OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

As artificial intelligence (AI) in cancer care continues to be better understood and refined, the number of potential clinical applications is rapidly expanding. An area of interest is combining the efficiency and accuracy of AI with already established clinical techniques to better understand the underlying biology of cancer in order to make quick and effective treatment decisions. 

, Zhang et al aimed to assess AI integration with targeted transcriptome for the differential diagnosis of hematologic cancers and solid tumors. They concluded that the approach was useful for the classification and ultimate diagnosis of a variety of cancer types.

“Next-generation sequencing [NGS] is able to interrogate not only the DNA of a malignancy, but also its transcription through RNA, giving us insights into how to best treat patients,” Andrew Pecora, MD, chief innovations officer and vice president of Cancer Services at Regional Cancer Care Associates in Hackensack, New Jersey, and a coauthor of the study, said in an interview with 

®. “Parallel to that, you can’t treat a patient properly unless you know exactly what they have. Many times, pathology is not conclusive as to what is the underlying true diagnosis. We wanted to see whether we could mimic the accuracy of [using] DNA and RNA transcription to make a proper diagnosis. You can’t do that manually because the amount of data you get from a NGS report is enormous—it’s hundreds of millions, if not billions, of pieces of data. A person can never look through that, but machine learning and AI can. We have married information technology at the highest level with genomics at the highest level.” 

Between November 2018 and November 2021, investigators collected 5450 bone marrow and formalin-fixed, paraffin-embedded samples and included hematologic neoplasms (n = 2606) and solid tumors (n = 2038). Leukemia, myelodysplasia, and normal tissue samples were collected from fresh bone marrow, and lymphomas and solid tumors were based on formalin-fixed, paraffin-embedded cancer samples. Morphologic analysis, flow cytometry, immunohistochemistry, and molecular profiling of the DNA and RNA were used to confirm the tumor diagnoses within in 72 hours of collection. NGS was performed via a targeted 1408-gene panel. The most common sample diagnoses included lung cancer (n = 794), diffuse large B-cell lymphoma (n = 746), and myelodysplastic syndrome (MDS; n = 316). For comparative purposes, 782 samples of normal bone marrow and 24 normal lymph node samples were collected. In total, 20 hematologic neoplasm and 24 solid tumor subtypes were identified. 

Following NGS, data were fed into an AI machine learning algorithm, which used RNA expression data to determine a diagnosis to discern the difference between diagnostic classes. Investigators applied the geometric mean naïve Bayes method, designed to address the numeric underflow that occurs with a high-dimensional problem.

Findings from the study showed that targeted transcriptome in combination with the AI algorithm mostly displayed high accuracy with sensitivity and specificity when differentiating between any 2 disease classes. The highest area under the curve (AUC) was observed when the algorithm was asked to distinguish between sarcoma vs gastrointestinal stromal tumor (1.00; 95% CI, 0.997-1.00), pancreas vs esophageal (0.999; 95% CI, 0.990-1.00), and breast vs colorectal (0.997; 95% CI, 0.991-1.00). For a large majority of comparisons, the AUC was above 0.90.

Overall, the sensitivity and specificity of the algorithm were also very high, with most comparisons boasting a sensitivity of above 90% and a specificity of at least 90%. The highest sensitivity ratings were seen between breast vs ovarian (100%), sarcoma vs ovarian (99.2%), and marginal vs chronic lymphocytic leukemia (98.7%). The highest sensitivity figures occurred when comparing sarcoma vs gastrointestinal stromal tumor (100%), Hodgkin vs lymph node (100%), and pancreas vs esophageal (98.9%). 

Conversely, the lowest AUC was observed between normal vs MDS, at 0.831 (95% CI, 0.8010.861). The sensitivity and specificity ratings for this comparison were also low compared with the rest of the study, at 78.1% and 75.3%, respectively. Study authors noted that significant overlap between these 2 specific classes was likely the cause of the decreased reliability. 

To determine the efficacy of the approach at distinguishing among multiple classes to achieve a differential diagnosis, investigators used all 1408 biomarkers without selection to determine a ranked score to predict the likelihood of a given diagnostic class. More than 3000 cases were used to train the machine learning algorithm and the approach was subsequently evaluated using 1415 cases. 

Differential diagnosis efficacy varied among disease classes, with most disease classifications being accurately diagnosed on the first attempt at least 51% of the time. In acute lymphoblastic leukemia (ALL) all 26 cases were accurately given a first-choice diagnosis with a positive predictive value (PPV) of 84%; among 17 chronic myeloid leukemia cases, none were correctly diagnosed the first time. Other disease classifications receiving the most accurate first choice diagnoses were colorectal cancer (n = 83/101; PPV, 79%), brain cancer (n = 12/16; PPV, 75%), lung cancer (n = 177/201; PPV, 73%), and diffuse large B-cell lymphoma (n = 127/149; PPV, 73%). 

“The key fundamental finding is that you can use DNA analysis and RNA transcription to make diagnoses,” Pecora said. “That was not known before, to the extent that we were able to show it. It means that for all of cancer, and possibly in the future other diseases, the ability to make a much more precise diagnosis [that is] much more information content rich...will not only give you a diagnosis, but insights into why the person has a disease, and how best to treat them.” 

To further evaluate the diagnostic accuracy of the approach, investigators generalized the diagnostic classes into 5 groups: lymphoid, myeloid, carcinoma (including brain tumors), sarcoma, and normal. Overall, the algorithm was much more effective in correctly placing a given sample into 1 of these general diagnostic categories on the f irst attempt; 84% of cases were correctly given a first-choice diagnosis.

More specifically, carcinoma (n = 427), lymphoid (n = 427), and myeloid (n = 295), cases were given a correct first-choice diagnosis at a rate of 94%, 91%, and 87%, respectively. Sensitivity ratings for these groups were 81% (95% CI, 77%-84%), 77% (95% CI, 72%-81%), and 44% (95% CI, 38%-49%), respectively. The specificity figures were 95% (95% CI, 92%-96%), 88% (95% CI, 86%-90%), and 77% (95% CI, 75%-80%), respectively. 

Discussing their findings, study authors wrote that their approach is not intended to replace clinical decision-making by pathologists and clinicians but could be used to aid decision-making and add objectivity, efficiency, and reproducibility to the process. Cited limitations of the research included the exclusion of precise molecular mutations and chromosomal abnormalities in the algorithms, adding that integrating these abnormalities would probably significantly improve prediction accuracy. Other limitations included too few cases in some instances, some samples being in the early stages of disease, and variation in tumor fraction. 

