Biomarker Consortium

GI Cancer

Gastric Cancer

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF)

The v-Raf murine sarcoma viral oncogene homolog B1 (

) gene was discovered in 1988, and it encodes a kinase protein in the RAS-RAF-MEK-ERK signal transduction pathway.

BRAF is located on chromosome 7 and belongs to the RAF family of serine/threonine-specific protein kinases but is the only one known to be a proto-oncogene in humans.

Under normal circumstances, RAF proteins participate in the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation and differentiation.

Activated BRAF phosphorylates MEK proteins, which subsequently activate ERK proteins, which activate cellular transcription factors.

BRAF contains 3 conserved regions: CR1, CR2, and CR3. CR1 and CR3 produce autoinhibitory interaction for BRAF, with CR2 functioning as a hinge of the other conserved regions.

 mutation is V600E, resulting in constitutively activated BRAF kinases that stimulate tumor growth.

 mutations occur within 2 different protein locations, exons 11 and 15, resulting in the loss of the autoinhibitory region combined with targeting BRAF to the plasma membrane.

The prevalence of BRAF V600E mutations in gastric cancer is relatively low, ranging from 

 mutations in gastric cancer, the role of mutation status and clinicopathological variables is unclear.

BRAF is a known predictor of poor prognosis in colorectal cancer (CRC) to EGFR-targeted agents, but the predictive value in gastric cancer is unknown.

Gastric cancer is characterized by high tumor heterogeneity, so biomarker testing has a high impact on appropriate treatment selection.

Patients with gastric cancer should undergo testing for BRAF mutations and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.

 BRAF testing can be performed using immunohistochemistry (IHC) or, preferably, next-generation sequencing (NGS).

 Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include 

 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, 

 Gastric cancer accounts for only about 1.5% of new cancer cases in the United States each year.

The relative rarity means that targeted treatments are limited, and most treatments include traditional chemotherapy.

 Currently, the only FDA-approved treatment for gastric cancer with a BRAF V600E mutation is dabrafenib plus trametinib.

 Dabrafenib inhibits mutated BRAF kinases and wild-type BRAF, deactivating the BRAF cascade that promotes cell growth and differentiation.

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2, deactivating upstream regulation of the extracellular signal-related kinase (ERK) pathway.

Learn more about Dabrafenib and Trametinib >

Wan PTC, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. 

. 2004;116(6):855-867. doi:10.1016/s0092-8674(04)00215-6

TAFINLAR (dabrafenib). Prescribing information. GSK; 2024. Accessed May 5, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf

MEKINIST (trametinib). Prescribing information. Novartis; 2024. Accessed May 5, 2024. 

https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf

Hewitt LC, Hutchins GG, Melotte V, Saito Y, Grabsch HI. KRAS, BRAF and gastric cancer. 

. 2015;4(6). doi:10.3978/j.issn.2224-4778.2015.09.08

Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. 

. 2019;11(8):1197. doi:10.3390/cancers11081197

Choi YY, Noh SH, Cheong JH. Molecular dimensions of gastric cancer: translational and clinical perspectives. 

. 2016;50(1):1-9. doi:10.4132/jptm.2015.09.10

Van Grieken NCT, Aoyma T, Chambers PA, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. 

. 2013;108(7):1495-1501. doi:10.1038/bjc.2013.109

NCCN guidelines version 1.2024: gastric cancer

https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf

Zhu X, Pigazzi A, Zell J, Lu Y. Changing disparity of gastric cancer incidence by histological types in US race-specific populations. 

 2020;27(1):1073274820977152. doi:10.1177/1073274820977152

National Comprehensive Cancer Network. NCCN guidelines version 1.2024: pancreatic adenocarcinoma. 2024. Accessed May 5, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf

Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF V600E mutations: results of the NCI-MATCH trial subprotocol H. 

. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762

Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. 

. 2023;29(5):1103-1112. doi:10.1038/s41591-023-02321-8

BRAF V600E

Neurotrophic tropomyosin kinase receptors (NTRK)

Neurotrophic tropomyosin kinase receptors (NTRK) are transmembrane kinases involved in neural cells’ development, proliferation, and survival.

After localization to cell membranes, the protein family is activated by nerve growth factor (NGF) ligands, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4, and NT-5.

The TRK family consists of 3 members, including TKRA, TKRB, and TRKC and activation of these proteins leads to downstream activation of the signal pathways RAS-RAF-MEK-ERK, phosphatidylinositol-3 (PI3) kinase, and phospholipase C gamma (PLC-γ).

