Molecular Oncology Almanac Patient Report

Molecular Oncology Almanac classifies each curated assertion with a "predictive implication" that describes the strength of evidence for a given relationship between a molecular feature and clinical action. The evidence levels used are:

Evidence level	Description
FDA-Approved	The Food and Drug Association (FDA) recognizes an association between the alteration and recommended clinical action.
Guideline	This relationship is catalogued as a guideline for standard of care treatment.
Clinical trial	The alteration is or has been used as an eligibility criterion for a clinical trial.
Clinical evidence	The relationship is reported in a clinical study that did not directly involve a clinical trial.
Preclinical evidence	This relationship is reported in a study involving mice, cell lines, or patient derived models.
Inferential evidence	The relationship is inferred as a result of mathematical modeling or an association between molecular features.

Molecular Oncology Almanac evaluates alterations based on how closely they match an alteration-action relationship, as given by catalogued assertions.

To illustrate by example, consider matching variants against the assertion that BRAF p.V600E suggests sensitivity to Vemurafenib:

Bin	Example	Description
Putatively Actionable	BRAF Mutation Missense p.V600E	An exact match
Investigate Actionability	BRAF Mutation Missense p.V500L	Gene (feature) and feature type match but not either the alteration type or specific alteration
Biologically Relevant	BRAF Amplification	Gene (feature) match only

Molecular Oncology Almanac leverages several datasources to evaluate the predictive implication of each feature. Datasources and versions used to create this report are:

Datasource	Release
Molecular Oncology Almanac - Interpreter	0.6.0
Molecular Oncology Almanac - Database	v.2024-04-11
American College of Medical Genetics and Genomics - Secondary Findings	3.0
Cancer Gene Census	97
Cancer Hotspots	2.0
3D Hotspots	1.0
ClinVar	Accessed October 25th, 2018
COSMIC	97
ExAC	1.0
Molecular Signatures Database (MSigDB)	Accessed October 25th, 2018
Oncotree	Accessed March 9th, 2023

Molecular Oncology Almanac

Patient Report

Generated on: Jul 03 2024

Patient Information

Identifiers

Patient ID:	example
Tumor Barcode:	example_tumor_profile
Normal Barcode:	example_normal_profile

Disease

Code:	MEL
Ontology:	Melanoma
Stage:	Metastatic

Metrics

Tumor Purity:	0.85
Tumor Ploidy:	4.02
Microsatellite Stability:	MSI-High

Actionability Report

About:

Variants and Features associated with Therapeutic Sensitivity

Predictive Implication

Feature Type

Feature

Therapy & Rationale

FDA-Approved
Putatively Actionable

The following assertion was the strongest match to the observed molecular feature.

Evidence:	FDA-Approved
Molecular feature:	BRAF p.V600E (Missense)
Assertion:	Sensitivity to Trametinib in Melanoma (MEL)

The U.S. Food and Drug Administration (FDA) granted approval to trametinib as a single agent for the treament of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E or V600K mutation, as detected by an FDA-approved test. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Vemurafenib in Melanoma (MEL) The U.S. Food and Drug Administration (FDA) granted regular approval to vemurafenib for the treatment of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E mutation, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Encorafenib in Melanoma (MEL) The U.S. Food and Drug Administration (FDA) granted regular approval to encorafenib for the treatment of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E mutation, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib in Melanoma (MEL) The U.S. Food and Drug Administration (FDA) granted approval to dabrafenib as a single agent for the treament of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E mutation, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib + Trametinib in Melanoma (MEL) The U.S. Food and Drug Administration (FDA) granted approval to dabrafenib in combination with trametinib for the treament of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E or V600K mutation, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib + Trametinib in Melanoma (MEL) The U.S. Food and Drug Administration (FDA) granted approval to dabrafenib in combination with trametinib for the adjuvant treament of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E or V600K mutation, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Binimetinib + Encorafenib in Non-Small Cell Lung Cancer (NSCLC) The U.S. Food and Drug Administration (FDA) approved encorafenib in combination with binimetinib for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib + Trametinib in Low-Grade Glioma, NOS (LGGNOS) The U.S. Food and Drug Administration (FDA) granted approval to dabrafenib in combination with trametinib for the treament of pediatric patients 1 year of age or older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib + Trametinib in Any solid tumor () The U.S. Food and Drug Administration (FDA) granted accelerated approval to dabrafenib in combination with trametinib for the treatment of adult and pediatric patients 6 years of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Dabrafenib + Trametinib in Non-Small Cell Lung Cancer (NSCLC) The U.S. Food and Drug Administration (FDA) granted approval to dabrafenib in combination with trametinib for the treament of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E, as detected by an FDA-approved test. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Cetuximab + Encorafenib in Colorectal Adenocarcinoma (COADREAD) The U.S. Food and Drug Administration (FDA) granted regular approval to encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer (CRC) with BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. [source]
BRAF p.V600E (Missense) FDA-Approved	Sensitivity to Vemurafenib in Non-Langerhans Cell Histiocytosis/Erdheim-Chester Disease (ECD) The U.S. Food and Drug Administration (FDA) approved vemurafenib for the treatment of patients with Erdheim-Chester disease and whose tumors harbor a BRAF V600 mutation. [source]

