Colorectal cancer (CRC) is the most common cancer in the United States, and is the second most common cause of cancer-related death.

 However, molecular testing is drastically changing the treatment landscape and improving patient outcomes in this specialty, according to Kelley A. Rone, DNP, RN, ADNP-C.

“One of the things that is most relevant is the molecular profiling portion of cancer in general. [But] it's such a rapidly changing part of oncology, that it is sometimes hard to keep up,” Rone, who is an advanced practice nurse specializing in [gastrointestinal] GI cancers at Mayo Clinic in Phoenix, Arizona, said in an interview with 

 “As new mutations become recognized and become linked to certain treatments, that is going to change a lot of the way treatments are matched.”

Rone recently presented on advances in gastrointestinal cancers as part of the 

. In her talk, she highlighted the various biomarkers that patients with colorectal cancer should be tested for, and the corresponding treatment options.

“It is important for the nurses to understand the importance of testing,” Rone told 

®, noting that nurses can be critical in ensuring that the appropriate tests have been ordered for different patients.

“If someone comes in and [we do not believe their cancer is] metastatic, or if the have had their prior biopsy done at an outside institution, we may not necessarily think about doing the molecular profiling. [But] sometimes myself or the clinic nurses will say to the physician: Did we do molecular profiling on this patient? Because if it hasn’t been done, we can order it,” she said.

Mismatch repair deficiency (dMMR) and microsatellite stability testing is recommended for all patients with newly diagnosed colon cancer, regardless of disease stage.

 In addition, patients with metastatic disease should be screened for 

 mutations are the most frequently mutated oncogenes and these variants are present in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. 

prior to initiating any EGFR-inhibiting therapy, such as cetuximab (Erbitux) or panitumumab (Vectibix). Patients who present with 

mutations (1.7%) should not receive anti-EGFR therapy, as these biomarkers have negative predictive value with these therapies.

 mutations, as they serve as the primary effector of 

signaling. These mutations are most likely to occur in exon 15 (V600E). Identified in approximately 10% of patients with CRC, 

mutations. If a molecular profile comes back as 

Approximately 2% to 3% of patients with CRC will show a degree of 

 amplification is increased; approximately 5% of these patients will have this amplification. Uncommon among patients with 

 amplification is frequently associated with left-sided CRC. Identifying this amplification is key in determining if a patient may benefit form a HER2-directed therapy.

As of August 2022, patients with metastatic disease may receive a combination of bevacizumab (Avastin) plus either FOLFOX,

 FOLFIRI, or FOLFOXIRI. They may also receive any of these chemotherapies as monotherapy.

 mutations) left-sided tumors may receive monotherapy with cetuximab

or panitumumab. They also may receive one of the anti-EGFR therapies in addition to chemotherapy (FOLFOX or FOLFIRI).

Patients with dMMR and microsatellite instability–high disease are eligible for monotherapy with pembrolizumab (Keytruda), nivolumab (Opdivo), or ipilimumab (Yervoy). They may also receive dual immunotherapy with nivolumab plus ipilimumab.

Patients with HER2-positive disease and no 

 mutations may receive either a combination of trastuzumab (Herceptin) plus pertuzumab (Perjeta).

 They may also receive lapatinib (Tykerb).

 fusion positive disease, with no evidence of 

mutations, may receive larotrectinib (Vitrakvi) or entrectinib (Rozlytrek).

Rone KA. Advances in gastrointestinal cancers: shifting evidence into practice. Presented at: 

 School of Nursing Oncology™; July 29-30, 2022; San Diego, CA.

Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. 

. 2015;16(7):30. doi:10.1007/s11864-015-0348-2

Dienstmann R, Salazar R, Tabernero J. Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer. 

. 2018;38:231-238. doi:10.1200/EDBK_200929

Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. 

. 2018;37(1):57. doi:10.1186/s13046-018-0719-1

Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. 

. 2016;34(2):179-185. doi:10.1200/JCO.2015.63.9674

Al-Shamsi HO, Alhazzani W, Wolff RA. Extended RAS testing in metastatic colorectal cancer-Refining the predictive molecular biomarkers. 