NTRK genes are proto-oncogenes that activate into oncogenic driver mutations via gene fusions that lead to chimeric TRK proteins.

 gene fusions is approximately 1% in solid tumors, but there is a lack of data regarding the prevalence in gastroesophageal cancer.

gene fusions occur through chromosome rearrangements, point mutations, deletions, or gene fusions and cause spontaneous ligand-independent dimerization.

These chimeric proteins have constitutive TRK protein activity or overexpression of the kinase function.

Current research suggests that oncogenic mutations cause a change exclusively in the extracellular domain of chimeric proteins, suggesting a common regulatory domain.

 Patients with gastric cancer should undergo testing for 

 gene fusions and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.

 Feasible testing methods include immunohistochemistry (ICH), fluorescence in situ hybridization (FISH), DNA-based next-generation sequencing, and RNA-based NGS.2,4 The ideal approach appears to be RNA-based NGS because of the higher rates of false positives and lack of evidence of functional transcription present in other methods.

 Currently, 2 FDA-approved options exist for treating unresectable or metastatic NTRK gene fusion–positive solid tumors.

 Larotrectinib and entrectinib are recommended as second- or subsequent-line treatments in NTRK+ patients. Their favorable safety profile and clinically meaningful response support regular screening for gene fusions.

Approval for larotrectinib was based on the data from 3 trials, LOCO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431).

The overall response rate in 55 patients was 75% (95% CI, 61-85), 71% of responses remained ongoing at 1 year, and 55% remained progression-free at 1 year.

 Entrectinib approval was based on data from the trials STARTRK-2 (NCT02568267) and STARTRK-1 (NCT02097810), and ALKA-372-001.

The study population comprised 54 adults with an overall response rate of 57% (95% CI, 43-71), progression-free survival 11.2 months (95% CI, 8.0-14.9), and overall survival 20.9 (95% CI, 14.9-NR).

 Larotrectinib and entrectinib are tyrosine kinase inhibitors specifically targeting TRKA, TRKB, and TRKC, anaplastic lymphoma kinase (ALK), and the proto-oncogene tyrosine-protein kinase 1 (ROS1).

Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK fusions in cancer. 

. 2022;79:103893. doi:10.1016/j.amsu.2022.103893

 fusions: merits and limitations of current diagnostic platforms. 

. 2019;79(13):3163-3168. doi:10.1158/0008-5472.CAN-19-0372

Lange A, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. 

. 2018;10(4):105. doi:10.3390/cancers10040105

Arnold A, Daum S, Von Winterfeld M, et al. Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry. 

. 2019;215(11):152662. doi:10.1016/j.prp.2019.152662

ROZLYTREK (entrectinib). Prescribing information. Genentech; 2019. Accessed May 5, 2024. 

https://www.gene.com/download/pdf/rozlytrek_prescribing.pdf

VITRAKVI (larotrectinib). Prescribing information. Loxo Oncology; 2018. Accessed May 5, 2024. 

https://labeling.bayerhealthcare.com/html/products/pi/vitrakvi_PI.pdf

Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in 

 fusion-positive cancers in adults and children. 

. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. 

. 2018;29(suppl 8):viii713. doi:10.1093/annonc/mdy424.017

NTRK fusions

) gene is a DNA sequence localized to chromosome 10.

It encodes a glycoprotein membrane receptor with tyrosine kinase activity with 4 cadherin-like domains (CLDs) and a cysteine-rich domain in the extracellular region.

CLDs are involved in calcium-mediated cellular adhesions.

The RET kinase is critical for developing the enteric nervous system during embryogenesis, including thyroid C cells, enteric ganglia, peripheral nervous system (PNS) ganglia, fetal kidney cells, and testes germ cells.

The endogenous ligand for RET protein is glial cell line-derived neurotrophic factor (GDNF), a growth factor-like protein; persephin, neurturin, and artemin.

These ligands do not agonize RET directly but instead attach to a co-receptor GDNF family receptor-α (GDNFα) protein.

After activation, RET homodimerizes, which leads to autophosphorylation of tyrosine residues and activation of multiple signal pathways, including PI3K, MAPK, phospholipase C-γ, JAK-STAT, and PKA.

fusions and rearrangements are present in 0%-2% of solid tumors and are found most commonly in cases of medullary thyroid cancer (>80%) due to their crucial role in the formation of thyroid C cells.

fusions in gastric cancer is even more rare and is 

breakpoints occur in intron 11, followed by introns 10 and 7.