[More details]

Somatic Variant

BRAF p.V600E (Missense)

Trametinib
The U.S. Food and Drug Administration (FDA) granted approval to trametinib as a single agent for the treament of patients with unresectable or metastatic melanoma (MEL) with BRAF V600E or V600K mutation, as detected by an FDA-approved test. [source]

Trametinib

Cell lines from the Sanger Institute's Genomics of Drug Discovery in Cancer (GDSC) are stratified by wild type and mutant status for the following molecular features. We then compare the drug response to the recommend therapy (or therapies) based on data from the GDSC.

Feature	N WT tested	N Mut tested	MWW statistic	MWW p-value
BRAF	634	137	57546.5	2.344e-09
BRAF Somatic Variant	672	99	48043.5	9.083e-13
BRAF Somatic Variant Missense	681	90	45139.0	2.900e-13
BRAF Somatic Variant Missense p.V600E	721	50	29698.0	1.793e-14

[Preclinical evidence]

FDA-Approved
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	FDA-Approved
Molecular feature:	MSI-High
Assertion:	Sensitivity to Dostarlimab-gxly in Endometrial Carcinoma (UCEC)

The U.S. Food and Drug Administration (FDA) granted approval to dostarlimab-gxly in combination with carboplatin and paclitaxel, followed by single agent dostarlimab-gxly, for the treatment of adult patients primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR), as determined by an FDA-approved test, or microsatellite-instability-high. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
MSI-High FDA-Approved	Sensitivity to Pembrolizumab in Endometrial Carcinoma (UCEC) The U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal ca [source]
MSI-High FDA-Approved	Sensitivity to Pembrolizumab in Any solid tumor () The U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. [source]
MSI-High FDA-Approved	Sensitivity to Pembrolizumab in Colorectal Adenocarcinoma (COADREAD) The U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. [source]

[More details]

Microsatellite Stability

MSI-High

Dostarlimab-gxly
The U.S. Food and Drug Administration (FDA) granted approval to dostarlimab-gxly in combination with carboplatin and paclitaxel, followed by single agent dostarlimab-gxly, for the treatment of adult patients primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR), as determined by an FDA-approved test, or microsatellite-instability-high. [source]

FDA-Approved
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	FDA-Approved
Molecular feature:	BRCA2
Assertion:	Sensitivity to Abiraterone acetate + Niraparib in Prostate Adenocarcinoma (PRAD)

The U.S. Food and Drug Administration (FDA) granted approval to niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor indicated with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Invasive Breast Carcinoma (BRCA) The U.S. Food and Drug Administration (FDA) granted approval to olaparib for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Invasive Breast Carcinoma (BRCA) The U.S. Food and Drug Administration (FDA) granted approval to olaparib for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative high risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Abiraterone + Prednisone + Olaparib in Prostate Adenocarcinoma (PRAD) The U.S. Food and Drug Administration (FDA) has granted approval to olaparib in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Pancreatic Adenocarcinoma (PAAD) The U.S. Food and Drug Administration (FDA) has granted approval to olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regime. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Ovarian Epithelial Tumor (OVT) The U.S. Food and Drug Administration (FDA) granted approval for olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in High-Grade Serous Fallopian Tube Cancer (HGSFT) The U.S. Food and Drug Administration (FDA) granted approval for olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Peritoneal Serous Carcinoma (PSEC) The U.S. Food and Drug Administration (FDA) granted approval for olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Talazoparib in Invasive Breast Carcinoma (BRCA) The U.S. Food and Drug Administration (FDA) granted approval for talazoparib indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Olaparib in Prostate Adenocarcinoma (PRAD) The U.S. Food and Drug Administration (FDA) granted approval to olaparib for adult patients with deleterious or suspected deleterous germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), who have progressed following prior treatment with enzalutamide or abiraterone. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Niraparib in Ovarian Epithelial Tumor (OVT) The U.S. Food and Drug Administration (FDA) granted approval for niraparib for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation or genominc instability and who have progressed more than six months after response to the last platinum-based chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Niraparib in High-Grade Serous Fallopian Tube Cancer (HGSFT) The U.S. Food and Drug Administration (FDA) granted approval for niraparib for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation or genominc instability and who have progressed more than six months after response to the last platinum-based chemotherapy. [source]
BRCA2 (Pathogenic) FDA-Approved	Sensitivity to Niraparib in Peritoneal Serous Carcinoma (PSEC) The U.S. Food and Drug Administration (FDA) granted approval for niraparib for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation or genominc instability and who have progressed more than six months after response to the last platinum-based chemotherapy. [source]

[More details]

Germline Variant

BRCA2 p.S1982fs (Frameshift)