. 2015;6(3):314-321. doi:10.3978/j.issn.2078-6891.2015.016

Gong J, Cho M, Fakih M. RAS and BRAF in metastatic colorectal cancer management. 

. 2016;7(5):687-704. doi:10.21037/jgo.2016.06.12

Larki P, Gharib E, Yaghoob Taleghani M, Khorshidi F, Nazemalhosseini-Mojarad E, Asadzadeh Aghdaei H. Coexistence of 

 mutations in colorectal cancer: a case report supporting the concept of tumoral heterogeneity. 

. 2017;19(suppl 1):113-117. doi:10.22074/cellj.2017.5123

Sandhu J, Wang C, Fakih M. Clinical response to T-DM1 in HER2-amplified, KRAS-mutated metastatic colorectal cancer. 

. 2020;18(2):116-119. doi:10.6004/jnccn.2019.7371

Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. 

Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients With KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. 

. 2017;317(23):2392-2401. doi:10.1001/jama.2017.7105

Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. 

. 2014;15(10):1065-1075. doi:10.1016/S1470-2045(14)70330-4

Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. 

. 2008;99(3):455-458. doi:10.1038/sj.bjc.6604530

Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. 

. 2010;28(31):4706-4713. doi:10.1200/JCO.2009.27.6055

Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. 

. 2015;16(13):1306-1315. doi:10.1016/S1470-2045(15)00122-9

Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. 

. 2012;30(23):2861-2868. doi:10.1200/JCO.2011.40.9243

Van Cutsem E. Optimizing administration of epidermal growth factor receptor-targeted agents in the treatment of colorectal cancer. 

. 2007;6(suppl 2):S60-S65. doi:10.3816/ccc.2007.s.004

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. 

. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596

Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. 

. 2017;18(9):1182-1191. Published correction appears in 

Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. 

. 2018;36(8):773-779. doi:10.1200/JCO.2017.76.9901

Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. 

. 2019;20(4):518-530. doi:10.1016/S1470-2045(18)30904-5

Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. 

. 2016;17(6):738-746. Published correction appears in 

Articles

At the 6th Annual SONO meeting, Kelley A. Rone, DNP, RN, AGNP-C, reviewed evidence supporting molecular testing in patients with colorectal cancer. 

Molecular Profiling Is a Necessity in Colorectal Cancer Treatment 

Although the use of immunotherapy in gastrointestinal (GI) cancers is still limited, new research is bringing this treatment approach to the forefront, according to Kelley A. Rone, DNP, RN, AGNP-c, a nurse practitioner at Mayo Clinic in Arizona.

“The addition of immunotherapy will [hopefully] give a boost to some of these difficult-to-treat cancers,” said Rone, who recently gave a presentation on advances in GI cancers as part of the 

 School of Nursing Oncology®. In an interview with 

®, she discusses how immunotherapy represents a promising avenue for many patients in this population.

According to Rone, 3 recently published studies are changing the landscape of GI oncology. These include the CheckMate 648 trial (NCT03143153),

 which assessed nivolumab (Opdivo) plus ipilimumab (Yervoy), and nivolumab plus chemotherapy, against chemotherapy alone in patients with esophageal squamous cell carcinoma (ESCC); the MOUNTAINEER trial (NCT03043313),

 in which tucatinib (Tukysa) combined with trastuzumab (Herceptin) was evaluated in patients with HER2-positive metastatic colorectal cancer; and TOPAZ-1 (NCT03875235), a head-to-head trial of durvalumab (Imfinzi) in combination with gemcitabine plus cisplatin vs chemotherapy alone in patients with advanced biliary tract cancer.

Findings from CheckMate 648 showed that the addition of immunotherapy in the frontline treatment of ESCC improved overall survival (OS) in the intention-to-treat population. The median OS with nivolumab plus ipilimumab was 12.8 months (95% CI, 11.3-15.5) and 13.2 months (95% CI, 11.1-15.7) with the chemoimmunotherapy regimen. These were compared with patients treated in the chemotherapy alone arm who had a median OS of 10.7 months (95% CI, 9.4-11.9). The reduction in risk of death was 22% (HR, 0.78; 95% CI, 0.65-0.95; 

 = .0110) and 26% (HR, 0.74; 95% CI, 0.61-0.90; 

 = .0021), respectively. The OS benefit was consistent across subgroups, irrespective of PD-L1 status.

