Gregory Botta, MD, PhD, a medical oncologist and an associate professor of medicine at the University of California, San Diego (UCSD) Health, Moores Cancer Center at UCSD, discusses the diagnosis and treatment of patients with esophageal squamous cell carcinoma (ESCC).

Patients with ESCC may initially seek treatment due to trouble or pain with swallowing, dysphasia, or weight loss. Patients may also experience excess salivation or regurgitation of food. Additionally, some patients may experience hoarseness due to the disease’s local invasion around the vocal cords. Moreover, some patients will be diagnosed from a laboratory analysis that is conducted due to chronic blood loss and anemia associated with ESCC, Botta explains. When a symptomatic patient seeks care, the priority is to refer the patient for assessment by a gastroenterologist, who can perform an esophagogastroduodenoscopy (EGD), Botta continues.

However, approximately 5% to 10% of patients with ESCC are asymptomatic, according to Botta, who adds that a diagnosis of ESCC may be made only because a patient happened to receive an EGD or another scan.

When a patient is diagnosed with ESCC, it is important to note that this histology differs from esophageal adenocarcinoma, Botta explains. When a patient is diagnosed with ESCC, clinicians look for PD-L1 expression with the tumor proportion score (TPS) or the combined positive score (CPS), which could serve as indicators to how well a given patient may respond to treatment. However, chemoimmunotherapy is generally the standard of care for patients with ESCC, irrespective of PD-L1 status, Botta notes. although.

Although there are some instances where immunotherapy may not be combined with chemotherapy, most patients with ESCC are responsive to immunotherapy, even without a high expression of PD-L1. A longer or more robust response could be expected from the addition of immunotherapy for patients with a higher PD-L1 TPS or CPS, Botta concludes.

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Gregory Botta, MD, PhD, discusses the diagnosis and treatment of patients with esophageal squamous cell carcinoma.

Dr. Botta on the Diagnosis and Treatment of ESCC

Gregory Botta, MD, PhD, medical oncologist, associate professor of medicine, University of California, San Diego Health (UCSD), discusses unmet needs in the salvage setting of gastrointestinal cancers.

A phase 1b trial (NCT04404595) is evaluating CT041, a Claudin18.2 (CLDN18.2)–specific CAR T-cell therapy as another potential treatment option for patients with advanced gastric or pancreatic cancer.

Limited treatment options currently exist in the salvage setting for patients with advanced disease in these populations, Botta says. Additionally, comorbidities that increase over time make treatment decisions more difficult, Botta explains. For example, the patients may lose the ability to eat or drink, Botta adds.

By shifting treatments into earlier settings, patients may be able to benefit from these therapies before developed comorbidities become an issue, and that could prolong the time until patients need to be on chemotherapy, Botta concludes.

Gregory Botta, MD, PhD, discusses unmet needs in the salvage setting of gastrointestinal cancers.


Dr. Botta on Unmet Needs in the Salvage Setting of GI Cancers

Gregory Botta, MD, PhD, medical oncologist, associate professor of medicine, University of California, San Diego Health (UCSD), discusses the rationale for investigating CT041 in patients with advanced gastric and pancreatic cancers in a phase 1b trial (NCT04404595). 

In the single-arm, open-label, multicenter study, investigators evaluated CT041, a Claudin18.2 (CLDN18.2)–specific CAR T-cell therapy, in patients with advanced gastric or pancreatic cancer.

Since these patients with gastric and pancreatic cancers failed or were intolerant to prior systemic therapies, the trial evaluated for a different mechanism of action with CT041, Botta say. Though chemotherapy can still be an option for these patients, its limited efficacy and unfavorable toxicity leaves an unmet need, Botta adds. Enrolled patients experienced as many as 6 previous lines of therapy, had comorbidities, and had a poor quality of life, Botta explains.

On the trial, investigators were able to get patients through treatment while eliciting responses in this difficult-to-treat population, Botta concludes.