Abiraterone acetate + Niraparib
The U.S. Food and Drug Administration (FDA) granted approval to niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor indicated with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). [source]

Guideline
Putatively Actionable

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Guideline
Molecular feature:	CDK4 Amplification
Assertion:	Sensitivity to Palbociclib in Well-Differentiated Liposarcoma (WDLS)

Palbociclib (Ibrance) is recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with well-differentiated liposarcoma and CDK4 amplification. CDK4 amplification is characteristic of well-differentiated and dedifferentiated liposarcomas, and palbociclib shows activity in this context. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
CDK4 Amplification Guideline	Sensitivity to Palbociclib in Dedifferentiated Lipsarcoma (DDLS) Palbociclib (Ibrance) is recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with dedifferentiated liposarcoma and CDK4 amplification. CDK4 amplification is characteristic of well-differentiated and dedifferentiated liposarcomas, and palbociclib shows activity in this context. [source]

[More details]

Copy Number

CDK4 Amplification

Palbociclib
Palbociclib (Ibrance) is recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with well-differentiated liposarcoma and CDK4 amplification. CDK4 amplification is characteristic of well-differentiated and dedifferentiated liposarcomas, and palbociclib shows activity in this context. [source]

Palbociclib

Feature	N WT tested	N Mut tested	MWW statistic	MWW p-value
CDK4	734	36	12116.0	0.4
CDK4 Copy Number	747	23	5880.0	0.01
CDK4 Copy Number Amplification	750	20	4877.0	0.008

[Preclinical evidence]

Guideline
Investigate Actionability
[More details]

Rearrangement

COL1A1--CITED4 Fusion

Imatinib
Imatinib (Gleevec) is recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with localized or metastatic dermatofibrosarcoma tumors containing t(17;22)(q22;q13). [source]

Imatinib

Feature	N WT tested	N Mut tested	MWW statistic	MWW p-value
COL1A1	370	37	6702.0	0.835
CITED4	407	0
COL1A1 Fusions	407	0
CITED4 Fusions	407	0
COL1A1--CITED4	407	0

[Preclinical evidence]

Clinical evidence
Putatively Actionable
[More details]

Copy Number

CDKN2A Deletion

Palbociclib
A patient with uterine leiomyosarcoma whose tumor harbored a CDKN2A mutant which inactivated p16INK4a experienced clinical benefit from treatment with palbociclib. [source]

Palbociclib

Feature	N WT tested	N Mut tested	MWW statistic	MWW p-value
CDKN2A	467	303	63514.0	0.016
CDKN2A Copy Number	531	239	59748.0	0.194
CDKN2A Copy Number Deletion	537	233	59077.0	0.219

[Preclinical evidence]

Clinical evidence
Investigate Actionability
[More details]

Somatic Variant

MSH2 p.D887N (Missense)

Pembrolizumab
Patients with defects in DNA mismatch repair genes may have enhanced sensitivity to immune checkpoint blockade. [source]

Preclinical
Putatively Actionable
[More details]

Copy Number

TP53 Deletion

Talazoparib
Response to talazoparib in osteosarcoma cell lines was associated with homologous recombination deficiency in a study of 5 cancer cell lines. Osteosarcoma cell lines MG63 and ZK-58 displayed the highest sensitivity to talazoparib, SaOS-2 and MNNG-HOS displayed intermediate sensitivity, and U2OS cells remained resistant. Cell lines MG63, ZK-58, and MNNG-HOS scored HRD-LOH positive according to a score (Abkevich et al. 2012). MG63 cells harbored copy losses in BAP1, FANCA, and FANCD2 while ZK-58 carried disruptive copy loss in BARD1 and copy gain in FANCD2. SaOS-2 cells harbored copy losses in CHEK2 and TP53 and MNNG-HOS cells have copy loss of ATM and disruptive copy gains in PTEN and FANCD2. The talazoparib-resistant cell line, U2OS, carried a heterozygous BRCA2 copy loss and one intact BRCA2 alelle. [source]

Talazoparib

Feature	N WT tested	N Mut tested	MWW statistic	MWW p-value
TP53	205	543	42643.5	7.932e-07
TP53 Copy Number	662	86	24893.5	0.058
TP53 Copy Number Deletion	668	80	24135.5	0.157

[Preclinical evidence]

Preclinical
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Preclinical
Molecular feature:	FGFR2 Amplification
Assertion:	Sensitivity to Infigratinib in Colorectal Adenocarcinoma (COADREAD)

A study of 32 Cancer Cell Line Encyclopedia cell lines demonstrating FGFR1 and FGFR2 amplification demonstrated sensitivity to Infigratinib. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
FGFR2 Amplification Preclinical	Sensitivity to Infigratinib in Non-Small Cell Lung Cancer (NSCLC) A study of 32 Cancer Cell Line Encyclopedia cell lines demonstrating FGFR1 and FGFR2 amplification demonstrated sensitivity to Infigratinib. [source]
FGFR2 Amplification Preclinical	Sensitivity to Infigratinib in Osteosarcoma (OS) A study of 32 Cancer Cell Line Encyclopedia cell lines demonstrating FGFR1 and FGFR2 amplification demonstrated sensitivity to Infigratinib. [source]
FGFR2 Amplification Preclinical	Sensitivity to Infigratinib in Invasive Breast Carcinoma (BRCA) A study of 32 Cancer Cell Line Encyclopedia cell lines demonstrating FGFR1 and FGFR2 amplification demonstrated sensitivity to Infigratinib. [source]