“We used to not have a lot of immunotherapy options for our [patients with] GI cancer,” Rone said. “We still only use immunotherapy in colon cancer or pancreas cancer if [it is] microsatellite instability–high, but we are seeing more immunotherapy used in ESCC.” She added that although patients with ESCC used to require PD-L1 tumor positivity to receive immunotherapy, new findings have shown that this is no longer necessary, and more patients are able to receive immunotherapy along with chemotherapy.

Data from the phase 2 MOUNTAINEER trial, presented at the 2022 ESMO World Congress on Gastrointestinal Cancer (World GI) showed that patients with previously treated metastatic HER2-positive colorectal cancer had a sustained response to treatment with dual-HER2 inhibitors tucatinib plus trastuzumab.2 Specifically, among 84 treated patients the confirmed objective response rate by blinded independent central review was 38.1% (95% CI, 27.7%-49.3%). Further, at a median follow-up of 20.7 months, the median progression-free survival was 8.2 months (95% CI, 4.2-10.3) with a median OS of 24.1 months (95% CI, 20.3-36.7).

Data from phase 3 TOPAZ-1 trial presented at the 2022 ASCO Annual Meeting showed a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy for patients with biliary tract cancer (HR, 0.80; 95% CI, 0.66-0.97; 

“The use of immunotherapy to treat something like cholangiocarcinoma is very intriguing to me,” Rone remarked. “I just saw our first patient this week who had durvalumab added to her gemcitabine and cisplatin. That opens up a lot of doors for patients, because chemotherapy plus immunotherapy seems to have better longevity for [patients with] cholangiocarcinoma.

“Sometimes if we can treat with the combination of chemotherapy and immunotherapy initially, then, at some point, we can drop the chemotherapy and use immunotherapy alone to keep the cancer stable,” she explained. “Immunotherapy, in general, is much more tolerable [for] patients. It does not cause all the toxicities that chemotherapy does.”

Rone cautioned that, when administering immunotherapy to patients, there are some key factors to keep in mind. In addition to other immune-related adverse events, patients will likely experience diarrhea with this treatment modality, and joint pain is also quite prevalent. According to Rone, nurses need to stay abreast of these possibilities and to patients directed questions to determine if they are being affected by these toxicities.

“You have to be aware of kind of the subtle immune-mediated toxicities that can occur and you [need] to ask more directed questions,” she concluded.

1. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. 

 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001

2. Seagen announces results from pivotal MOUNTAINEER trial demonstrating clinically meaningful antitumor activity of Tukysa (tucatinib) in combination with trastuzumab in previously treated HER2-positive metastatic colorectal cancer. News release. Seagen Inc. July 2, 2022. Accessed August 1, 2022. https://bwnews.pr/3yC4xQH

3. Oh DY, He AW, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 

. 2022;40(suppl 4):378. doi:10.1200/JCO.2022.40.4_suppl.378

Kelley A. Rone, DNP, RN, ADNP-c, highlights the pivotal trials assessing the role of immunotherapy in gastrointestinal cancer and what the findings may mean for oncology nurses.

Rone Discusses Exciting Immunotherapy Research in Gastrointestinal Cancer 

Each month, we take a look back at the most popular 

Topics from July 2022 include key advances in cancer survivorship toxicity management and efforts towards targeting 

mutations in the treatment paradigm for patients with pancreatic cancer. Additionally, recently reported data showed the potential quality-of-life benefit observed with ribociclib (Kisqali) for patients with hormone receptor–positive, HER2-negative breast cancer.

Other top stories include an interview with Gretchen McNally PhD, ANP-BC, AOCNP, on the need for naloxone training for oncology nurses and advanced practice providers (APPs) and a conversation between 2 palliative care experts on why buprenorphine should be considered for the treatment of cancer-related pain.

