with a median follow-up of 14.3 months. The pretreatment CTC level (cells captured/mL) was not associated with the number of disease sites (median one metastatic site/patient, range 1-5) or metastasis location (bone, brain, visceral) on Wilcoxon signed-rank test, P > .05. Post-RT, 56% of patients received systemic therapy, and 72% of patients experienced subsequent local or systemic progression. For 90% of patients, a CTC level <15 within 130 days post-RT corresponded to a durable control of irradiated lesions. Patients with a favorable versus an unfavorable clearance profile experienced significantly longer progression-free survival after RT (median 13 v 4 months, log-rank test, P = .0011). On logistic regression, CTC level >15 at a given time point was associated with clinical disease progression within the subsequent 6 months (odds ratio 3.31, P = .007). In 26% of patients with disease progression, a CTC level >15 preceded radiographic or clinical progression. CONCLUSION: CTCs may serve as a biomarker for disease control in OMD and may predict disease progression before standard assessments for patients receiving diverse cancer-directed therapies.

Associations With Virtual Visit Use Among Patients Receiving Radiation Therapy.

Purpose: The objective of this study was to test for patient characteristics associated with virtual versus office visits among radiation oncology patients. Methods and Materials: Using the electronic health record, we extracted encounter data and corresponding patient information for the 6 months before and 6 months of COVID-19-enabled virtual visits (October 1, 2019, to March 22, 2020 vs March 23, 2020, to September 1, 2020) at a National Cancer Institute-Designated Cancer Center. Encounters during COVID-19 were categorized as in-person or virtual visits. We compared patient demographic variables including race, age, sex, marital status, preferred language, insurance status, and tumor type during the pre-COVID-19 period as a baseline versus during the COVID-19 period. Multivariable analyses examined associations between these variables and virtual visit use. Results: We analyzed 4974 total encounters (2287 before COVID-19 and 2687 during COVID-19) for 3960 unique patients. All (100%) pre-COVID-19 encounters were in-person. During COVID-19, 21% of encounters were via virtual visits. There were no differences identified in pre- versus during-COVID-19 patient characteristics. However, we found significant differences in patient characteristics for in-person versus virtual encounters during COVID-19. On multivariable analysis, virtual visit use was less common among patients who were Black versus White (odds ratio [OR], 0.75; 95% CI, 0.57-0.99; P = .044) and not married versus married (OR, 0.76; 95% CI, 0.59-0.98; P = .037). Patients with head and neck (OR, 0.63; 95% CI, 0.41-0.97; P = .034), breast (OR, 0.36; 95% CI, 0.21-0.62; P ≤ .001), gastrointestinal/abdominal (OR, 0.31; 95% CI, 0.15-0.63; P = .001), or hematologic malignancy (OR, 0.20; 95% CI, 0.04-0.95; P = .043) diagnoses were less likely to be scheduled for virtual visits relative to patients with genitourinary malignancy. No Spanish-speaking patients engaged in a virtual visit. We did not identify differences in the insurance status or sex of patients scheduled for virtual visits. Conclusions: We found significant differences in virtual visit use by patient sociodemographic and clinical characteristics. Further investigation into implications of differential virtual visit use including social and structural determinants and subsequent clinical outcomes is indicated.

Post-irradiation intratumoral heterogeneity modulates response to immune checkpoint inhibition therapy in a murine melanoma model.

PURPOSE: The underlying mechanism for radiation as a potentiator of immune checkpoint inhibition (ICI) is unclear. We developed a novel murine model to investigate the effects of post-irradiation intratumoral heterogeneity (ITH) on response to ICI. EXPERIMENTAL DESIGN: Parental mouse melanoma B16F10 cells were irradiated in vitro (5Gy x 3 fractions), then an a priori determined number of resulting colonies were implanted in C57BL/6J immunocompetent mice creating syngeneic models of unirradiated (parental) and irradiated tumors with low (irradiated-L) and high (irradiated-H) ITH. Mice were treated with placebo, α-PD-L1, α-CTLA-4 or dual ICI. Murine tumors underwent whole exome sequencing (WES). Clinically correlated paired pre- and post-irradiation patient rectal adenocarcinoma samples underwent WES. RESULTS: Irradiated-L tumors showed increased tumor mutational burden (TMB) and a sustained decrease in ITH. Irradiated-L tumors were predicted to express five neoantigens with high variant allele frequency/clonal distribution. Mice with irradiated-L and irradiated-H versus parental B16F10 tumors demonstrated longer overall survival with dual ICI. Only mice with irradiated-L tumors experienced an overall survival benefit with single agent ICI. Clinically correlated rectal adenocarcinoma samples showed similarly increased TMB and decreased ITH following irradiation. CONCLUSIONS: Post-irradiation ITH modulates ICI response in a murine melanoma model. Irradiation may offer a mechanism to widen the therapeutic window of ICI.

A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities.

Gene expression profiles provide an opportunity to dissect the heterogeneity of solid tumors, including colon cancer, to improve prognosis and predict response to therapies. Bayesian binary regression methods were used to generate a signature of disease recurrence in patients with resected early stage colon cancer validated in an independent cohort. A 50-gene signature was developed that effectively distinguished early stage colon cancer patients with a low or high risk of disease recurrence. RT-PCR analysis of the 50-gene signature validated 9 of the top 10 differentially expressed genes. When applied to two independent validation cohorts of 55 and 73 patients, the 50-gene model accurately predicted recurrence. Standard Kaplan-Meier survival analysis confirmed the prognostic accuracy (P < 0.01, log rank), as did multivariate Cox proportional hazard models. We tested potential targeted therapeutic options for patients at high risk for disease recurrence and found a clinically important relationship between sensitivity to celecoxib, LY-294002 (PI3kinase inhibitor), retinol, and sulindac in colon cancer cell lines expressing the poor prognostic phenotype (P < 0.01, t test), which performed better than standard chemotherapy (5-FU and oxaliplatin). We present a genomic strategy in early stage colon cancer to identify patients at highest risk of recurrence. An ability to move beyond current staging by refining the estimation of prognosis in early stage colon cancer also has implications for individualized therapy.

Prognostic and Predictive Clinical and Biological Factors in HPV Malignancies.

Human papillomavirus (HPV) causes the majority of oropharyngeal, cervical, and anal cancers, among others. These HPV-associated cancers cause substantial morbidity and mortality despite ongoing vaccination efforts. Aside from the earliest stage tumors, chemoradiation is used to treat most HPV-associated cancers across disease sites. Response rates are variable, and opportunities to improve oncologic control and reduce toxicity remain. HPV malignancies share multiple commonalities in oncogenesis and tumor biology that may inform personalized methods of screening, diagnosis, treatment and surveillance. In this review we discuss the current literature and identify promising molecular targets, prognostic and predictive clinical factors and biomarkers in HPV-associated oropharyngeal, cervical and anal cancer.

Dosimetric Comparison of Proton Versus Photon Radiosurgery for Treatment of Pituitary Adenoma.

PURPOSE: To compare the dosimetric differences in stereotactic radiosurgery between use of passively scattered protons (PSRS) versus photons (XSRS) for pituitary adenomas. METHODS AND MATERIALS: Nine patients with pituitary adenomas were selected among patients receiving single-fraction proton stereotactic radiosurgery (PSRS) between 2016 and 2017. These cases were replanned with XSRS using volumetric-modulated arc therapy with 2.5 mm and 5 mm multileaf collimators (2.5XSRS and 5XSRS, respectively). PSRS was planned with a dedicated single scattering stereotactic proton unit delivered via 3 equally or unequally weighted isocentric fields. XSRS plans were created with optimization to spare organs at risk. Plans were generated using the original total treatment dose delivered in 1 fraction. RESULTS: Plans were evaluated for target volume dosimetry and estimated clinical toxicity. There was no significant difference in clinical target volume V100%, V95%, V90% or homogeneity index between treatment modalities. PSRS offered lower maximum dose (Dmax) to organs at risk and equivalent uniform dose (EUD) compared with 5XSRS and 2.5XSRS, respectively, for critical structures including optic nerve (right, Dmax 4.18, 5.32, 5.41; EUD 3.35, 4.08, 4.20) and hypothalamus (Dmax 1.71, 3.94, 3.77; EUD 0.94, 2.47, 2.39; P < .05 for PSRS vs 5XSRS and 2.5XSRS). The projected risk of secondary tumors in excess of baseline was lowest for PSRS plans (PSRS 5.28, 5XSRS 12.93, 2.5XSRS 12.66 cases per 10,000 patient-years; P = .008 for PSRS vs 5XSRS, PSRS vs 2.5XSRS, and P = .77 for 5XSRS vs 2.5XSRS). CONCLUSIONS: We demonstrate that neither modality has empirically superior dosimetry and identify potential clinical advantages as well as limitations of each technique. PSRS, 5XSRS and 2.5XSRS demonstrate comparable target volume dosimetry for pituitary adenoma. PSRS compared with XSRS modalities offers modestly decreased maximum dose and EUD to critical proximal structures and decreases risk of radiation-induced secondary tumors by more than half.

Underascertainment of Clinically Meaningful Symptoms During Prostate Cancer Radiation Therapy-Does This Vary by Patient Characteristics?

PURPOSE: It is well known that physicians underascertain chemotherapy-related toxicity compared with patient self-report. However, symptom underascertainment in radiation therapy and characterization of patient groups at increased risk for underascertainment have not been examined. METHODS AND MATERIALS: As part of routine clinical care, 7 urinary and gastrointestinal symptoms were prospectively collected with both patient-report outcomes (PROs) using the validated Prostate Cancer Symptom Indices and physician-graded symptoms using Common Terminology Criteria for Adverse Events (CTCAE) for 544 consecutive patients from 2010 to 2018 who received intensity modulated radiation therapy to the prostate or prostate bed. Data from weekly treatment visits and the first posttreatment follow-up were analyzed. Underascertainment was defined as an occurrence when a clinically meaningful symptom was indicated on PROs but not physician CTCAE assessment. Univariate and multivariable logistic regression examined characteristics associated with underascertainment. RESULTS: Overall, 85.3% of patients had underascertainment of at least 1 symptom. Per PRO, 16.9% of assessments reported clinically meaningful symptoms, in contrast to only 3.4% per CTCAE, representing an approximate 5-fold difference. Multivariable analysis showed underascertainment was more common in patients who were unmarried (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.18-1.38), lived in rural regions (OR 1.10; 95% CI, 1.01-1.21), incarcerated (OR 1.58; 95% CI, 1.36-1.84), retired/unemployed (OR 1.29; 95% CI, 1.18-1.40), received prostate gland (vs prostate bed) treatment (OR 1.43; 95% CI, 1.31-1.58), and received concurrent hormone therapy (OR 1.16; 95% CI, 1.04-1.29). Patients age >70 years were less likely to have underascertainment compared with those age <60 years (OR 0.82; 95% CI, 0.73-0.92). CONCLUSIONS: This is the first study to show underascertainment of clinically meaningful symptoms in radiation therapy patients in routine clinical care and further to demonstrate that certain patient groups are especially vulnerable to underascertainment. These results highlight the importance of incorporating PROs in the clinical care of radiation therapy patients. If PROs are not routinely used, vulnerable patient groups may need additional attention during cancer treatment to ensure accurate toxicity assessment and management.

A Prospective Analysis of Radiation Oncologist Compliance With Early Peer Review Recommendations.

PURPOSE: We conducted a prospective observational cohort study of physician compliance with daily early pretreatment planning peer review recommendations and quantified factors associated with compliance. METHODS AND MATERIALS: All patient cases in our department are presented at 2 peer review conferences: (1) "early" preplanning, occurring daily for patients who have undergone simulation review, and (2) "late" (chart rounds), occurring weekly for patients who have started treatment. Peer review recommendations were prospectively recorded during early review, and compliance with recommendations was determined at chart rounds. Recommendations were assigned magnitude scores (minor, moderate, or major). We analyzed the association of patient, physician, and recommendation characteristics and compliance (scored as a binary variable) with early peer review recommendations, using logistic regression with a mixed effects model. RESULTS: From February 2017 to May 2018, 1271 patient cases underwent early peer review, and 326 (26%) received peer-based recommendations. Of 356 recommendations, 37% were minor, 36% were moderate, and 27% were major. Overall compliance was 59% (95% confidence interval, 54%-64%). On univariate analysis, compliance decreased as the recommendation magnitude increased (minor, 65%; moderate, 60%; major, 47%; P = .019; odds ratio, 0.71 per increase in magnitude). Compliance also differed among different treating physicians (range, 38%-73%, χ2 test, P = .003) but was not associated with other physician characteristics. Disease group and treatment technique were not associated with compliance. On multivariable analysis, increasing recommendation magnitude remained significantly associated with decreased compliance (multivariate P = .042; odds ratio, 0.74). CONCLUSIONS: Daily early peer review resulted in a substantial proportion of recommended changes. Compliance with early peer review recommendations was fair but varied among physicians. Compliance declined with increasing recommendation magnitude, suggesting that physicians may be reluctant to adopt major changes. These results highlight the potential importance of peer review timing.