Looking ahead, encouraging findings from research such as this could incentivize entities such as diagnostic and biotechnology companies to invest in the space, Pecora said, adding that this could lead to more efficient development of better therapeutics with better outcomes as well as better tools to aid in the proper diagnosis and understanding the genetic reasons a patient has a given disease with unique characteristics. 

“We’ve talked a lot over the past decade about 3 fields of science coming together: biologic sciences, material sciences, and computational science,” Pecora said. “When these fields ultimately come together, we’re talking about changing the whole paradigm of how we approach and treat human disease. In fact, if you take it to its natural extension, you might be on the precipice of changing the human experience. [It’s] no different than over a century ago when we first discovered antibiotics. This is that big of a deal.

Articles

Oncology Live®

As artificial intelligence in cancer care continues to be better understood and refined, the number of potential clinical applications is rapidly expanding.

Adding AI Analysis to Targeted Transcriptome Represents Potential Aid for Differential Diagnosis

Increasing in incidence, neuroendocrine neoplasms include a spectrum of tumors that arise from the specialized cells of the neuroendocrine system.

 Unfortunately, the majority of neuroendocrine tumors (NETs) present in advanced stages and treatment options are limited to somatostatin analogues, radiopeptide therapy, everolimus (Afinitor), and a few chemotherapy and liver-directed options. Novel options are needed, and advances in immunotherapy have not been optimized in NETs. 

To identify novel immune approaches to treat NETs, we explored survivin as a target. Survivin is a ubiquitous protein expressed in various cancer cells, such as glioblastoma, multiple myeloma, and others. Expression of survivin is associated with increased resistance to therapy through inhibition of apoptosis and enhanced cell proliferation.

 Recently, our colleagues from Roswell Park Comprehensive Cancer Center reported findings from a phase 2a study (NCT024455557) showing encouraging survival with SurVaxM, an antisurvivin peptide conjugate vaccine in patients with newly diagnosed glioblastoma.

To learn how prevalent survivin expression is in NETs, we examined NET samples from patients with all grades of cancer and found that survivin expression was a prognostic marker of aggressive biology and shorter survival and correlated with high Ki-67 index.

Survivin was present (≥ 1% or higher) in 51.5% of all NETS that we tested. It was more prevalent in lung NETs (59%), followed by gastrointestinal-pancreatic NETs (16%). Lung NETs are generally aggressive, are associated with poor overall survival of approximately 17 months, have few therapeutic options, and are underrepresented in clinical trials.

 Thus, targeting survivin in NETs has the potential to treat refractory and progressing metastatic NETs that express this protein. We are conducting a pilot study in this group with funding from the Neuroendocrine Tumor Research Foundation.

The key eligibility for this phase 1 study (NCT03879694) of safety and immunogenicity of a SurVaxM in patients with survivin-positive metastatic NETs and neuroendocrine carcinomas (NECs) include the following, biopsy proven NETs or NECs with RECIST 1.1 disease progression within the past 6 months on 2 successive CT scans, and survivin expression confirmed by immunohistochemgranulocyte-macrophage colony-stimulating factor sargramostim (Leukine) at 0, 2, 4, and 6 weeks followed by booster injections every 3 months until tumor progression. Response is assessed with CT scans and immune markers (antibodies and T cells) at baseline, 6, 9, and 12 months. The primary end points of this study are to assess safety, tolerability, and toxicity of this combination. Secondary objectives are assessed in the form of clinical benefit and include rate of progression, immunogenicity measured by antisurvivin IgG levels in serum, survivin specific cytotoxic T lymphocytes, and time to progression.

SurVaxM has been well tolerated in the first 11 patients enrolled, with 2 injection site events (both grade 1) and 1 unrelated cardiac event. Our interim analyses have shown 3 patients with stable disease, including 1 with a high-grade neuroendocrine carcinoma who had disease control for 9 months and 1 with a gastrointestinal NET who had disease control for 3 years. 

To date, patients with prolonged stable disease had high antibody responses, as were observed in the newly diagnosed glioblastoma study, but the sample size here is too small to be conclusive. As we continue enrollment and immune biomarker analysis, we expect to move these findings to larger studies and explore combinations with other potentially synergistic agents. 

Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. 

. 2008;26(18):3063-3072. doi:10.1200/JCO.2007.15.4377 

Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. 

. 2017;3(10):1335-1342. doi:10.1001/jamaoncol.2017.0589 

Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer.

. 2003;22(53):8581-8589. doi:10.1038/sj.onc.1207113 

Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. 

. 2006;5(5):1087-1098. doi:10.1158/1535-7163.MCT-05-0375 

Mita AC, Mita MM, Nawrocki AT, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. 

. 2008;14(16):5000-5005. doi:10.1158/1078-0432.CCR-08-0746 

Ahluwalia MS, Reardon DA, Abad AP, et al. Phase IIa study of SurVaxM plus adjuvant temozolomide for newly diagnosed glioblastoma. 

. 2022;JCO2200996. doi:10.1200/JCO.22.00996 

Hanif A, Lee S, Gupta M, et al. Exploring the role of survivin in neuroendocrine neoplasms. 

. 2020;11(23):2246-2258. doi:10.18632/oncotarget.27631 

NETRF announces $2.5 million in research to advance the NETs. Neuroendocrine Tumor Research Foundation. February 1, 2019. Accessed January 30, 2023. bit.ly/40gcOWa 

A pilot study of SurVaxM in children progressive or relapsed medulloblastoma, high grade glioma, ependymoma and newly diagnosed diffuse intrinsic pontine glioma. ClinicalTrials. gov. Updated January 13, 2023. Accessed January 30, 2023. https://clinicaltrials.gov/ ct2/show/NCT04978727

Novel treatment options are needed in neuroendocrine tumors, and advances in immunotherapy have not been optimized in this population.

Survivin-Targeted Anticancer Vaccine Undergoes Investigation in Metastatic Neuroendocrine Neoplasms

The phase 3 BEACON CRC trial (NCT02928224) served as a landmark study introducing a new standard of care (SOC)— encorafenib (Braftovi) plus cetuximab (Erbitux)—for patients with previously treated microsatellite stable (MSS) BRAF V600E metastatic colorectal cancer (mCRC). Now investigators have set their sights on further improving outcomes with the addition of a third agent, nivolumab (Opdivo).