Gregory Botta, MD, PhD, discusses the rationale for investigating CT041 in patients with advanced gastric and pancreatic cancers in a phase 1b trial. 


Dr. Botta on the Rationale of Investigating CT041 in Gastric and Pancreatic Cancers

Gregory Botta, MD, PhD, medical oncologist, associate professor of medicine, University of California, San Diego Health (UCSD), discusses the evaluation of CT041 in patients with advanced gastric and pancreatic cancers in a phase 1b trial (NCT04404595).

In the open label, multi-center study, investigators evaluated CT041, a CAR T-cell therapy that targets Claudin18.2 (CLDN18.2).

Heavily pretreated patients in the population were able to achieve responses up to 60% in the salvage line setting, Botta says. Moreover, patients who have been on multiple lines of chemotherapy and present with various comorbidities were able to safely complete the CAR T-cell therapy and lymphodepletion, Botta explains.

The patient population had previously been treated with years of chemotherapy, and by moving to CAR T-cell therapy, patients have the potential to be off of chemotherapy for up to 10 months, Botta continues. Overall, during the chemotherapy holidays patients saw a marked improvement in quality of life, representing a component of nonchemotherapeutic efficacy that is being observed in these patients, Botta concludes.

Gregory Botta, MD, PhD, discusses the evaluation of CT041 in patients with advanced gastric and pancreatic cancers in a phase 1b trial.

Dr.  Botta on the Evaluation of CT041 in Gastric and Pancreatic Cancer

 The CIRCULATE-US study is basically an NRG Oncology NCI [National Cancer Institute]-developed protocol that has been FDA approved for the Signatera assay. It’ll be enrolling in the first half of this year. The study is going to enroll approximately 2000 patients with stage II or III colon cancer after resection. Similar to the CIRCULATE-Japan study, it’s going to follow them over time to determine if their ctDNA [circulating tumor DNA] remains negative after surgery or adjuvant therapy or whether it initiates to a positive study.

At the end of the day, the endpoints in these are molecular residual disease–negative patients and whether initiating therapy immediately vs later changes their outcomes. Meaning that after your surgery, your adjuvant therapy isn’t initially given if your ctDNA is negative. However, if it turns positive, then adjuvant therapy is given. The other is that the patients who are postsurgical who have molecular residual disease positivity are either going to be given standard of care CAPOX [capecitabine, oxaliplatin] or FOLFOX [fluorouracil, leucovorin, oxaliplatin] regimens, or an intensified adjuvant chemotherapy regimen. That’s very similar to the CIRCULATE-Japan study.

Ultimately, the big question is going to be whether the results of these studies can be combined so that we have an enlarged or enriched patient population. However, the CIRCULATE-US trial will be following in the footsteps of the CIRCULATE-Japan trial. Considering how quickly the CIRCULATE-Japan trial has enrolled and how many patients are now involved, we’d expect to see a similarly enrolled patient population in the US, and I’d expect us to be able to have very comprehensive and sensitive data with those numbers of patients.

Other very intriguing studies for the use of ctDNA are the neoadjuvant studies in which we’re determining whether a patient should go to surgery. I’m thinking about rectal cancer in particular. When we’re evaluating rectal cancer, the overwhelming standard of care leans toward total neoadjuvant therapy [TNT], in which we’re using both a chemotherapy-based regimen as well as chemoradiation. Ultimately, at the end of TNT, the idea is to move to surgical resection. However, we know that some patients have curative, complete responses, seen both radiographically as well as on flexible sigmoidoscopy. In those cases, patients are being initiated on watch-and-wait protocols in which they’re not moving forward with surgery.

That’s a big deal in the rectal world. Surgical resection of rectal cancer can lead to colostomies and sometimes permanent colostomies. We also know that (patients diagnosed with) rectal and colorectal cancer are becoming increasingly younger. It makes a significant deal for a patient in their 30s and 40s to move forward with resection of their rectal cancer and have a colostomy for the rest of their life. As such, we’re looking for tools to help us better understand the watch-and-wait protocol.