Oncogenesis can occur via several mechanisms, including the alteration of transcriptional control or via fusion partners that dimerize RET proteins independently of endogenous ligands, which leads to constitutive expression.

Patients with gastric cancer should undergo testing for 

 mutations and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.

RET testing can be conducted using immunohistochemistry (IHC) or NGS. However, NGS is the preferred method, as IHC is less reliable for detecting RET alterations due to its low sensitivity and variable specificity.

Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include 

 gene-fusion–positive gastric tumors is selpercatinib, approved in 2022.

Selpercatinib has demonstrated antitumor activity against cells harboring constitutively active RET proteins from gene fusions and mutations.

 Selpercatinib is generally well tolerated with a permanent discontinuation rate of 8%.

Selpercatinib is a kinase inhibitor that attaches to wild-type 

Belli C, Penault-Llorca F, Ladanyi M, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. 

. 2021;32(3):337-350. doi:10.1016/j.annonc.2020.11.021

Carlomagno F. Thyroid cancer: role of RET and beyond. 

Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. 

. 2018;15(3):151-167. doi:10.1038/nrclinonc.2017.175

Ibanez CF. Structure and physiology of the RET receptor tyrosine kinase. 

. 2013;5(2):a009134-a009134. doi:10.1101/cshperspect.a009134

Zhao L, Wang N, Zhang D, Jia Y, Kong F. A comprehensive overview of the relationship between RET gene and tumor occurrence. 

. 2023;13:1090757. doi:10.3389/fonc.2023.1090757

Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. 

 aberrations in diverse cancers: next-generation sequencing of 4,871 patients. 

. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679

Skórzewska M, Gęca K, Polkowski WP. A clinical viewpoint on the use of targeted therapy in advanced gastric cancer. 

. 2023;15(22):5490. doi:10.3390/cancers15225490

Shi M, Wang W, Zhang J, et al. Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing. 

. 2022;113(1):308-318. doi:10.1111/cas.15181

Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of 

 rearrangements in non-small cell lung cancer. 

Naidoo J, Drilon A. Molecular diagnostic testing in non-small cell lung cancer. 

RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company; 2022. Accessed May 5, 2024. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213246s008lbl.pdf

FDA D.I.S.C.O. burst edition: FDA approvals of Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive solid tumors, and Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive non-small cell lung cancer. FDA. Updated November 7, 2022. Accessed April 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-retevmo-selpercatinib-adult-patients-locally-advanced-or

Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. 

. 2022;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1

Li JJ, Rogers JE, Yamashita K, Waters RE, Blum Murphy M, Ajani JA. Therapeutic advances in the treatment of gastroesophageal cancers. 

. 2023;13(5):796. doi:10.3390/biom13050796

Human epidermal growth factor receptor 2 (

); erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (

, is a proto-oncogene found on chromosome 17q12 that encodes a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor family.

When activated following phosphorylation, the HER2 receptor triggers signaling pathways associated with cell division, proliferation, differentiation, and anti-apoptosis. 

of gastroesophageal adenocarcinomas (GEAs) exhibit HER2 amplification or overexpression.

Overexpression rates are slightly higher in cancers at the gastroesophageal junction compared to those in the stomach, with variations based on histologic type and differentiation.

 In contrast to breast carcinomas, GEA typically displays greater heterogeneity in immunostaining and tiered scoring systems, such as the one used in the ToGA trial (NCT01041404), have been proposed to better define GEA-associated HER2 expression.

HER2 testing should be performed at diagnosis in patients with gastric cancer patients if metastatic disease is confirmed or suspected.

: Testing for HER2 overexpression is generally performed via immunohistochemistry (IHC) assays, with positivity defined as 3+ staining in greater than 50% of tumor cells. Reflex testing with fluorescence in situ hybridization (FISH) is recommended in patients with IHC 2+ to identify HER2 amplification, with positivity defined as a HER2:CEP17 ratio greater than or equal to 2 in more than 50% of tumor cells. Next generation sequencing (NGS) may also be used to identify HER2 amplification.

 The FDA has approved 2 targeted therapies for HER2+ metastatic CRC.

 The first of these, trastuzumab, received approval in combination with chemotherapy for use in patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma based on findings from the phase 3 ToGA study.

 T-DXd was granted approval for locally advanced or metastatic HER2+ gastric or gastroesophageal (GEJ) adenocarcinoma patients who have received a prior trastuzumab-based regimen, based on findings from DESTINY-Gastric01 (NCT03329690).