 Because a positive correlation has been shown between expression of PD-L1 and 

 V600E mutations in CRC, several combination therapies with checkpoint inhibitors and targeted agents are currently being explored.

Following first-line therapy with cytotoxic chemotherapy plus bevacizumab (Avastin), therapy with the BRAF inhibitor encorafenib plus the EGFR inhibitor cetuximab is the subsequent SOC treatment for this subgroup of patients.

 The addition of the PD-1 immune checkpoint inhibitor nivolumab has demonstrated early promising efficacy and safety data and will be explored in a recently launched phase 2 SWOG 2107 trial (NCT05308446).

 mutations occur in approximately 8% to 10% of all patients with mCRC,” Van Karlyle Morris, MD, said in an interview with 

. “MSS BRAF-mutated CRC by numbers probably [occurs] more than the microsatellite instability–high mismatch repair–deficient population— it’s a sizable number of patients who have this [disease].” Morris is an associate professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

“Unfortunately for these patients, this is among the most aggressive subpopulations of patients with mCRC, and we know that chemotherapy is not as effective [in this group],” he said. “Most recently, the phase 3 BEACON trial did demonstrate an improvement in survival outcomes with encorafenib and cetuximab [for these patients, but] median progression-free survival [PFS] was only 4 months, and the overall response rate [ORR] was approximately 20%. BEACON was a step forward, [but] it was a small step forward.” 

The optimal first-line therapy for patients with MSS 

V600E mutations are characteristics that are associated with higher immune activation compared with MSS 

 Investigators have suggested that these “cold” tumors do not responds to immunotherapy treatment, but acknowledge that limited data exist for combination strategies in this population.6 Patients with MSS disease have a poor prognosis and standard cytotoxic combinations as well as monotherapy treatments have provided limited efficacy, resulting in a large unmet need for this subgroup of patients. 

 V600E–mutant CRC demonstrated that tumors may be primed for response to immunotherapy by inhibiting BRAF and EGFR, which cause a loss of expression in mismatch repair genes and promote an microsatellite instability–high phenotype.2 BRAF inhibitors alone are an ineffective treatment because signal upregulation via the EGFR occurs, making it necessary to include an EGFR inhibitor in care.

 To further improve outcomes by suppressing other possible downstream effectors in the MAPK pathway, inhibitors such as MEK and PI3K are being investigated in addition to nivolumab to expand on findings from the BEACON CRC trial.

 This treatment strategy is based on melanoma therapies and similar to earlier trials that evaluated targeting BRAF in metastatic CRC.

To begin assessing the role of PD-1 inhibition in MSS 

 V600E-mutant CRC, a phase 1/2 trial (NCT04017650) is being conducted at MD Anderson Cancer Center by Morris and colleagues.

“We looked at this population of patients with MSS 

-mutated metastatic CRC, [and] treated them with the SWOG 2107 combination of encorafenib, cetuximab, and nivolumab,” Morris said. “We treated 26 patients [and] saw an overall response rate of 50%. We saw a median PFS of approximately 7.5 months, and approximately one-quarter of the patients on our study stayed on the trial for over 1 year. When you think about this very poor prognostic subpopulation of patients staying on a well-tolerated treatment for 1 year, that’s unprecedented and hasn’t been seen before.”

Results presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium demonstrated that at a median follow-up of 16.3 months (95% CI, 6.9-not applicable [NA]), median overall survival with the triplet was 15.1 months (95% CI, 7.7-NA) compared with 9.3 months (95% CI, 8.0-11.3) with encorafenib and cetuximab alone. When assessed for PFS, the doublet had a median delay in disease progression of 4.2 months (95% CI, 3.7-5.4) vs 7.4 months (95% CI, 5.6-NA) with the triplet.

Among the responders, the median duration of response was 7.7 months (95% CI, 3.8-NA) for patients treated with the triplet. Additionally, among 22 evaluable patients, all achieved a partial response, and the disease control rate was 96% (95% CI, 77%-100%). No dose-limiting toxicities occurred; however, 18% of patients experienced grade 3 or 4 treatment-related adverse effects (AEs). Grade 3 AEs included colitis, maculopapular rash, and leukocytosis, as well as elevated amylase/lipase in one patient experiencing a grade 4 event of myositis/myocarditis. Common AEs of any grade included headache (65%), nausea (35%), and maculopapular rash (31%).

“We saw quite striking clinical outcomes on that trial, and [although] exciting, that was at MD Anderson, a single-institution trial, so we’re moving this forward to a randomized trial to test more formally the difference between encorafenib/cetuximab, the current standard alone, or with the addition of nivolumab,” Morris said. 

On the heels of these promising prior results, SWOG 2107 is seeking to enroll approximately 75 patients to further evaluate the triplet therapy vs the SOC doublet in this patient population (FIGURE 9). Patients must have unresectable or metastatic adenocarcinoma of the colon/rectum and must have received 1 to 2 prior lines of treatment for mCRC but not been treated with BRAF, EGFR, or MEK inhibitors or immunotherapies.

Investigators hypothesize that adding nivolumab will result in an improved median PFS of 7.3 months using 80% power and a 1-sided α level of .10. They will compare this against the anticipated outcome with the SOC, which has a median PFS of 4.2 months and overall response rate of 20%.

Patients in the investigative arm of the trial will receive encorafenib once daily orally at 300 mg on days 1 through 28, cetuximab intravenously (IV) at 500 mg/m2 on days 1 and 15, and nivolumab IV at 480 mg on day 1. Patients in the control arm will receive the same doses of encorafenib once daily orally on days 1 through 28 and cetuximab IV on days 1 and 15. The cycles are to repeat every 28 days until disease progression or unacceptable toxicity, and tissue and blood specimen banking will also occur for future correlative studies.

The primary end point is to compare PFS per RECIST 1.1 criteria in the 2 arms, and secondary objectives include comparing overall response rate, overall survival, duration of response, safety, and tolerability and assessing immune- related PFS. The final analysis of PFS is planned for all eligible patients after 66 PFS events occur in the intention-to-treat population. The study was activated in the United States in June 2022; as of January 2023, 8 patients were enrolled.

“We recognize there’s this huge unmet need to do better for our patients with MSS 

-mutated CRC,” Morris said. “If this trial is positive, this can move forward to potentially a larger hopefully registration study, we’ll have to see, but it could mean that there’s a well- tolerated triplet therapy that is extending survival outcomes for this group who, as it stands right now, don’t have many effective options for their treatment.”

Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088 

Morris VK, Guthrie KA, Kopetz S, et al. Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer: SWOG S2107. J Clin Oncol. 2023;41(suppl 4):TPS265. doi:10.1200/JCO.2023.41.4_suppl.TPS265 

Mauri G, Bonazzina E, Amatu A, et al. The evolutionary landscape of treatment for BRAFV600E mutant metastatic colorectal cancer. Cancers (Basel). 2021;13(1):137. doi:10.3390/cancers13010137 

Ciombor KK, Strickler JH, Bekaii-Saab TS, Yaeger R. BRAF-mutated advanced colorectal cancer: a rapidly changing therapeutic landscape. J Clin Oncol. 2022;40(24):2706-2715. doi:10.1200/JCO.21.02541

Tabernero J, Ros J, Élez E. The evolving treatment landscape in BRAF-V600E-mutated metastatic colorectal cancer. Am Soc Clin Oncol Educ Book. 2022;42:1-10. doi:10.1200/EDBK_349561 

Fang C, Lin J, Zhang T, et al. Metastatic colorectal cancer patient with microsatellite stability and BRAFV600E mutation showed a complete metabolic response to PD-1 blockade and bevacizumab: a case report. Front Oncol. 2021;11:652394. doi:10.3389/fonc.2021.652394 

Encorafenib, cetuximab, and nivolumab in treating patients with microsatellite stable, BRAFV600E mutated unresectable or metastatic colorectal cancer. ClinicalTrials.gov. Updated September 2, 2022. Accessed January 27, 2023. https://clinicaltrials.gov/ct2/show/ NCT04017650 

Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAF V600E metastatic colorectal cancer. J Clin Oncol. 2022;40(suppl 4):12. doi:10.1200/JCO.2022.40.4_suppl.012 

Testing the addition of nivolumab to standard treatment for patients with metastatic or unresectable colorectal cancer that have a BRAF mutation. ClinicalTrials.gov. Updated January 31, 2023. Accessed January 31, 2023. https://www.clinicaltrials.gov/ct2/show/ NCT05308446

Because a positive correlation has been shown between expression of PD-L1 and BRAF V600E mutations in CRC, several combination therapies with checkpoint inhibitors and targeted agents are currently being explored.

Triplet Regimen for Microsatellite Stable, BRAF V600E–Mutant mCRC Aims to Build Upon SOC

As carcinoembryonic antigen–related cell adhesion molecule 5 (CEACAM5) continues to show promise a target in patients with non–small cell lung cancer (NSCLC), refinements in testing and the understanding of the implications of its inhibition remain under investigation.

CEACAM5 has been documented to affect expression of cell cycle and apoptotic genes, which may inhibit the efficacy of agents such as fluorouracil.

 As a cell adhesion molecule, the gene encodes the cell surface glycoprotein, a member of the carcinoembryonic antigen family of proteins.

Lung cancer, colorectal cancer, and pancreatic cancer have all been documented as having expression of CEACAM5. In NSCLC, CEACAM5 expression and activity in tissue, cell lines, and murine models have been reported using immunohistochemistry (IHC). These analyses confirmed that CEACAM5 stimulated cancer progression in NSCLC through cell proliferation and migration via the p38-SMAD2/3 signaling pathway.

“It’s more expressed in adenocarcinoma and would potentially be a greater target in non–small cell adenocarcinoma histology,” Chao H. Huang, MD, FACP, said in an interview with 

. “It probably does not have as high an expression in squamous cell [disease], therefore, it might be a more viable target in adenocarcinoma as opposed to squamous cell. [This indicates that] we need more options for squamous cell [disease].” Huang is an associate professor and clinical professor of medical oncology at the University of Kansas Medical Center in Kansas City.

Finding and Delivering Effective Therapies

Delivering cytotoxic agents to CEACAM5-expressing tumors has been effective in early studies leveraging antibody-drug conjugates (ADCs). In lung cancer, for example, using the agent tusamitamab ravtansine (SAR408701) is highly selective for CEACAM5, and is designed to deliver a cytotoxic payload of maytansinoid DM4. Additionally, the ADC has a cleavable linker that remains stable in plasma.

“CEACAM5 [is most often detected] in tissue [and current] clinical trial protocol is to send the tumor biopsy to a central lab to identify expression of this gene through immunohistochemistry [IHC],” Huang said. “[There are different classifications for CEACAM5 expression level based on] the percentage of cancer cells that express it. [Tumors can have] low, intermediate, or high expression.”

Validation of CEACAM5 expression via IHC was conducted in an analysis of samples using the CEACAM5 IHC 769 from Agilent Technologies and Sanofi.

 Using cutoffs of at least 50% expression at least 2+ intensity, the assay was sensitive, specific, precise, reproducible, and robust in evaluating CEACAM5 expression nonsquamous NSCLC.

 The assay was first used for validation in a phase 1/2 study of tusamitamab ravtansine and is now being used in future studies of the agent.

However, Huang noted that issues that persist with other markers that require testing, exist for CEACAM5 as well, including obtaining adequate and ample tissue samples. “Because [CEACAM5 detection] requires tissue, testing for it can sometimes be a challenge,” he said. “Nowadays, when we do a lung cancer biopsy, we want to do molecular testing, and doing that sometimes exhausts the biopsy sample. It could be a challenge to use additional tissue for this IHC [analysis].”

Other barriers to testing include administrative barriers as well as turnaround time. “Although this antibody [test] can be acquired commercially, this testing is not yet standardized, so we cannot just order it in our laboratory and get it done,” Huang said. “[There is] a specific platform, and [testing is performed] by a central laboratory. In the future, once this platform is validated, [testing] can potentially be done in any laboratory, but our challenge right now is getting the tissue and sending it to the central lab, which can have a turnaround time of 7 to 10 days.”

One avenue forward may come in the form of a blood-based assay. “The more reliable and accurate test is done in tissue. However, in the future, we may develop or refine bloodbased testing to better identify CEACAM5 expression,” Huang said. “Testing in the blood is a bit different [because it] relies on the presence of circulating tumor cells. First you need to identify the cancer cells in the blood, then isolate them and do IHC staining on them. Technically, it can be done, but the challenge is finding those circulating tumor cells. If you don’t find them, you cannot do the testing. Even if you do the testing, [you may not truly find] cancer cells, meaning you could have a false-positive result.”