This is where ctDNA would come into play. If a patient is able to get to MRI negativity on their radiographic response after TNT and they’re able to have a flexible sigmoidoscopy that shows that there’s no disease burden, and then they have a ctDNA that shows no molecular residual disease, can we feel more confident in moving to a watch-and-wait approach? Can that ctDNA help guide that watch-and-wait approach? Can we reduce the number of MRIs that we’re getting in a year? Can we reduce the number of flexible sigmoidoscopies that we’re getting in a year? Can we show that these patients who get to ctDNA negativity should avoid surgery? Should patients who don’t get to ctDNA negativity go to surgery to help their outcomes? There are very exciting data that are going to be coming out.

Gregory P. Botta, MD, PhD, highlights key trials of interest exploring ctDNA analyses to better inform treatment decisions for patients with rectal cancers.

Assessing the Full Potential of ctDNA in Colorectal Cancer

 CIRCULATE-Japan is a multiplatform study that is enrolling patients from basically stage I through stage IV colorectal cancer. It’s a conglomeration of a variety of studies. One is the GALAXY study, which is an observational study. There are also 2 other studies: VEGA and ALTAIR. The purpose of this large platform study is to determine 2 things: No. 1, how ctDNA [circulating tumor DNA] helps guide our prognostic information of our patients in the GALAXY setting; and No. 2, in the VEGA and ALTAIR setting, whether it’s able to either de-intensify patients or intensify patients to get chemotherapy.

What we’re finding is that patients who have ctDNA negativity after the resection of their colon cancer, are we able to observe a subset of these patients without giving them chemotherapy? We know that we over-treat approximately 20% to 25% of patients or even more who receive no additional benefit of chemotherapy and are likely cured from their disease after surgery. The issue is that pathologically, we’re unsure about who these patients are. Can ctDNA guide us and help remove chemotherapy from patients who don’t necessarily need it?

We also know that there are some patients who are undertreated. Approximately 20% or 25% of patients are undertreated. In those situations, if the ctDNA remains positive after their surgery, can we give them both standard of care therapy, whether that’s CAPOX [capecitabine, oxaliplatin] or FOLFOX [fluorouracil, leucovorin, oxaliplatin]? Or can we even intensify it further to something like FOLFIRINOX or FOLFOXIRI to help change the patients’ outcomes?

In the spectrum of colon cancer, we know that every patient is different, every pathology is different, and every prognosis is different. At this point, we try to fit everybody into a one-size-fits-all. A lot of studies initially based on the IDEA trial and these molecular residual disease trials are trying to substratify each group of patients into risk bins, which help to personalize the treatment recommendation for them so that they’re not overexposed to chemotherapy and the adverse effects that occur with it. It’s also so that we’re not trying to get through a therapy regimen that would have no benefit for that patient.

The CIRCULATE study in general is large. It has thousands and thousands of patients. However, they’re enrolling very well and quickly. The GALAXY observational arm had over 1500 patients in April 2021. I believe over 2500 patients have now enrolled, so it’s enrolled quickly. In the initial analysis, those patients have been broken down between stage I, stage II, stage III, and stage IV. These patients are overwhelmingly stage II and stage III, which makes sense. That’s where the ctDNA will really help inform us about decision-making.

Among the stage I patients, there are patients who have molecular residual disease, and we know that those patients will make ctDNA that can be tracked. However, at this time, stage I patients aren’t recommended adjuvant therapy. Of course, stage IV patients are recommended therapy. In stages II and III, the question is ultimately whether we can pick from some of these stage II and III patients, or whether we initiate therapy in some of the high-risk stage III patients. That’s where the rubber meets the road in the GALAXY study.

What to know about the design and results of the CIRCULATE-Japan study in colorectal cancer, in terms of using ctDNA analyses to help inform treatment decisions in the postoperative setting.