[More details]

Copy Number

FGFR2 Deletion

Infigratinib
A study of 32 Cancer Cell Line Encyclopedia cell lines demonstrating FGFR1 and FGFR2 amplification demonstrated sensitivity to Infigratinib. [source]

Inferential
Investigate Actionability
[More details]

Mutational Signature

SBS5 (22%)

Cisplatin
COSMIC Signature 5 is associated with somatic ERCC2 mutations, which may suggest sensitivity to cisplatin based chemotherapy. [source]

Inferential
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Inferential
Molecular feature:	Cosmic signature SBS10b (version 3.4)
Assertion:	Sensitivity to Durvalumab in Any solid tumor

COSMIC Signature 10 is observed in some of the most hypermutant samples and recurrent POLE mutations. POLE mutant tumors are being included along with MMR-deficient tumors in several ongoing trials for sensitivity to immunotherapy. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
Cosmic signature SBS10b (version 3.4) Inferential	Sensitivity to Pembrolizumab in Any solid tumor () COSMIC Signature 10 is observed in some of the most hypermutant samples and recurrent POLE mutations. POLE mutant tumors are being included along with MMR-deficient tumors in several ongoing trials for sensitivity to immunotherapy. [source]
Cosmic signature SBS10b (version 3.4) Inferential	Sensitivity to Pembrolizumab in Any solid tumor () Signature 10 is related to mutant pole, which may suggest sensitivity to immunotherapy. [source]

[More details]

Mutational Signature

SBS10b (12%)

Durvalumab
COSMIC Signature 10 is observed in some of the most hypermutant samples and recurrent POLE mutations. POLE mutant tumors are being included along with MMR-deficient tumors in several ongoing trials for sensitivity to immunotherapy. [source]

Variants and Features associated with Therapeutic Resistance

Predictive Implication

Feature Type

Feature

Therapy & Rationale

Guideline
Putatively Actionable

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Guideline
Molecular feature:	BRAF p.V600E (Missense)
Assertion:	Resistance to Panitumumab in Colorectal Adenocarcinoma (COADREAD)

Panitumumab (Vectibix) is not recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with metastatic colorectal cancer, BRAF V600E makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
BRAF p.V600E (Missense) Guideline	Resistance to Cetuximab in Colorectal Adenocarcinoma (COADREAD) Cetuximab (Erbitux) is not recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with metastatic colorectal cancer, BRAF V600E makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor. [source]

[More details]

Somatic Variant

BRAF p.V600E (Missense)

Panitumumab
Panitumumab (Vectibix) is not recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with metastatic colorectal cancer, BRAF V600E makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor. [source]

Guideline
Investigate Actionability
[More details]

Microsatellite Stability

MSI-High

5-Fluorouracil
5-Fluorouracil is not recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for patients with MSI-High colorectal cancer. These patients appear to not benefit from, and may be resistant to, 5-fluorouracil therapy. [source]

Clinical evidence
Putatively Actionable
[More details]

Copy Number

BRAF Amplification

Vemurafenib
Amplification of BRAF may predict resistance to RAF inhibition. [source]

Variants and Features associated with Prognostic Information

Predictive Implication

Feature Type

Feature

Prognosis & Rationale

Guideline
Putatively Actionable

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Guideline
Molecular feature:	BRAF p.V600E (Missense)
Assertion:	Not favorable prognosis in Colorectal Adenocarcinoma

BRAF V600E alterations are associated with an unfavorable prognosis in MSI-low and microsatellite-stable patients. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
BRAF p.V600E (Missense) Guideline	Not favorable prognosis in Colorectal Adenocarcinoma (COADREAD) BRAF V600E alterations are associated with an unfavorable prognosis in MSI-low and microsatellite-stable patients. [source]

[More details]

Somatic Variant

BRAF p.V600E (Missense)

Not favorable
BRAF V600E alterations are associated with an unfavorable prognosis in MSI-low and microsatellite-stable patients. [source]

Guideline
Putatively Actionable
[More details]

Copy Number

TP53 Deletion

Not favorable
Deletion of 17p13 leads to LoH of TP53 and is considered a high-risk feature of multiple myeloma. [source]

Guideline
Investigate Actionability
[More details]

Microsatellite Stability

MSI-High

Favorable
Patients with MSI-High colorectal cancer often have a favorable prognosis. [source]

Guideline
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Guideline
Molecular feature:	STAG2 (Nonsense)
Assertion:	Not favorable prognosis in Myelodysplasia