Alexander I. Spira, MD, PhD, FACP, noted that CEACAM5 is not currently detectable in the blood, but it could be a pathway forward should testing for the marker increase. “It would be great if we had a blood test instead because we wouldn’t [face issues such as] needing to wait for tissue or running out of tissue,” Spira, who is codirector of the Virginia Cancer Specialists Research Institute and the Phase I Trial Program in Fairfax and an assistant professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland, said in an interview with 

. “This is something that, with hard work, should be surmountable, although it’s proving more challenging [than we initially thought], until CEACAM5 [testing is done routinely]. However, that usually happens once the drug is commercially available, rather than in clinical trials.”

Blumenthal RD, Leon E, Hansen HJ, Goldenberg DM. Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers. 

CEACAM5 CEA cell adhesion molecule 5 [ Homo sapiens (human)] National Cancer Institute. Updated January 1, 2023. Accessed February 2, 2023. https://www.ncbi.nlm.nih.gov/gene/1048#gene-expression

Zhang X, Han X, Zuo P, Zhang X, Xu H. CEACAM5 stimulates the progression of non-small-cell lung cancer by promoting cell proliferation and migration. 

. 2020;48(9):300060520959478. doi:10.1177/0300060520959478

LaPointe N, Hertle N, Chi Hsu S, et al. Validation of an immunohistochemical assay, CEACAM5 IHC 769, under development for use with the antibody-drug conjugate tusamitamab ravtansine (SAR408701). 

. 2021;39(suppl 15):e21030. doi:10.1200/JCO.2021.39.15_suppl.e21030

Johnson ML, Chadjaa M, Yoruk S, Besse B. Phase III trial comparing antibody-drug conjugate (ADC) SAR408701 with docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) failing chemotherapy and immunotherapy. 

. 2020;38(suppl 15):TPS9625. doi:10.1200/JCO.2020.38.15_suppl.TPS9625

As carcinoembryonic antigen–related cell adhesion molecule 5 continues to show promise a target in patients with non–small cell lung cancer, refinements in testing and the understanding of the implications of its inhibition remain under investigation.

Finding and Leveraging CEACAM5 Presents Opportunities and Pitfalls

As targeted agents for various levels of HER2 expression have demonstrated dynamic interoperability and efficacy, the prognosis for HER2-positive disease has improved. Because 15% to 20% of breast cancers are HER2-positive, investigators have carefully examined what makes each pathology unique and how best to address it.

 is a gene that when turned on really drives how a breast cancer will behave,” Virginia F. Borges, MD, said in a recent 

. “Twenty years ago, women would often lose their lives to this type of cancer within 6 to 12 months. Now, with the advance of disease understanding and drugs that we’re going to be spending a lot of time talking about today, that’s been totally flipped on its head.”

Moderator Joyce A. O’Shaughnessy, MD, concurred, “It is absolutely remarkable, isn’t it, just in our lifetime we’ve gone from one of the worst possible cancers to really arguably the best [to treat] in terms of outcomes. Those days are well in the past.” During the discussion, the panel reviewed advances in early-stage and metastatic disease, including the latest standards of care and treatment sequencing changes.

Early-Stage Disease Standards Align With Patient Specificities 

Debu Tripathy, MD, noted that although anthracycline-based regimens in HER2-positive disease are not common, there are scenarios in which neoadjuvant use of this antibiotic may be appropriate. “We tend to use a taxane and trastuzumab [Herceptin] or pertuzumab [Perjeta], for higher-risk disease,” he said. “The addition of platinum is also still controversial as we haven’t formally tested it, but in the metastatic setting the platinum doesn’t seem to add much.”

Tripathy added that he would consider keeping anthracycline-based therapy in patients with higher-risk disease “but will de-escalate and drop the carboplatin if there is resistance.” Additionally, if there is no response to neoadjuvant therapy, or if a patient has a biphenotypic tumor, he would do so as well, although that is not the usual practice. “If the lymph node is HER2-negative, but the primary tumor is HER2positive, those would be situations in which we would use anthracyclines.”

Preoperative therapy considerations for earlystage resectable disease require a more nuanced approach.3 In patients with stage I disease, “we proceed with surgery first to make sure that they are not upstaged, and then we use the [adjuvant paclitaxel and trastuzumab] APT regimen,” Tripathy explained.

Borges, agreed, adding that “in general, I am only holding off on preoperative therapy for those times when a patient is diagnosed early. For example, a screening mammogram just happened to catch it at the right moment, so you’re looking at tumor that is subcentimeter or even below 1.5. The below–0.5-to–2 zone starts to become the inflection point where I might lean in towards the neoadjuvant therapy,” she said.

In early-stage disease, O’Shaughnessy said, the pathology report influences her decisions. “There are few of those stage I patients out there that I’m just not ready to not give 2 chemotherapy agents to,” she said, citing how data from the FeDeriCa trial (NCT03493854) exploring the efficacy of subcutaneous pertuzumab and trastuzumab in a fixed-dose combination may impact practice.

Maryam Lustberg, MD, MP, noted that in her experience, this regimen has demonstrated a notable effect. “The FeDeriCa [dose] was able to be implemented and was very well-tolerated and accepted by patients,” she said. “The primary advantage is that it absolutely reduces chair time and frees up our nursing colleagues to be able to take care of additional patients.”

All panel members said they use this regimen, with O’Shaughnessy elaborating: “The primary end point for the FeDeriCa trial was the trough levels of the pertuzumab, and a secondary end point was the trough level of the trastuzumab at cycle 8, and in both the pertuzumab and the trastuzumab, the subcutaneous trough levels were actually a little higher in the subcutaneous delivery than in the [intravenous]. There was no hint that even after 3 weeks we were losing the bioavailability and the persistence, so that was very reassuring.” She also noted that the pathologic complete response (pCR) was also equivocal at 60% for both arms.

 “You couldn’t get more identical and the disease-free survival data, which came later, were also spot-on.”

Moving on to adjuvant considerations, the panel noted that ado-trastuzumab emtansine (T-DM1; Kadcyla) has become the standard of care for individuals with residual disease

 but that there are other treatment considerations depending on response to neoadjuvant therapy. “For our patients who receive their upfront neoadjuvant chemotherapy regardless of the regimen chosen, if they’ve achieved complete cell-killing in the tumor and lymph nodes, have the pCR, then we think that’s a fantastic situation and we would feel comfortable leaving them on the trastuzumab/pertuzumab for completion of the year of adjuvant therapy,” Borges said. “But then for the data that we saw in the KATHERINE trial [NCT01772472],

 which was practice-changing, we know that for those patients who don’t have pCR, their risk of developing metastatic disease is much more significant.”