5. Frontline Ribociclib-Related Quality of Life Favorable to Abemaciclib in HR+/HER2-Advanced Breast Cance

Ribociclib was favorable over abemaciclib (Verzenio) in reducing diarrhea, fatigue, appetite loss, and arm symptoms (such as pain or swelling in the shoulder or arm and difficulty raising the arm), according to a matched-adjusted indirect comparison using published data from individual patients treated in the MONALEESA-2 (NCT01958021) and MONARCH-3 trials (NCT02246621).

4. Targeting KRAS Mutations May Help Address Unmet Need in Pancreatic Cancer Treatment

In recent years, the identification of genetic mutations such as 

 in pancreatic cancer has shifted the treatment landscape toward targeted therapies. Despite this progress, combination chemotherapy remains the standard frontline treatment for patients with localized or advanced disease. Today, many investigators are turning their eye to 

 mutations, as these mutations are the most common genetic alterations for patients with pancreatic cancer and may represent a viable treatment landscape, according to Philip A. Philip, MD, PhD, FRCP.

3. Key Advances in Cancer Survivorship Toxicity Management

, Lidia Schapira, MD, FASCO, highlights from the 2022 ASCO Symptoms and Survivorship track anddiscusses key advances in the treatment of toxicities that may present later in cancer survivorship care. She discusses the importance of baseline measurements and health equity considerations in clinical practice and underscores the potential effect evolving technologies may have on the treatment landscape.

2. Are Oncology Nurses Underutilized in Positively Affecting the Opioid Epidemic?

a nurse practitioner in hematology at The Ohio State University Comprehensive Cancer Center– Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, discusses how oncology nurses might have the opportunity to save more lives with proper naloxone training. Responses obtained from nurses and APPs at McNally’s institution demonstrated that they would feel comfortable administering naloxone, provided they had the proper training, and would be interested in pursuing educational trainings on the agent

1. Experts Make the Case for Buprenorphine Use in Cancer-Related Pain Management

At the Annual Meeting on Supportive Care in Cancer, Mary Lynn McPherson, PharmD, BCPS, FAAHPM, and Amy A. Case, MD, FAAHPM, argued that buprenorphine should play a larger role in cancer-related pain management because of its unique pharmacology and consequent safety profile. As a partial agonist, buprenorphine has less μ-receptor signaling, which may result in fewer opioid-related adverse events. However, this does not mean buprenorphine is not an effective analgesic. It has a higher binding affinity compared with most full μ-opioid agonists, suggesting that it is a very effective pain management option.

Each month, we take a look back at the most popular Oncology Nursing News® stories. Here are the top 5 stories from July 2022.


Oncology Nursing News Top Stories: July 2022

The role for immunotherapy has evolved over the past decade for patients with gastrointestinal (GI) cancers, according to Kelley A. Rone, DNP, RN, AGNP-c.

Rone, a nurse practitioner in the GI department at Mayo Clinic in Arizona, will discuss advances in GI Cancer as part of the Physician’s Education Resources’ 

® to unpack the latest changes in the field.

Treatment options with immunotherapy are still limited for patients with GI cancers compared with other tumor types, says Rone, adding that patients with colon or pancreatic cancer still need to have microsatellite instability–high disease in order to qualify for immunotherapy. However, the recent FDA approval of 2 nivolumab (Opdivo)-based regimens for the frontline treatment of patients with esophageal squamous cell carcinoma, found that the immunotherapy in combination with chemotherapy or ipilimumab (Yervoy), resulted in durable responses in this population, according to findings from the 

Moreover, Rone is optimistic about the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin for patients with cholangiocarcinoma, and its potential for 

 compared with chemotherapy alone, especially because, for many patients, immunotherapy is more tolerable, she says.

“Chemotherapy is difficult,” Rone says. “Immunotherapy, in general, is much more tolerable [for] patients. It does not cause all of the toxicities that chemotherapy does.”