CIRCULATE-Japan: Using ctDNA to Guide Adjuvant Therapy in Colorectal Cancer

 Cancer Research UK is evaluating the PRIMA studies. The PRIMA studies are precision pancreatic clinical studies that are evaluating biomarkers to tell if patients will do better on either a FOLFOX [leucovorin calcium (folinic acid), fluorouracil, oxaliplatin] or oxaliplatin-based treatment regimen or an Abraxane/gemcitabine–based regimen that’s based off of a patient’s homologous recombination deficiencies or lack thereof. In this scenario, the patients who are neoadjuvantly treated with either FOLFOX or gemcitabine/Abraxane will be followed for biomarker analysis to determine if the patients who were initially on the FOLFOX-based regimen did better based on their circulating tumor DNA [ctDNA] or deficient homologous recombination mutations vs a gemcitabine/Abraxane regimen.

In these studies, it will be very important for us to understand if the patient should be switched to a different therapy if we find that they’re not responding, or if a predictive biomarker, such as homologous recombination deficiency, predicts that oxaliplatin works better. There are other ways that companies are doing this based on artificial intelligence and gene sequencing analysis. At the end of the day, we’re uncertain about whether gemcitabine/Abraxane or a FOLFOX/FOLFIRINOX [leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, oxaliplatin]-based regimen is better for each individual patient. We may also find that patients treated neoadjuvantly with 1 regimen and go to surgery may be preferable to treating with another regimen in the adjuvant setting based on this evidence. These are upcoming studies that will help guide whether the ctDNA predictive biomarkers in molecular residual disease are able to help us determine whether we should make treatment decisions in our patients with pancreatic cancer.

Using ctDNA in pancreatic cancer is very early. It’s in its infancy. We’re still trying to determine what ctDNA means for our patients with pancreatic cancer. Ordering it through all stages of disease, we’ve definitely found that some patients get to ctDNA negativity. Whether that’s with surgery or adjuvant therapy, they’re getting to a point where we’re unable to detect molecular residual disease in their body. We’re following that and using that as a surveillance tool in many of our patients: those who don’t create CA 19-9 or in whom CA 19-9 is not informative. We have been able to find recurrences very early, much earlier than radiographically that anyone would be able to find regularly based on the guidelines currently for surveillance.

The question ultimately is, what do we do with that data? In some cases, I tell the patients early on that this means that it’s an early morning detection system, that there’s smoke but we need to find if there is fire. Currently, we’re not making treatment decisions based on ctDNA turning negative to positive in our patients who are on surveillance. But we’re using it as a manner of preparing for clinical trials and as a method to prepare for finding additional radiographic evidence perhaps sooner than we would order a CT scan.

Further, we find that a lot of patients who go to ctDNA negativity unfortunately don’t stay there. This gets back to the histologic and pathologic pancreatic cancer conundrum that we’ve run into, that despite our ability to treat with chemotherapeutics, despite our ability to go through resection, and despite our ability to get to a point where our patients are at some point in remission, it seems as though we’re unable to completely eradicate this disease and that there’s always some type of residual disease in the patient’s body.

The ctDNA is a marker of whether we’re detecting that in the bloodstream. However, there’s likely a source in a lot of these patients that are recurring that hasn’t yet hit the bloodstream and has either remained local or in the liver or another niche. Ultimately…ctDNA…when they become negative, they are performing very well off of therapy and feeling quite confident. However, when they become positive, we’re getting them into the clinic earlier. We are radiographically evaluating them more often and earlier, and we’re finding these recurrences earlier. Obviously the question is whether that makes a difference to our patients. That’s to be determined.

Current trials investigating the potential of ctDNA analyses in pancreatic cancer.