The study evaluated trastuzumab vs T-DM1 in patients with HER2-positive breast cancer who have residual tumor in the breast or axillary lymph nodes following preoperative therapy.

 “There was about a 50% difference there, depending on the treatment that was administered in the adjuvant setting, and therefore the KATHERINE trial used T-DM1 in that space and showed that that would improve the cure rates, with approximately 12.5% of those patients potentially experiencing metastatic disease in the future,” Borges said. “So, for us that became practice-changing overnight, that anyone with residual disease would go on to receive the T-DM1.”

Overtreatment with preoperative and postoperative regimens has sparked interest in de-escalating regimens and led to such studies as the CompassHER2-pCR trial (NCT04266249),

 in which investigators are looking to use neoadjuvant docetaxel, trastuzumab, and pertuzumab followed by 1 year of trastuzumab and pertuzumab without additional chemotherapy after a pCR. “This does what I call Goldilocks it. Just right, not too little, not too much, knowing that you can always give more [therapy] after surgery if the patient doesn’t achieve a pCR and offer them T-DM1 with or without the addition of tucatinib [Tukysa], which is a tyrosine kinase inhibitor that specifically targets HER2,” Borges said.

Tucatinib received FDA approval in 2020 based on data from the HER2CLIMB trial (NCT02614794), in which the agent was administered to patients in the metastatic setting.

 In the adjuvant, early-stage setting, tucatinib is being investigated in the phase 3 CompassHER2 RD trial (NCT04457596) as a dual HER2 blockade option for those receiving T-DM1. Other antibody-drug conjugates under investigation include fam-trastuzumab deruxtecan-nxki (Enhertu), in DESTINY-Breast05 (NCT04622319) (

For now, T-DM1 remains the treatment of choice and current recommendation of the National Comprehensive Cancer Network (NCCN) for patients with residual/metastatic disease.

 “The very long preoperative chemotherapy regimen does a lot to patients, and the most common complaints that I’ve experienced with my patients are fatigue and neuropathy,” Lustberg said. “Initially, there was a question about whether T-DM1 could be safely combined with concurrent radiation therapy, and now we have a study that was reported out that it can. We are following that practice, with the concern being whether there would be increased rates of pneumonitis or interstitial lung disease, which were not seen with T-DM1.” Lustberg said that conveying expectations to patients is a key factor in delivering these treatments and that active symptom management also plays a role.

Tripathy pointed out that thrombocytopenia is also an adverse effect (AE) that should be monitored, but that neuropathy is more difficult for patients to cope with: “We monitor those patients closely, and a lot of them do drop off ahead of time.” O’Shaughnessy added that her experience with adjuvant T-DM1 has “largely has been very favorable. There are exceptions, [but] once they get a couple cycles, [patients] feel great. I’m impressed at the lack of fatigue and the fact that they can, pretty much, quickly get back into full life. The hair comes back, so the vast majority do well. However, I’ve had some patients go down on the dose because of thrombocytopenia or neuropathy. If it persists or worsens, I switch them back to the trastuzumab/pertuzumab, but they’re the distinct small minority and the vast majority do very well.”

In the adjuvant setting for patients who received pertuzumab in addition to the backbone regimen of a taxane, carboplatin, and trastuzumab, there was an equivalent response to treatment with taxane, carboplatin, and trastuzumab alone in the phase 3 APHINITY trial (NCT01358877).

At a preplanned 6-year analysis, a statistically significant difference was observed in invasive disease-free survival (iDFS) of 91% vs 88% with placebo (HR 0.76; 95% CI, 0.64 -0.91).

 The largest benefit was in the node-positive cohort, with a 5% difference in iDFS between the investigative and control study arms (HR, 0.72; 95% CI, 0.59-0.87), at 88% and 83%, respectively. “The node-negative population really didn’t seem to benefit,” O’Shaughnessy said. “Where I run into problems is T2 disease, maybe even 1.5 cm and above as an inflection point. Do you give them the [trastuzumab and chemotherapy] or you go with the APHINITY data [with the addition of pertuzumab] there?”

Tripathy said that he uses the FDA criteria of 2 cm or greater and that it is important to consider cost and adverse effects when weighing the small benefit provided by the addition of pertuzumab.

 “When you look at it more closely, cardiotoxicity is no different. There is more diarrhea, even in the maintenance phase there’s more diarrhea, but I still go by those criteria,” he said. “I discuss that with the patient. It’s important for them to know the small benefits and overwhelmingly, our patients really want to go ahead with the FDA 2-cm-cutoff. That’s what we use, but I agree with the numbers you provided, and they need to be shared with the patient and discussed.”

For patients who have had surgery first and have node-negative disease, Lustberg favors a dual HER2 approach: “I also see a bit of practice variation for patients who have had preoperative chemotherapy and achieve a pCR. If dual HER2-targeted therapy worked for them to help them achieve a pCR, it’s clear to me that you would continue that in the adjuvant setting. But I think perhaps it’s important to know that there is some practice variation across the country on this with some practitioners de-escalating to trastuzumab, especially in those who have node negativity.”

The prescribing information for pertuzumab in the neoadjuvant setting specifies that if dual blockade is given, it should be continued, even if patients achieve a pCR, O’Shaughnessy emphasized.

“There have been data from the community setting that there’s been this tendency towards not continuing the pertuzumab in the setting of a pCR, which I would not do,” Borges added. “If I felt like the patient was high enough risk at the get-go to merit the combinatorial regimen, then that is what I’m committed to as the baseline, that’s what I’m going to carry through into the adjuvant setting even if they’ve achieved a pCR based on the data that we have today.”

Another potential escalation strategy is to use neratinib (Nerlynx), an oral pan-HER inhibitor tested in the adjuvant setting following trastuzumab in the ExteNET study (NCT00878709).

 “This study was [done] before we had pertuzumab and before T-DM1,” Tripathy noted. “[After] just the antecedent trastuzumab, the primary end point of iDFS was met. And it was, interestingly, very similar to the APHINITY, which also broadened the inhibition of the HER family which is, of course, what neratinib does as well.”