Rone notes that immunotherapy does come with a host of adverse effects unique to its class. Therefore, nurses who care for patients receiving immunotherapy must ask more directed questions in order to be aware of subtle immune-mediated toxicities that may occur.

Videos

Kelley A. Rone, DNP, RN, AGNP-c, discusses the advantages associated with immunotherapy in the treatment of patients with gastrointestinal cancers. 

Kelley Rone on the Evolving Role of Immunotherapy in GI Cancers

Ripretinib (Qinlock) may be more tolerable than sunitinib (Sutent) in patients with advanced gastrointestinal stromal tumors (GIST) whose disease has progressed following imatinib (Gleevec), according to an analysis of patient-reported outcomes (PROs) presented during the 

Although progression-free survival (PFS) was similar between the 2 agents according to data from the phase 3 INTRIGUE trial (NCT03673501), patients who received ripretinib had fewer total number of days with grade 3 or worse treatment-related toxicities and significantly less physical decline symptoms.

Overall, 24% of patients receiving ripretinib experienced at least 1 grade 3 or worse treatment-emergent adverse event (TEAE) compared with 51% of those receiving sunitinib. In addition, the mean number of days patients experienced a grade 3 or worse TEAE was 11 days with ripretinib vs 42 days with sunitinib (

 < .0001). Among patients who experienced a grade 3 or greater TEAE, the mean number of days was 48 days vs 81 days, respectively.

“Despite not meeting the primary end point of superior PFS, ripretinib may provide meaningful benefit to patients with advanced GIST previously treated with imatinib,” study authors wrote in the poster.

Ripretinib is a switch-control kinase inhibitor approved to treat patients with advanced GIST tumors.

INTRIGUE randomly assigned patients with advanced GIST whose disease had either progressed beyond, or were intolerant to, imatinib, 1:1 to receive ripretinib (n = 223) once daily at 150 mg or sunitinib (n = 221) once daily at 50 mg on a 4-weeks-on, 2-weeks-off regimen. Treatment was administered in a 42-day cycle until discontinuation. To manage toxicities, providers were allowed to modify dosage in accordance with the package insert or institutional guidance, in the case of sunitinib, or at investigator discretion per protocol outlined dose modification, in the case of ripretinib.

Using the EORTC QLQ-C30 and Dermatology Life Quality Index, investigators assessed the PROs reported in the clinical trial. Data were collected on days 1, 15, and 29 of cycle 1, and on days 1 and 29 of all other cycles. Investigators estimated minimum clinically important differences using half of a standard deviation of the response at baseline.

PRO completion rates were similar between the 2 arms. Except for constipation, patients receiving ripretinib reported superior outcomes for all commonly observed TEAEs. Patients in the ripretinib arm also reported significantly less diarrhea, fatigue, appetite loss, nausea and vomiting, and pain, compared with sunitinib, at many follow-up assessments. These patients also demonstrated significantly less decline in role function and physical function at multiple assessments.

Notably, patients receiving ripretinib experienced less impactful skin toxicities than those treated with sunitinib. Upwards of 35% percent of patients treated with sunitinib reported that skin toxicities as having a moderate impact compared with less than 25% of patients receiving ripretinib. Similarly, more than 20% of patients treated with sunitinib experienced skin toxicities that had a very large impact on their quality of life vs less than 10% of those in the ripretinib arm.

“Moderate or severe effect of skin toxicity on patient quality of life as measured by DLQI was more commonly experienced in patients in the sunitinib arm vs patients in the ripretinib arm,” the study authors wrote.

Gelderblom H, Jones RL, Blay JY, et al. Patient reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after imatinib in INTRIGUE, a phase 3 open-label study. 

. 2022;40(suppl 16):11541. doi:10.1200/JCO.2022.40.16_suppl.11541

An analysis of patient-reported outcomes from the phase 3, INTRIGUE trial (NCT03673501) showed that ripretinib had a more tolerable safety profile than sunitinib in treating patients with advanced GIST tumors. 