Future Role of ctDNA in Pancreatic Cancer

 In our abstract, “Association of personalized and tumor-informed ctDNA [circulating tumor DNA] with patient survival outcomes in pancreatic adenocarcinoma,” we were trying to identify biomarkers in pancreatic cancer that are predictive of recurrence. We were also trying to characterize an association between circulating tumor DNA positivity before or after surgery as well as with adjuvant therapy, and if there’s an association with recurrence-free survival. Lastly, we wanted to see how that stacked up against the standard of care marker CA 19-9 and see if we have an improved sensitivity or improved prognostic information based on the ctDNA.

Pancreatic cancer CA 19-9 levels can be elevated for a variety of reasons, including biliary obstruction or liver failure. In those cases, the CA 19-9 doesn’t reflect the actual tumor burden in the body. We also know that about 5% to 10% of our patients with pancreatic cancer fail to make CA 19-9. In those cases, we’re left with either radiographic evidence of their recurrence or clinical symptoms. At the end of the day, we wanted to have another tool in our toolbox to help guide decision-making as well as when to decide on whether a treatment was working.

We evaluated 116 patients, and of those 116 patients, we had 450 plasma time points in which we were able to evaluate ctDNA. This was done in a tumor-informed approach. We took the patient’s pancreatic cancer, ran whole-exome sequencing on it, removed the germline mutations, and were left with the pathologic mutations in which we formed a gene signature. That gene signature was followed in the blood over time. The median time from follow-up from the surgery was about a year in all of these patients. We evaluated the recurrence rates for all stages in stage I through stage III, but also in some stage IV metastatic patients. The division between male and female was nonsignificant, at about 50% on each side. Some patients were given neoadjuvant therapy prior to their resection.

Ultimately, we were able to find that in patients with stage I, stage II, and stage III disease, the ctDNA increase—not just that was positive or negative—the amount of mean tumor molecules or ctDNA circulating was correlated with the stage of disease. If we saw that the ctDNA was highly elevated, that usually meant that the patient had a higher stage of disease. In addition, we were able to determine if a patient was either going to relapse before radiographic prediction or if they had a response to adjuvant therapy.

In these cases, we were able to find that after surgery, some patients actually become ctDNA negative. In addition, those patients who didn’t become ctDNA negative after surgery were able to become ctDNA negative after being given adjuvant therapy. Furthermore, the patients who remained ctDNA negative over a longer period of time had an improved relapse-free survival. We found that the ctDNA was able to be more prognostic of survival compared with CA 19-9 with a hazard ratio of about 8.2, meaning that patients whose ctDNA remained negative over a longer period of time had a much improved recurrence-free survival of up to about 60 months.

In addition, as I discussed earlier, can ctDNA predict recurrence significantly earlier than radiographic recurrence? That would make sense. When you’re looking at mean tumor molecules, the sensitivity is very high compared with radiographic evidence of approximately a half of a cm. We found that that was the case, that many times with our patients, we were able to detect that their tumor had recurred. Their ctDNA went from negative to positive before imaging was able to do so.

In those cases, the question that’s ultimately left is, what do we do in those situations? Do we continue to monitor the ctDNA as it rises, preparing the patient for either additional therapy or possibly a clinical trial? Do we initiate therapy immediately, knowing that there’s molecular residual disease and that we will possibly be able to change the patient’s outcome by starting our treatment early? Or is it lead time bias and that it doesn’t matter that the patient has recurred and it doesn’t matter when we determine the patient recurs, because their overall survival is going to remain the same? These are questions that are left to be determined in future prospective studies.

Dr Gregory P. Botta reacts to results of a study that recently explored the association of tumor-informed and personalized ctDNA with patient survival outcomes in pancreatic cancer, as presented at ASCO GI 2022.

Personalized/Tumor-Informed ctDNA and Patient Survival in Pancreatic Cancer

 At this point, it’s very early to know the possible clinical outcome data that we can get from ctDNA [circulating tumor DNA] in pancreatic cancer. What ctDNA in pancreatic cancer would help us understand is if there’s any chance of a patient’s recurrence from their pancreatic cancer after surgery or after adjuvant therapy.