A more pronounced benefit was seen among those with estrogen receptor–positive disease. “It was 2.5% absolute improvement, but if you look at the subset analysis, all the benefit was in the ER–positive patients, where it was larger,” Tripathy said. “It went up to around 4.5% or so. And then they did an exploratory analysis of the 250 patients in the ExteNET who had gotten preoperative therapy. They still had residual disease and then they finished up their year of trastuzumab and were randomized to neratinib versus not. Which, of course, is how we treat the higher-risk patients. And there in the highest-risk population they saw the greatest benefit only in the ER-positive patients. But they had a 7.5% improvement in basic diseasefree survival and a surprising 9% absolute improvement in overall survival in the highest-risk population. And it was in those patients who were randomized within a year of having finished up their adjuvant trastuzumab.”

Tripathy said he reserves neratinib for higher-risk patients, generally those with residual disease or those who may have received adjuvant therapy but have node-positive disease. “I think it’s really interesting that we know the interaction of the HER2 and ER pathway to some extent, and I think that because HER signaling creates resistance to endocrine therapies, the blockade of that pathway may be making patients more sensitive to the endocrine therapy they’re getting,” he said. “That may be part of the benefit. But in any event, now that we have some methods to abate the diarrhea, which is really the biggest problem, by slow escalation of the dose, and I even go slower than what was published in the control study, and that has definitely helped me keep patients on treatment.”

Tripathy said he starts at 120 mg neratinib, escalating by the 40-mg tablet size. “I do it more slowly. I’ll go a whole week at the lower dose and then go up for another week. It may take me several weeks to get there, but I find that that’s a little bit better. Some patients are impatient, and they want to get up to the doses, so I just go with the control schema, which is a little more accelerated, as you know.”

Long-term data from the APT trial (NCT00542451), in which adjuvant paclitaxel and trastuzumab were administered to patients with node-negative, HER2-positive breast cancer was presented at the 2022 San Antonio Breast Cancer Symposium. At the final, 10-year follow-up, analysis showed an iDFS rate of 91.3% (95% CI, 88.3%-94.4%) among 406 patients in the intention-to-treat population. The recurrence-free interval was 96.3% (95% CI, 94.3%-98.3%), and these results were consistent across patients with hormone receptor–positive (96.2%) and hormone receptor–negative (96.4%) disease.

“At 5 years, the invasive disease-free survival was 96%, at 7 years it was 93%, and [at] the 10-year update, it’s down to 91%,” Tripathy said. “More hormone receptor–positive cancers, as you might expect, are having delayed recurrences. It’s still holding up to what the design was in terms of the event rate, but it is something that we need to track and maybe recalibrate who we might put on that study.”

Long-term follow-up was also presented from the ATEMPT trial (NCT01853748), in which patients received 1 year of adjuvant T-DM1 (n = 383) or trastuzumab/paclitaxel (n = 114).16 At a median follow-up of 5.8 months, the 5-year iDFS rate with T-DM1 was 97.0% (95% CI, 95.2%-98.7%), the 5-year recurrence-free interval was 98.3% (95% CI, 96.3%-99.0%), and the 5-year OS rate was 97.8% (95% CI, 96.3%-99.3%).

The T-DM1–alone regimen may actually be a better, but we don’t have the formal comparisons to be able to say that,” Tripathy observed. The study was not powered to evaluate the efficacy of trastuzumab/paclitaxel, but investigators reported that the 5-year iDFS was 91.3% (95% CI, 86.0%-96.9%).

Another trial was initiated to compare these regimens, known as the ADAPT trial (NCT01817452).

 “This [was] really designed to compare the toxicities between the APT and the ATEMPT regimens, not to compare the outcomes,” Tripathy noted. “ATEMPT 2.0 [NCT04893109]

 is a larger study that is embarking. But again, the main objective there is to compare AEs. What we’re seeing preliminarily from the ATEMPT trial is that there is less long-term neuropathy, which is a problem you get [with] paclitaxel. Now there’s neuropathy, there’s thrombocytopenia, there’s higher discontinuation from treatment with T-DM1, but the longer-term neuropathy is actually less. There may, in the end, be some advantages from that that will be confirmed with the ATEMPT 2.0 trial.”

The clinical implications of these findings are already echoing in real-world practice.

“For the T-DM1 as adjuvant, I have used that for the patient who just digs in their heels and says, ‘I’m not going to do chemotherapy,’ ” Borges said. “And I realize what T-DM1 is as a drug but as a patient-facing option, it doesn’t quite feel the same as being asked to take something such as 12 weeks of paclitaxel or the regimen of [a taxane, carboplatin, trastuzumab]. Although it’s off guidelines, and I have a very careful conversation with the patient about that, I have in a few circumstances been able to get that approved. Or similarly, if I have a patient who has a cancer for which adjuvant therapy is going to be indicated but [she] has a lot of preexisting neuropathy, type 1 diabetes, for which a lot of steroids would be highly undesirable, [that] would be the other time I’ve turned to that as opposed to the no-treatment option that would be the alternative in those situations.”

Another consideration is the frequency of visits, especially if spikes in transmittable infections such as influenza or COVID-19 are reported. For instance, Lustberg said she used the ATEMPT regimen during COVID-19 surges. Additionally, drug-drug interactions play an important role. “There have been 2 patients who recently have had moderate interactions with their existing drugs and paclitaxel. For example, I have a patient who has a pretty severe preexisting seizure disorder and is on phenobarbital, and with paclitaxel, the interaction was moderate to severe, so I was able to get the 17 cycles of T-DM1 per ATEMPT approved and explained that ATEMPT 2.0 is looking at a much shorter duration of T-DM1. Depending on her toxicities, I will probably shorten off study.”

Patient profile also plays a role in the treatments Tripathy recommends. “I give the paclitaxel/trastuzumab or APT regimen for my patients with stage I, T1a, T1b, and even a few T1c disease for whom adjuvant treatment makes sense,” he said. “When a patient is T1a, you could say that gets into the territory of a no-adjuvant-treatment option. I treat a lot of very young women, aged 30 years, and they’re not comfortable with that. But I don’t want to subject them to the toxicities of [taxane, carboplatin, trastuzumab] or certainly not docetaxel, carboplatin, trastuzumab, and pertuzumab at that level. Trastuzumab/paclitaxel is a really nice comfort zone of being able to still give them something that I think is going to be effective against stage I disease, which some of these young women fall into a bit more than some of our older patients, although not exclusively.”