The National Comprehensive Cancer Network® (NCCN®) highlights STAG2 nonsense, frameshift, and splice site variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
STAG2 (Frameshift) Guideline	Not favorable prognosis in Myelodysplasia (MDS) The National Comprehensive Cancer Network® (NCCN®) highlights STAG2 nonsense, frameshift, and splice site variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]
STAG2 (Splice Site) Guideline	Not favorable prognosis in Myelodysplasia (MDS) The National Comprehensive Cancer Network® (NCCN®) highlights STAG2 nonsense, frameshift, and splice site variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

[More details]

Somatic Variant

STAG2 p.F467I (Missense)

Not favorable
The National Comprehensive Cancer Network® (NCCN®) highlights STAG2 nonsense, frameshift, and splice site variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

Guideline
Investigate Actionability

The following assertion was the strongest match to the observed molecular feature.

Evidence:	Guideline
Molecular feature:	ZRSR2 (Nonsense)
Assertion:	Not favorable prognosis in Myelodysplasia

The National Comprehensive Cancer Network® (NCCN®) highlights ZRSR2 nonsense and frameshift variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

The following assertions are equivalent matches within this patient's ontology or stronger in another cancer type.

Molecular feature & evidence	Assertion & rationale
ZRSR2 (Frameshift) Guideline	Not favorable prognosis in Myelodysplasia (MDS) The National Comprehensive Cancer Network® (NCCN®) highlights ZRSR2 nonsense and frameshift variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

[More details]

Somatic Variant

ZRSR2 p.N261I (Missense)

Not favorable
The National Comprehensive Cancer Network® (NCCN®) highlights ZRSR2 nonsense and frameshift variants as being associated with a poor prognosis in patients with myelodysplastic syndromes. [source]

Inferential
Investigate Actionability
[More details]

Aneuploidy

nan

Not favorable
WGD was associated with adverse survival pan-cancer in patients with advanced disease and in cancers with heterogeneous clinical outcomes, even following the development of metastasis. [source]

Variants and Features that may be Biologically Relevant

Feature Type	Features
Germline Variant	BRAF p.R509* (Nonsense)
Microsatellite Stability	Supporting variants: PRDM2 p.E282del (Deletion)
Mutational Signature	SBS30 (23%), SBS7a (42%)
Somatic Variant	NTRK2 p.H300Y (Missense), PDGFRB p.G674E (Missense)

Comparison of molecular profile to cancer cell lines

The Molecular Oncology Almanac compares the somatic variants, copy number alterations, and rearrangements present in this tumor
to identify similar cell lines and their corresponding therapeutic sensitivities to aid in treatment hypothesis generation.

The 5 most similar cancer cell lines, of 452 tested

Cell line name (CCLE)

Sensitive therapies

Clinically relevant features

SKHEP1_LIVER

Aliases: ACH-000361 (Broad/DepMap), SIDM01110 (Sanger)

Sensitive to: AGI-5198, SN-38

Clinically relevant features: BRAF p.V600E, CDKN2A Deletion, ERCC2 Missense, SMARCA4 Nonsense

Below lists somatic variants, copy number alterations, or fusions that appear in a Molecular Oncology Almanac, Cancer Hotspot, or Cancer Gene Census gene as well as the top 10 sensitive therapies that were tested against the cell line in GDSC1/GDSC2.

Somatic variants:

BRAF p.V600E, ERCC2 p.M724T, LEPROTL1 p.D57E, NF2 p.I264V, SMARCA4 p.E1582*

Copy number alterations:

BCR Deletion, BLM Deletion, CDKN2A Deletion, IRF4 Amplification, MUC4 Amplification, PTPRD Deletion

Fusions: None observed

Therapeutic sensitivity (10 most sensitive):

Dataset	therapy	ln(ic50)	AUC	z score
GDSC2	AGI-5198	2.2955970000000003	0.885606	-2.810423
GDSC1	SN-38	-9.38477	0.052603	-2.256093
GDSC1	Doxorubicin	-4.127894	0.094794	-1.746938
GDSC1	NSC-207895	1.7166580000000002	0.73632	-1.570315
GDSC2	Nilotinib	0.918093	0.901523	-1.5356889999999999
GDSC1	Tipifarnib	-0.860009	0.359995	-1.491999
GDSC1	Etoposide	-1.2080629999999999	0.30594899999999997	-1.420639
GDSC1	DMOG	4.415166999999999	0.32150300000000004	-1.369969
GDSC1	Veliparib	2.8033740000000003	0.9626610000000001	-1.303758
GDSC1	Bleomycin (10 uM)	-0.452696	0.502855	-1.264271

[More details]

AGI-5198, SN-38

BRAF p.V600E, CDKN2A Deletion, ERCC2 Missense, SMARCA4 Nonsense

A375_SKIN

Aliases: ACH-000219 (Broad/DepMap), SIDM00795 (Sanger)