Ripretinib Exhibits Better Tolerability Profile Vs Sunitinib in Advanced GIST Tumors

Recommendations for the use of liquid biopsies to detect circulating tumor DNA (ctDNA) were recently released by the European Society for Medical Oncology (ESMO). Investigators reviewed available evidence to provide tumor-specific and general consensus on the use of ctDNA and clarify quality standards required for decision-making.

The assay, which is minimally invasive and can provide more convenient and rapid results compared with tissue samples, has become increasingly used in clinical practice to molecularly profile tumors. The release of ctDNA is believed to be proportional to tumor growth with more ctDNA being shed as a tumor grows.

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response. Of note, the guideline authors state there is a lack of clinical evidence to support the recommendation of ctDNA assays in these areas.

“New technologies currently in development, such as methylation pattern-based sequencing, fragmentation pattern-based sequencing or novel ultra-sensitive mutation detection methods, have the potential to optimize utility in these new settings,” the study authors wrote. “Multiple clinical trials are underway that may provide the evidence base to adopt ctDNA assays for decision making in multiple clinical scenarios.”

However, ctDNA assays have a larger role for patients with advanced disease as it can be used to guide adoptive adjuvant strategies upon clinical relapse, identify biomarkers to guide therapy and monitor response to therapy, and, upon disease progression, ctDNA assays can be used to identify acquired resistance mechanisms and the emergence of driver and resistance clones.

The evaluation of ctDNA varies and a single ctDNA assessment is fit for all purposes. Investigators noted that the ctDNA fraction changes based on tumor features such as extent of necrosis, disease burden, tumor location, inflammation, rates of proliferation and apoptosis, tumor microenvironment and host-related phenomena. Treatments such as chemotherapy, targeted therapy, radiation, and immunotherapy can also affect levels of ctDNA and ctDNA fraction.

Liquid genotyping consists of polymerase chain reaction (PCR)-based technologies and many studies have shown positive predictive values between ctDNA liquid biopsy and tissue-based PCR and next-generation sequencing testing in advanced malignancies (95%-99%). High accuracy of liquid biopsy in breast, gastrointestinal and lung cancer for single-nucleotide variants have been reported in large prospective studies of liquid biopsy.

The ESMO guidelines include tumor-specific recommendations for tier 1 and tier 2 variants across tumor types including the following:

 ctDNA genotyping recommended in treatment-naïve patients with cancer with resistance to prior TKIs. ctDNA testing may not have adequate sensitivity to detect 

 true high copy number gain as resistance mechanism to osimertinib (Tagrisso) or lorlatinib (Lorbrena). Further, amplification and fusion detection is suboptimal with ctDNA assays, and should be repeated in tissue where possible.

mutations should preferentially be tested in ctDNA. 

fusions only when advanced tissue biopsy not available.

 ctDNA testing if tissue not available or when fast turnaround time is needed for urgent therapeutic decision-making.

 V600E/microsattelite instability for chemotherapy-naïve metastatic colorectal cancer is recommended when tissue testing is not feasible or urgent therapeutic decision-making. 

 pathogenic or likely pathogenic somatic variants may be carried out if tissue not available.

 for potential PARP inhibitor therapy. Caution is needed when interpreting results of ctDNA assays due to false-positive CHIP mutations in DNA repair genes.

Pancreatic, hepatocellular, endometrial, urothelial, thyroid, and soft tissue sarcoma

In terms of general tumor site recommendations, the ESMO guideline committee noted the occasions where tissue testing may provide confirmatory or more accurate guidance for treatment decision-making. These include interpretation of pathogenic variants such as 

; retesing results that are deemed “not detected” by ctDNA; and for the detection of fusions and copy number events. Further, liquid biopsy should not be taken when a tumor is responding to treatment.

Liquid biopsy may have limitations for the detection of specific deviations, and they risk false negative results and the authors recommend that clinicians take these into consideration when evaluating the results. A false negative result may occur when a patient’s plasma sample does not have sufficient levels of ctDNA or ‘non-shedding’ happens, preventing the detection of a variant. False positive results may occur when clonal expansion takes place in apoptotic hematopoietic cells, where plasma DNA mainly originates; the frequency of clonal hematopoiesis of indeterminate potential (CHIP) increases with age, previous systemic cancer treatment and smoking. False positives can be minimized with either the sequencing of white blood cell DNA or the pairing sequencing of a tumor tissue sample. Additional limitations of ctDNA testing include a low tumor fraction presence in the sample, which prevents reliable assessment of variant allele fraction and limits copy number alteration analysis.