Ultimately, ctDNA is a very early marker in pancreatic cancer. We use it to help us provide actionable mutation data, both in a tumor-naive approach as well as a tumor-informed approach. However, it’s a needle in a haystack approach. There are very limited targetable mutations in pancreas cancer. But when we come across those needle in a haystack mutations, they make a difference for our patients. Immunotherapy may be beneficial in things like 

-driven pancreas cancer, or possibly even 

 wild-type pancreatic cancer. When we do circulating tumor DNA analysis, that means a lot for those patients in whom it comes back positive.

In terms of molecular residual disease, pancreatic cancer is a very aggressive malignancy. The recommendation of all oncologists is that patients usually receive either neoadjuvant or adjuvant therapy, regardless of the staging. We’re wondering if ctDNA can help substratify a group of patients and help us determine whether they may not need adjuvant therapy or neoadjuvant therapy prior to resection. The theory is that given an aggressive malignancy, such as pancreatic cancer, that likely won’t happen. We’re trying to substratify whether our therapies are making a difference.

There are other studies that are evaluating that as well, whether you should switch a patient from gemcitabine/Abraxane to a FOLFIRINOX [leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, oxaliplatin] or oxaliplatin-based regimen, and whether the surgical resection was successful enough that the patient became molecular residual disease negative. If the patient goes to negativity but later becomes positive, are we able to treat earlier and change that patient’s outcome, or does it not matter? In many cases, ctDNA analysis is able to determine that there’s recurrence prior to radiographic recurrence. If that’s the case, are we able to head off a patient’s tumor burden earlier by getting them on therapy, or is it just lead time bias? These are questions that need to be answered.

The potential clinical applications of ctDNA analyses in pancreatic cancer.

ctDNA Testing in Pancreatic Cancer

 Molecular residual disease, or MRD, is being evaluated in solid tumors. In just a couple…evaluated is determined if there’s prognostic information that can be given to the patient. Basically, it’s how well they’ll do after either a surgical resection or neoadjuvant or adjuvant therapy. It gives us an end point of either disease-free survival or recurrence-free survival. Those tend to be the end points of a lot of studies. The prognostic information is a tool that the oncologist uses to help guide their treatment decisions. Just as CEA [carcinoembryonic antigen] is a tool, radiographic evidence of disease is a tool, and pathologic staging is a tool, ctDNA [circulating tumor DNA] is being incorporated as a tool to help make these treatment decisions and evaluate surveillance and if there’s recurrence.

Molecular residual disease is evaluated in both a tumor-informed approach and a tumor-naive approach. In the tumor-informed approach, we’re generally taking the tumor out of the patient and running whole-exome sequencing on it. With whole-exome sequencing, you’re getting a variety of genes, not only actionable mutations but also possibly passenger mutations or housekeeper gene mutations. Then they’re taking the germline from the patient and subtracting that from the whole-exome sequencing of the tumor. You’re left with only the tumor pathologic mutations. Those tumor pathologic mutations provide a gene signature, or a gene thumbprint. That gene thumbprint can be extracted from the bloodstream and used to guide whether there’s still residual tumor or molecular residual tumor MRD.

When we find that there’s a positive ctDNA or positive molecular residual disease, that means that genes from the original tumor are found circulating in the bloodstream. That gives us prognostic information depending on the histology. At the end of the day, ctDNA is basically tumor agnostic. It doesn’t matter what histology the tumor is. Every tumor has DNA, and you’re going to be able to get ctDNA from every tumor type. Ultimately, the question that’s left is what that information means for that histology, what prognostic information, and if there are any additional predictive information that we can get from it that help guide treatment. Those are the ongoing studies that we’ll evaluate prospectively.

The present role of minimal residual disease in solid tumor cancers, and current evaluations further exploring its potential in pancreatic and colorectal cancer.

Gregory P. Botta, MD, PhD

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