Sensitive to: (5Z)-7-Oxozeaenol, AS605240, CHIR-99021, CI-1040, Dabrafenib, ERK_2440, LIMK1 inhibitor BMS4, PD0325901, PLX-4720, Pilaralisib, RAF_9304, Refametinib, SB590885

Clinically relevant features: BRAF p.V600E, CDKN2A Deletion, MTOR somatic variant, PRPF8 somatic variant, RUNX1 somatic variant

Somatic variants:

A1CF p.D305N, ASPSCR1 p.S513F, BCL11B p.V690M, BIRC6 p.H1328Y, BMP5 p.R44Q, BRAF p.V600E, CDKN2A p.E61*, CDKN2A p.E69*, DNMT1 p.P879S, EPHB1 p.Q431K, EZR p.I580V, FAT4 p.I4112V, FGFR1OP p.V51G, FGFR2 p.E636K, GPC5 p.M557L, HGF p.D462Y, MECOM p.G610R, MTOR p.R2152C, MUC16 p.E522A, MUC16 p.G4120R, MUC16 p.G5250R, MUC16 p.H1252Y, MUC4 p.G466R, MYH9 p.A1407T, NFKBIE p.G34E, PDE4DIP p.P705R, PRDM14 p.Y36H, PRPF8 p.N322S, PTPN13 p.K1640fs, PTPN13 p.S1619fs, PTPRD p.G272R, ROBO2 p.P1233L, RUNX1 p.S276L, SLC45A3 p.L18F, SPEN p.LTGLVSA2647del, TACC3 p.S190F, TPR p.T1822N, TRRAP p.S722F, WNK2 p.A138V, WNK2 p.E146*, ZNF331 p.H209Y

Copy number alterations:

CDKN2A Deletion, ETV5 Deletion, RAF1 Amplification

Fusions:

EP300--L3MBTL2, HIF1A--PRKCH

Therapeutic sensitivity (10 most sensitive):

Dataset	therapy	ln(ic50)	AUC	z score
GDSC1	SB590885	-0.872252	0.548574	-3.473819
GDSC2	Dabrafenib	-3.467089	0.22456399999999999	-3.437089
GDSC1	LIMK1 inhibitor BMS4	1.910779	0.767753	-3.242003
GDSC1	(5Z)-7-Oxozeaenol	-3.804743	0.063251	-3.014737
GDSC1	Pilaralisib	0.237907	0.5024689999999999	-2.916171
GDSC2	PLX-4720	0.06802899999999999	0.6525	-2.660593
GDSC1	CI-1040	-1.0143959999999999	0.409418	-2.197268
GDSC1	AS605240	-0.192438	0.430708	-2.134757
GDSC1	RAF_9304	-0.765096	0.45072799999999996	-2.1104849999999997
GDSC2	PD0325901	-3.8717589999999995	0.621938	-2.108898

[More details]

(5Z)-7-Oxozeaenol, AS605240, CHIR-99021, CI-1040, Dabrafenib, ERK_2440, LIMK1 inhibitor BMS4, PD0325901, PLX-4720, Pilaralisib, RAF_9304, Refametinib, SB590885

BRAF p.V600E, CDKN2A Deletion, MTOR somatic variant, PRPF8 somatic variant, RUNX1 somatic variant

IGR37_SKIN

Aliases: ACH-000650 (Broad/DepMap), SIDM01066 (Sanger)

Sensitive to: (5Z)-7-Oxozeaenol, CI-1040, Dabrafenib, ERK_2440, ERK_6604, PD0325901, PLX-4720, RAF_9304, Refametinib, SB52334, SB590885, Selisistat, Selumetinib, Trametinib

Clinically relevant features: AURKB Deletion, BRAF p.V600E, MLH3 somatic variant, TP53 Deletion, TP53 Frameshift

Somatic variants:

AKAP9 p.Y3128N, AURKB p.F88L, BRAF p.V600E, COL3A1 p.P895S, CSMD3 p.C2078S, DCC p.E2K, DIS3 p.P770S, EPAS1 p.P673S, ERC1 p.H721Q, ITK p.H121Y, KTN1 p.K141fs, LRP1B p.D61N, MEN1 p.D210E, MLH3 p.R1232S, MLLT1 p.S369F, MUC16 p.G4350R, MUC16 p.P700L, MUC16 p.R13398C, PAX7 p.K175N, PTPRD p.R561Q, RGPD3 p.E938K, TP53 p.C229fs

Copy number alterations:

AKT1 Deletion, ANKRD11 Deletion, AURKB Deletion, BCL11B Deletion, CBFA2T3 Deletion, DICER1 Deletion, FANCA Deletion, FGFR3 Deletion, FLCN Deletion, FSTL3 Deletion, GAS7 Deletion, GATA3 Deletion, GOLGA5 Deletion, GPS2 Deletion, HSP90AA1 Deletion, KLF6 Deletion, LARP4B Deletion, MAF Deletion, MAP2K4 Deletion, MC1R Deletion, MITF Amplification, N4BP2 Deletion, NCOR1 Deletion, NCOR2 Deletion, PER1 Deletion, PHOX2B Deletion, PLAG1 Amplification, PRPF8 Deletion, PTCH1 Amplification, RABEP1 Deletion, RFWD3 Deletion, RHOH Deletion, STK11 Deletion, TACC3 Deletion, TCL1A Deletion, TMPRSS2 Deletion, TP53 Deletion, TRIP11 Deletion, USP6 Deletion, WHSC1 Deletion, YWHAE Deletion, ZFHX3 Deletion