The guidelines recommend that clinicians consult a molecular tumor board for to assess results.

Pascual J, Attard G, Bidard FC, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. 

. Published online July 6, 2022. doi:10.1016/j.annonc.2022.05.520

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response.



ESMO Guideline on Liquid Biopsy Address Quality Standards for Clinical Implementation

The combination of mental, physical, and emotional toxicities of cancer treatment result in a very large burden for patients, according to Lidia Schapira, MD, FASCO. Therefore, finding innovative strategies to improve supportive care and symptom management should be top of mind for all practicing oncology providers.

Schapira, who is a professor of medicine, and director of the Cancer Survivorship Program, at Stanford University, met with 

® to discuss key takeaways from this year’s Symptoms and Survivors’ track at the 2022 ASCO Annual meeting. Schapira’s clinical research is focused on the psychosocial aspects of cancer care and issues that relate to patient experience and health equity, and she participated on the track as an invited speaker in a poster discussion session.

One key takeaway from the session is the value of uniform baseline measurements in clinical practice, she said.

“Having good baseline measurements in clinical practice, and of course, in research, is essential, especially in the field of symptom management,” she told 

®, explaining that a great example of this was an ASCO presentation on vitamin D insufficiency-related peripheral neuropathy which compared the clinician assessment and patient reported assessment of neuropathy.

In this study, participants were evaluated at baseline for 25-OH-vitamin D (D2 + D3) via LC-MS assay. Investigators used logistic regression to identify the association between vitamin D insufficiency and grade 3 or greater sensory neurotoxicity. Vitamin D insufficiency was defined as 20 ng/mL with higher levels signifying vitamin D sufficient status.

Results were adjusted for paclitaxel regimen assignment, age, self-reported race, and body mass index and found that the rate of grade 3/4 chemotherapy-induced peripheral neuropathy (CIPN) was 21% (n = 397) among patients with sufficient status compared with 14% (n = 794) among those with vitamin D insufficiency (odds ratio [OR], 1.57; 95% CI, 1.14-1.15; 

= .005). After adjusting for covariates, the odds ratio was 1.39 (95% CI, 0.98-1.97; 

“Neuropathy is one symptom that has—for decades—been very difficult for us to properly measure,” Schapira said. “The importance of this is that if we don’t quite understand just how much toxicity somebody is experiencing, we could overdose them and [induce] irreparable harm.”

According to Schapira, routine exams which standardize the measurements evaluated alongside neuropathy, as well as encouraging patients to be completely forthcoming about their experience and the symptoms they may be experiencing before it affects their function or ability to move, is critical in providing better support to patients.

“We need to be more rigorous with measurements and the definitions. It is very important to have [uniform] baseline measurements,” she said. “I was very impressed [with the SWOG investigators] and I certainly know that most of my colleagues do not do such detailed physical exams before they see a patient who is about to [receive a] taxane in their practice. [This was] well done.”

Another symptom which calls for more uniform measurement is fear of cancer recurrence, she added.

“So many cancer survivors endure some level of fear, and we do not typically assess it in a rigorous manner,” she said. “Even in research, there are different scales for measuring worry about recurrence and fear of cancer recurrence. But there are no rigid cut offs that determine what is sort of clinically very meaningful and not.”

With a growing population of cancer survivors, the prevalence of this symptoms is continuing to demand attention as well. Without clear guides and rigorous assessment, it may be unclear to a provider which patients could suffice from clinician reassurance and empathic communication and which patients require expert referrals because of disabling distress.

“This is very difficult to measure in the clinic but can really lead to somebody not being able to work [or] being very affected by these symptoms [in other ways],” she noted.