Breast cancer HER2 status. American Cancer Society. Updated August 25, 2022. Accessed January 30, 2023. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html 

Cancer stat facts: female breast cancer subtypes. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed January 30, 2023. https://seer.cancer.gov/statfacts/html/breast-subtypes.html 

Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. 

. 2015;372(2):134-141. doi:10.1056/NEJMoa1406281

Tan AR, Im SA, Mattar A, et al; FeDeriCa study group. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study. 

. 2021;22(1):85-97. doi:10.1016/S14702045(20)30536-2

NCCN. Comprehensive Guidelines in Oncology. Breast cancer, version 1.2023. Accessed January 30, 2023. bit.ly/3X8bxxM

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. 

. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

File D, Curigliano G, Carey LA. Escalating and de-escalating therapy for early-stage HER2-positive breast cancer. 

FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed January 30, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer 

T-DM1 and tucatinib compared with T-DM1 alone in preventing relapses in people with high risk HER2-positive breast cancer, the CompassHER2 RD trial. ClinicalTrials.gov. Updated February 17, 2022. Accessed January 30, 2023. https://clinicaltrials.gov/ct2/show/ NCT04457596

A study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in high-risk HER2-positive participants with residual invasive breast cancer following neoadjuvant therapy (DESTINY-Breast05). Updated February 3, 2023. Accessed February 5, 2023. https://www. clinicaltrials.gov/ct2/show/NCT04622319

Jagosky M, Tan AR. Combination of pertuzumab and trastuzumab in the treatment of HER2-positive early breast cancer: a review of the emerging clinical data. 

. 2021;13:393407. doi:10.2147/BCTT.S176514

Piccart M, Procter M, Fumagalli D, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years’ follow-up. 

. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204

Phesgo. Prescribing information. Genentech, 2020. Accessed January 30, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf 

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. 

. 2021;21(1):80-91.e7. doi:10.1016/j.clbc.2020.09.014

Taratino P, Tayob N, Dang CT, et al. Adjuvant trastuzumab emtansine versus paclitaxel plus trastuzumab for stage I HER2+ breast cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033). Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Tolaney S, Taratino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab trial (APT) for node-negative, human epidermal growth factor receptor 2–positive (HER2+) breast cancer: final 10-year analysis. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

A prospective, randomized multicenter, open-label comparison of preoperative combination of trastuzumab and pertuzumab with or without concurrent taxane chemotherapy given for twelve weeks in patients with operable HER2+/HR- breast cancer within the ADAPT protocol (ADAPT). ClinicalTrials.gov. Updated July 23, 2019. Accessed February 5, 2023. https://www.clinicaltrials.gov/ct2/show/NCT01817452

ATEMPT 2.0: adjuvant T-DM1 vs TH. ClinicalTrials.gov. Updated January 31, 2023. Accessed February 5, 2023. https://clinicaltrials.gov/ct2/ show/NCT04893109

As targeted agents for various levels of HER2 expression have demonstrated dynamic interoperability and efficacy, the prognosis for HER2-positive disease has improved. 

Old Standards Are Revisited in HER2+ Early-Stage Breast Cancer

It is difficult to overstate the remarkable progress made in translating our understanding of cancer biology into beneficial therapeutic strategies for patients with malignant disease. Hardly a week or even a day goes by without a report published in a peer-reviewed journal or presented at a national cancer meeting about a new and possibly quite novel antineoplastic agent demonstrating an improved outcome (objective response rate, progression-free survival, overall survival) compared with an existing standard of care.

Successful manipulation of the immune system to achieve regression of cancer, long an unfulfilled goal of oncologic investigation, is an ever-increasing reality in multiple clinical settings. Checkpoint inhibitors, chimeric antigen receptor T-cell strategies, immune conjugates, and bispecific antibodies represent just some of the novel approaches to cancer management. Targeted therapies, based on the presence of specific molecular abnormalities within individual tumors, represent another exciting strategy that have become an increasingly routine approach to treatment.

The enormous effect of decades of advances in prevention (eg, tobacco control), screening, and therapeutics has been emphasized in a recent publication from the American Cancer Society, which noted that the cancer death rate in the United States decreased 33% from 1991 to 2020.

 This translates into “an estimated 3.8 million deaths averted.”

Unfortunately, an accompanying component of this revolution in cancer care is the well-documented escalation in the costs of these new therapeutics, resulting in serious financial toxicity for an expanding proportion of patients and their families. Further, there appears to be no meaningful barriers to the continuation, and even acceleration, of this distressing process.

The existing medical literature contains considerable content regarding the issues highlighted above, including several evolving approaches, such as “maintenance therapy.” However, in the opinion of this commentator, what has been surprisingly lacking in written or verbal discussions of the future of oncology is the evolution of cancer as a serious but more 

 process with critically relevant implications for patients, families, and society.

Before proceeding, it is critical to understand what the term chronic means in the context of cancer management. 

Webster’s New Twentieth Century Dictionary

, second edition, defines the term as “continuing a long time; also, recurring, as a disease; or having had an ailment or habit for a long time.” Thus, chronic implies a prolonged duration or a recurring process. It is essential to note there is nothing in this definition that implies a chronic illness is not serious, potentially debilitating, or fatal. One only needs to consider the well-recognized, potentially life-threatening complications associated with diabetes, perhaps the classic chronic medical condition.

No specific duration of a disease qualifies a particular malignant condition as chronic. However, it is reasonable to suggest characterizing the disease process for many patients as being more chronic than acute in settings where multiple lines of active therapy known to favorably affect survival are available and routinely employed.

Successful manipulation of the immune system to achieve regression of cancer, long an unfulfilled goal of oncologic investigation, is an ever-increasing reality in multiple clinical settings.

Vol. 24/No. 4 | Oncology Live®

Adding AI Analysis to Targeted Transcriptome Represents Potential Aid for Differential Diagnosis

Survivin-Targeted Anticancer Vaccine Undergoes Investigation in Metastatic Neuroendocrine Neoplasms

Triplet Regimen for Microsatellite Stable, BRAF V600E–Mutant mCRC Aims to Build Upon SOC

Finding and Leveraging CEACAM5 Presents Opportunities and Pitfalls

Old Standards Are Revisited in HER2+ Early-Stage Breast Cancer

The Implications of the Underappreciated, Evolving View of Cancer as a Chronic Illness