In April of 2023, T-DXd was granted accelerated approval for previously treated unresectable or metastatic HER2+ (IHC 3+) solid tumors with no satisfactory alternative treatment options, marking it as the first tumor-agnostic approved ADC. Accelerated approval was based on findings from three clinical trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).

 Trastuzumab is an anti-HER2 monoclonal antibody that binds to the HER2 receptor with high affinity, thereby inhibiting HER2-mediated tumor growth.

 Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 antibody linked to the topoisomerase I inhibitor payload, deruxtecan, via a cleavable tetrapeptide linker.

 Upon binding HER2 on tumor cells, T-DXd undergoes internalization and intracellular linker cleavage, thereby releasing the DXd payload and subsequently causing DNA damage and apoptotic cell death. 

Learn more about Fam-Trastuzumab Deruxtecan-nxki (T-DXd) >

Rubin I, Yarden Y. The basic biology of HER2. 

 2001;12(suppl 1):S3-S8. doi:10.1093/annonc/12.suppl_1.s3

Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. 

. 1984;312(5994):513‐516. doi:10.1038/312513a0

Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. 

 2016;140(12):1345-1363. doi:10.5858/arpa.2016-0331-CP

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 

. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X

Tanner M, Hollmén M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. 

2005;16(2):273-8. doi:10.1093/annonc/mdi064

Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. 

 2008;19(9):1523-1529. doi:10.1093/annonc/mdn169

National Comprehensive Cancer Network. Clinical Practice Guidelines in gastric cancer, version 2.2024. May 29, 2024. Accessed June 12, 2024. 

Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. 

 2011;18(1):53-59. doi:10.1097/PAP.0b013e3182026d72

Pirrelli M, Caruso ML, Di Maggio M, Armentano R, Valentini AM. Are biopsy specimens predictive of HER2 status in gastric cancer patients? 

 2013;58(2):397-404. doi:10.1007/s10620-012-2357-3

Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. 

 2008;52(7):797-805. doi:10.1111/j.1365-2559.2008.03028.x

National Comprehensive Cancer Network. Clinical Practice Guidelines in esophageal and esophagogastric junction cancers, version 2.2024. April 26, 2024. Accessed June 12, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf

HERCEPTIN (trastuzumab). Prescribing information. Genentech; 2021. Accessed June 12, 2024. 

https://www.gene.com/download/pdf/herceptin_hylecta_prescribing.pdf

ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo; 2024. Accessed June 12, 2024.

https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X

FDA approves Herceptin for HER2-positive metastatic stomach cancer. FiercePharma.com. Updated October 21, 2010. Accessed April 22, 2024. 

https://www.fiercepharma.com/pharma/fda-approves-herceptin-for-her2-positive-metastatic-stomach-cancer

FDA approved fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA.gov. Updated January 15, 2021. Accessed April 22, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer

FDA.gov. FDA grant accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. Updated April 5, 2024. Accessed April 22, 2024. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

Lei YY, Huang JY, Zhao QR, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. 

 2017;15(1):68. doi:10.1186/s12957-017-1132-5

Li W, Zhang X, Du Y, et al. HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives. 

 2022;10(1):71. doi:10.1186/s40364-022-00416-x

Phillips BE, Tubbs RR, Rice TW, et al. Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction. 

 2013;26(3):299-304. doi:10.1111/j.1442-2050.2012.01369.x

Radford M, Abushukair H, Hentzen S, Cavalcante L, Saeed A. Targeted and immunotherapy approaches in HER2-positive gastric and gastroesophageal junction adenocarcinoma: a new era. 

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Rüschoff J, Hanna W, Bilous M, et al. HER2 testing in gastric cancer: a practical approach. 

 2012;25(5):637-650. doi:10.1038/modpathol.2011.198

Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. 

2015;18(3):476-484. doi:10.1007/s10120-014-0402-y

Wang HB, Liao XF, Zhang J. Clinicopathological factors associated with HER2-positive gastric cancer: a meta-analysis. 

 2017;96(44):e8437. doi:10.1097/MD.0000000000008437

HER2

DNA mismatch repair/microsatellite instability.

DNA mismatch repair (MMR) is involved in preserving genomic fidelity by repairing DNA after mismatching errors after replication or recombination.

MMR is also involved in cell cycle regulation and apoptosis in response to DNA damage.

Four genes regulate MMR mechanisms, and the protein dimers they form are responsible for mismatch recognition, insertion-deletion loops, base excision, and other functions. 

Expert Sound Bites

HER2 Positive Gastric Cancer: Navigating Treatment Option