Of course, Schapira noted that these are just 2 examples where improvements are still needed, and that there are number of other potential symptoms which are hard to assess due, in part, to a lack of uniform measurements—such as hot flashes or cognitive decline, for example. Moving forward, she urges oncologists and oncology care teams to be diligent in their baseline measurements in order to improve clinical assessment capabilities.

Chen CS, McCann SE, Budd GT, et al. Vitamin D insufficiency as a peripheral neuropathy risk factor in White and Black patients in SWOG 0221. 

2022;40(suppl 16):12023. doi:10.1200/JCO.2022.40.16_suppl.12023

Lidia Schapira, MD, FASCO, discusses the importance of rigorous baseline measurement in improving the assessment and management of distressful cancer symptoms.

Uniform Baseline Measurements Are Crucial in Improving Standard of Supportive Care

Adding a single priming dose oftremelimumab to regular interval durvalumab (Imfinzi; the STRIDE regimen) was associated with superior overall survival (OS) compared withsorafenib (Nexavar) for patients receiving frontline treatments for unresectable hepatocellular carcinoma (HCC), according to updated data from the phase 3 HIMALAYA trial (NCT03298451). The findings, resented at the 2022 ESMO World Congress on Gastrointestinal Cancer, also found the OS benefit to be consistent, regardless of a patient’s baseline albumin-bilirubin (ALBI) grade.

In patients with ALBI grade 1, the STRIDE regimen elicited a median OS of 23.43 months (95% CI, 19.19-28.75), compared with 19.02 months (95% CI, 15.67-23.16) for sorafenib (HR, 0.79; 95% CI, 0.62-1.01). In patients with ALBI grade 2/3, the STRIDE regimen produced a median OS of 11.30 months (95% CI, 9.33-14.19), vs 9.72 months (95% CI, 7.23-11.76) for sorafenib (HR, 0.83; 95% CI, 0.65-1.05).

Additionally, single-agent durvalumab produced favorable OS outcomes vs sorafenib, irrespective of ALBI grade. In patients with ALBI grade 1, the median OS for durvalumab was 21.16 months (95% CI, 17.38-25.86), compared with 19.02 (95% CI, 15.67-23.16) for soreafenib (HR, 0.91; 95% CI, 0.71-1.15). In patients with ALBI grade 2/3, the median OS for durvalumab was 12.29 months (95% CI, 9.30-16.03), vs 9.72 (95% CI, 7.23-11.76) for sorafenib (HR, 0.87; 95% CI, 0.69-1.09).

“We need to acknowledge that this was a post-hoc analysis, and all analyses that we have performed so far have been in respect to liver function, and they have never been prospectively evaluated,” said Arndt Vogel, MD, PhD. “We have a very clear picture that liver function has a strong prognostic impact, which is important when we talk to our patients.”

®, Vogel, a managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology, and the head of the GI-Cancer Center at the Hannover Medical School, discussed the post-hoc analysis from the randomized, open-label, multicenter, global HIMALAYA trial presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.

®: Can you expand on the rationale of combining tremelimumab and durvalumab in the phase 3 HIMALAYA trial?

: We have seen in the past that immunotherapy has activity in HCC, but monotherapy with just a PD-1 or PD-L1 inhibitor has not been sufficient enough to achieve a positive phase 3 study. We have seen this in trials with pembrolizumab [Keytruda] and nivolumab [Opdivo].

We have seen in the past that CTLA-4 has activity in a subgroup of patients with HCC. This led to a clear rationale to combine CTLA-4- and PD-1­–targeted agents, as we have seen in other tumor types.

There were early data from the phase 3 CheckMate040 trial [NCT01658878] with nivolumab and ipilimumab [Yervoy] that suggested synergistic activity. There was a clear rationale to proceed with [HIMALAYA] in this setting.

What were the unmet needs that the trial aimed to address?

Arndt Vogel, MD, PhD, discusses a post-hoc analysis of the phase 3 HIMALAYA trial which found tremelimumab plus durvalumab to be superior to sorafenib in improving overall survival. 



Gastrointestinal Cancer