Fusions: None observed

Therapeutic sensitivity (10 most sensitive):

Dataset	therapy	ln(ic50)	AUC	z score
GDSC1	SB590885	-2.46916	0.293122	-4.755780000000001
GDSC1	Selisistat	2.49932	0.8350770000000001	-4.446638
GDSC1	(5Z)-7-Oxozeaenol	-4.632813	0.032905000000000004	-3.569748
GDSC2	Dabrafenib	-3.3622300000000003	0.216522	-3.390736
GDSC1	RAF_9304	-2.425218	0.203482	-3.337126
GDSC1	Refametinib	-3.763	0.130697	-3.018654
GDSC2	PLX-4720	-0.444047	0.595468	-2.982493
GDSC1	SB52334	0.439094	0.535281	-2.9639450000000003
GDSC2	ERK_6604	-1.500489	0.454987	-2.838606
GDSC1	CI-1040	-1.7863639999999998	0.291593	-2.738375

[More details]

(5Z)-7-Oxozeaenol, CI-1040, Dabrafenib, ERK_2440, ERK_6604, PD0325901, PLX-4720, RAF_9304, Refametinib, SB52334, SB590885, Selisistat, Selumetinib, Trametinib

AURKB Deletion, BRAF p.V600E, MLH3 somatic variant, TP53 Deletion, TP53 Frameshift

G361_SKIN

Aliases: ACH-000572 (Broad/DepMap), SIDM00857 (Sanger)

Sensitive to: Bexarotene, Bryostatin 1, Dabrafenib, Refametinib

Clinically relevant features: ALK Missense, ALK Missense, BRAF Amplification, BRAF p.V600E, CDKN2A Deletion, EGFR Amplification, MET Amplification

Somatic variants:

ALK p.G385S, ALK p.G689R, AMER1 p.R641*, BRAF p.V600E, CBLB p.F814S, CD79A p.E148G, CNTNAP2 p.P739S, CTNNA2 p.VRKQG96fs, MUC16 p.G9315V, MUC4 p.S534F, MUC4 p.V1571G, SPECC1 p.P907F, SPECC1 p.P907L, SPECC1 p.P907S, STK11 p.G279fs

Copy number alterations:

AKAP9 Amplification, ALK Deletion, BRAF Amplification, CARD11 Amplification, CDK6 Amplification, CDKN2A Deletion, CNOT3 Deletion, CNTNAP2 Amplification, CREB3L2 Amplification, CUX1 Amplification, EGFR Amplification, ELN Amplification, ETV1 Amplification, EZH2 Amplification, FAM131B Amplification, FKBP9 Amplification, GRM3 Amplification, GTF2I Amplification, HGF Amplification, HIP1 Amplification, HNRNPA2B1 Amplification, HOXA11 Amplification, HOXA13 Amplification, HOXA9 Amplification, IKZF1 Amplification, JAZF1 Amplification, KIAA1549 Amplification, LRP1B Deletion, MET Amplification, MNX1 Amplification, PDE4DIP Amplification, PMS2 Amplification, POT1 Amplification, RAC1 Amplification, RHEB Amplification, SBDS Amplification, SFRP4 Amplification, SMARCA4 Deletion, SMO Amplification, SND1 Amplification, TFPT Deletion, TRIM24 Amplification, TRRAP Amplification, ZBTB16 Deletion, ZNF479 Amplification

Fusions:

ACVR1--CYTIP

Therapeutic sensitivity (10 most sensitive):

Dataset	therapy	ln(ic50)	AUC	z score
GDSC2	Dabrafenib	-0.723223	0.555257	-2.2241619999999998
GDSC1	Bryostatin 1	-4.786909	0.887407	-2.159514
GDSC1	Bexarotene	1.265355	0.795426	-2.032625
GDSC1	Refametinib	-2.043773	0.35870799999999997	-2.00163
GDSC2	PLX-4720	1.120111	0.775351	-1.999236
GDSC1	rTRAIL	-3.4634	0.749522	-1.8961970000000001
GDSC2	Tamoxifen	1.791094	0.839701	-1.882421
GDSC1	QS11	0.706533	0.683033	-1.850396
GDSC2	Obatoclax Mesylate	-0.627835	0.5675060000000001	-1.81257
GDSC1	PAC-1	0.163003	0.800072	-1.6750669999999999

[More details]

Bexarotene, Bryostatin 1, Dabrafenib, Refametinib

ALK Missense, ALK Missense, BRAF Amplification, BRAF p.V600E, CDKN2A Deletion, EGFR Amplification, MET Amplification