Clinical analysis of speculum-based vaginal packing for high-dose-rate intracavitary tandem and ovoid brachytherapy in cervical cancer.

PURPOSE: Intra-vaginal packing is used to fix the applicator and displace organs at risk (OAR) during high-dose-rate intracavitary tandem and ovoid brachytherapy (HDR-ICB). We retain the speculum from applicator placement as a dual-function bladder and rectum retractor during treatment. Our objective is to review salient techniques for OAR displacement, share our packing technique, and determine the reduction in dose to OAR and inter-fraction variability of dose to OAR, associated with speculum-based vaginal packing (SBVP) in comparison to conventional gauze packing during HDR-ICB. MATERIAL AND METHODS: We reviewed HDR-ICB treatment plans for 45 patients, including 10 who underwent both conventional gauze packing and SBVP. Due to institutional inter-provider practice differences, patients non-selectively received either packing procedure. Packing was performed under conscious sedation, followed by cone beam computed tomography used for dosimetric planning. Maximum absolute and percent-of-prescription dose to the International Commission of Radiation Units bladder and rectal points in addition to D0.1cc, D1.0cc, and D2.0cc volumes of the bladder and rectum were analyzed and compared for each packing method using an independent sample t-test. RESULTS: Of the 179 fractions included, 73% and 27% used SBVP and gauze packing, respectively. For patients prescribed 6 Gy to point A, SBVP was associated with reduced mean D0.1cc bladder dose, inter-fraction variability in D0.1cc bladder dose by 9.3% (p = 0.026) and 9.0%, respectively, and statistically equivalent rectal D0.1cc, D1.0cc, and D2.0cc. Patients prescribed 5.5 Gy or 5 Gy to point A after dose optimization, were less likely to benefit from SBVP. In the intra-patient comparison, 80% of patients had reduction in at least one rectum or bladder parameter. CONCLUSIONS: In patients with conducive anatomy, SBVP is a cost-efficient packing method that is associated with improved bladder sparing and comparable rectal sparing relative to gauze packing during HDR-ICB without general anesthesia.

Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), lacking expression of hormone and human epidermal growth factor receptor 2 receptors, is an aggressive subtype that frequently metastasizes to the brain and has no FDA-approved systemic therapies. Previous literature demonstrates mitogen-activated protein kinase kinase (MEK) pathway activation in TNBC brain metastases. Thus, we aimed to discover rational combinatorial therapies with MEK inhibition, hypothesizing that co-inhibition using clinically available brain-penetrant inhibitors would improve survival in preclinical models of TNBC brain metastases. METHODS: Using human-derived TNBC cell lines, synthetic lethal small interfering RNA kinase screens were evaluated with brain-penetrant inhibitors against MEK1/2 (selumetinib, AZD6244) or phosphatidylinositol-3 kinase (PI3K; buparlisib, BKM120). Mice bearing intracranial TNBC tumors (SUM149, MDA-MB-231Br, MDA-MB-468, or MDA-MB-436) were treated with MEK, PI3K, or platelet derived growth factor receptor (PDGFR; pazopanib) inhibitors alone or in combination. Tumors were analyzed by western blot and multiplexed kinase inhibitor beads/mass spectrometry to assess treatment effects. RESULTS: Screens identified MEK+PI3K and MEK+PDGFR inhibitors as tractable, rational combinations. Dual treatment of selumetinib with buparlisib or pazopanib was synergistic in TNBC cells in vitro. Both combinations improved survival in intracranial SUM149 and MDA-MB-231Br, but not MDA-MB-468 or MDA-MB-436. Treatments decreased mitogen-activated protein kinase (MAPK) and PI3K (Akt) signaling in sensitive (SUM149 and 231Br) but not resistant models (MDA-MB-468). Exploratory analysis of kinome reprogramming in SUM149 intracranial tumors after MEK ± PI3K inhibition demonstrates extensive kinome changes with treatment, especially in MAPK pathway members. CONCLUSIONS: Results demonstrate that rational combinations of the clinically available inhibitors selumetinib with buparlisib or pazopanib may prove to be promising therapeutic strategies for the treatment of some TNBC brain metastases. Additionally, effective combination treatments cause widespread alterations in kinase pathways, including targetable potential resistance drivers.