SKMEL5_SKIN

Aliases: ACH-000730 (Broad/DepMap), SIDM00080 (Sanger)

Sensitive to: FH535, IAP_7638, SB590885, UNC0642

Clinically relevant features: BRAF p.V600E, CCND1 Amplification, CDKN2A Deletion, PIK3CB somatic variant, SMARCA4 Frameshift, TET2 somatic variant

Somatic variants:

APC p.L407F, BCL11B p.E504K, BIRC6 p.D2349N, BMP5 p.P417L, BRAF p.V600E, BRD3 p.Q662*, CNBD1 p.E304K, DGCR8 p.K561fs, FNBP1 p.337_344PHQPPPPP>P, IRS2 p.P934A, KDR p.S633F, KMT2D p.E4939K, KNSTRN p.S24F, LRP1B p.E72K, MLLT3 p.R298fs, MLLT6 p.G919R, NIN p.P1969S, NTRK2 p.P185L, PAK7 p.K247R, PIK3CB p.R48Q, PML p.R670H, POT1 p.F566C, PRDM14 p.E361K, PTPRB p.D1752N, PTPRT p.G1035fs, PTPRT p.P485S, RANBP2 p.P2215A, RICTOR p.P1602L, SETD2 p.P228L, SMARCA4 p.F1052fs, TET2 p.S477F, TPR p.T1553fs, USP44 p.S548F, WHSC1 p.P36S

Copy number alterations:

ASPSCR1 Amplification, AXIN2 Amplification, CANT1 Amplification, CCND1 Amplification, CDH10 Amplification, CDKN2A Deletion, DDX5 Amplification, GPC5 Deletion, H3F3B Amplification, INPPL1 Amplification, NUMA1 Amplification, PRKAR1A Amplification, PTCH1 Amplification, PTPRD Deletion, RNF213 Amplification, RPTOR Amplification, SEPT9 Amplification, SRSF2 Amplification

Fusions: None observed

Therapeutic sensitivity (10 most sensitive):

Dataset	therapy	ln(ic50)	AUC	z score
GDSC1	IAP_7638	-2.522011	0.223833	-4.2922400000000005
GDSC1	UNC0642	0.09192	0.907135	-2.481357
GDSC1	FH535	-0.802279	0.290811	-2.302486
GDSC1	SB590885	0.608066	0.743449	-2.285454
GDSC1	GSK1059615	-3.009578	0.11452799999999999	-1.9020580000000002
GDSC2	Obatoclax Mesylate	-0.5314479999999999	0.574621	-1.722739
GDSC1	Embelin	1.149381	0.5663630000000001	-1.7189009999999998
GDSC1	Lenalidomide	2.597514	0.918926	-1.5522280000000002
GDSC1	CI-1040	-0.083321	0.556309	-1.544637
GDSC1	(5Z)-7-Oxozeaenol	-1.608525	0.337809	-1.542728

[More details]

FH535, IAP_7638, SB590885, UNC0642

BRAF p.V600E, CCND1 Amplification, CDKN2A Deletion, PIK3CB somatic variant, SMARCA4 Frameshift, TET2 somatic variant

DIAGNOSTIC AND CLINICAL USE PROHIBITED. DANA-FARBER CANCER INSTITUTE (DFCI) and THE BROAD INSTITUTE (Broad) MAKE NO REPRESENTATIONS OR WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NONINFRINGEMENT OR VALIDITY OF ANY INTELLECTUAL PROPERTY RIGHTS OR CLAIMS, WHETHER ISSUED OR PENDING, AND THE ABSENCE OF LATENT OR OTHER DEFECTS, WHETHER OR NOT DISCOVERABLE.

In no event shall DFCI or Broad or their Trustees, Directors, Officers, Employees, Students, Affiliates, Core Faculty, Associate Faculty and Contractors, be liable for incidental, punitive, consequential or special damages, including economic damages or injury to persons or property or lost profits, regardless of whether the party was advised, had other reason to know or in fact knew of the possibility of the foregoing, regardless of fault, and regardless of legal theory or basis. You may not download or use any portion of this program for any non-research use not expressly authorized by DFCI or Broad. You further agree that the program shall not be used as the basis of a commercial product and that the program shall not be rewritten or otherwise adapted to circumvent the need for obtaining permission for use of the program other than as specified herein.

Van Allen Laboratory Dana-Farber Cancer Institute Broad Institute of MIT & Harvard
Molecular Oncology Almanac

Molecular Oncology Almanac

Patient Report

Patient Information

Identifiers

Disease

Metrics

Actionability Report

About: Predictive Implication Bins Datasources

Variants and Features associated with Therapeutic Sensitivity

Variants and Features associated with Therapeutic Resistance

Variants and Features associated with Prognostic Information

Variants and Features that may be Biologically Relevant

Comparison of molecular profile to cancer cell lines

The 5 most similar cancer cell lines, of 452 tested

About: