Pathophysiology, Transmission, Diagnosis, and Treatment of ...

stage 4 colon cancer with kras mutation :: Article Creator

AstraZeneca Joins KRAS Push In Cancer With Chinese Deal

AstraZeneca has added to its oncology pipeline by licensing a small-molecule KRAS inhibitor from Chinese biotech Usynova for $24 million upfront.

The compound – called UA022 – targets the KRASG12D mutation and is currently still in preclinical development. AZ has taken an exclusive worldwide license to the drug in a deal that also includes up to $395 million in development and commercial milestone payments, as well as royalties on future sales.

If it makes it through to market, UA022 would follow in the footsteps of pioneering KRAS inhibitors Amgen's Lumakras (sotorasib) and Mirati's Krazati (adagrasib), which have been approved as second-line therapies for KRAS-mutated non-small cell lung cancer (NSCLC), but target KRAS G12C, a different mutation.

KRAS G12C is the most common form of KRAS mutation in lung cancer, while G12D is found more commonly in other diseases like pancreatic and colorectal cancers.

Dr Hu Tao, co-founder and chief executive of Usynova, which is also known as Yousen Jianheng Biopharmaceutical, said in a statement that KRAS G12D is the most common KRAS mutation in cancer, accounting for around 26% of all KRAS mutations overall, but there are currently no approved drugs specifically targeting it.

According to Usynova, UA022 has shown potent anticancer activity in lab testing, with good oral bioavailability and a "favourable" safety profile.

With the licensing deal, AZ joins a select group of companies going after the target that includes Mirati – soon to become part of Bristol-Myers Squibb if a $5.8 billion takeover deal goes through – as well as Revolution Medicines, Quanta Therapeutics, and Roche/Chugai.

Mirati's MRTX1133 is in phase 1/1b testing, with results as a monotherapy due in the first half of next year and studies also underway of the drug in combination with cancer immunotherapies. Revolution's RMC-9805 recently started a phase 1/1b study, with results expected in 2025.

Roche/Chugai's pan-RAS inhibitor LUNA18 has already completed a dose-ranging study, while Quanta's multi-KRAS inhibitor QTX3034 is in preclinical development.

Stephen Fawell, AZ's head of oncology development, described the licensing deal as an "exciting opportunity" that builds on AZ's "heritage of targeting tumour drivers and mutations." He added that the deal "could accelerate the development of potential new treatments for patients whose tumours carry the KRAS G12D mutation, an area of unmet medical need."

Liquid Biopsy For Cancer Recurrence Creates A New Kind Of Patient-in-waiting

My husband's cancer came back this summer after not being evident for almost two years.

With advances in cancer surveillance, we now speak of cancer survivors being cancer-free far less frequently. If you are among the luckiest unlucky who survive treatment for metastatic cancer and receive clear scans, you simply have "no evidence of disease."

Jesse was diagnosed with metastatic colon cancer in June 2021 after a routine colonoscopy, his first. His cancer was considered curable because his metastases were limited to two tumors in his liver that were surgically resected, along with the primary tumor, with clear margins. He underwent six months of adjuvant chemotherapy, and none of his surveillance scans have revealed any evidence of disease.

But in June, he received a positive result on a Signatera test, which predicts disease recurrence in patients with some types of cancer months before it shows up on a scan. Signatera is a novel personalized assay designed around the patient's tumor profile that can identify circulating tumor DNA (ctDNA) in the blood. It's also known as a liquid biopsy. A positive result signals minimal residual disease (MRD), an accumulation of cancer cells too small to be detected on imaging.

Until Jesse's positive result, which followed two negatives earlier this year, I had assumed that his cancer had been eradicated. The five-year survival rate for stage 4 colon cancer, at 13%, is grim, but the more time passed, the more his odds improved.

After a recurrence, however, one's odds drop precipitously. For the first time since his diagnosis, I let my mind wander to a future without my 45-year-old husband.

We are both academics, so we immediately launched into research mode. There is no clear standard of care for colon cancer patients with positive ctDNA results but no radiologic evidence of disease. Some start oral chemotherapy prophylactically, but most oncologists — including Jesse's — will not begin treatment until something appears on a scan. Pushing up scans and bloodwork, which we decided to do, is common. I also started investigating MRD clinical trials, some of which are quite promising.

The main thing to do, though, is wait. Typically, the values will creep up on repeat testing until a tumor eventually appears on a scan.

In Jesse's case, however, six weeks after the positive result, a repeat Signatera test returned negative. What did this mean? The Signatera test is highly accurate for colorectal cancer — the risk of cancer recurrence after a positive result is 97%. Still, Jesse's oncologist thought his positive result was likely a false positive in part because the test value, at .05, was extremely low.

On the other hand, a low positive result followed by a negative could also suggest that Jesse had trace cancer cells hovering at the threshold of detectability, which his immune system cleared, at least temporarily, on its own.

Which of these scenarios is more likely may become clearer with time. Jesse will undergo Signatera testing every three months for the foreseeable future. If he continues to test negative and evidence of cancer never returns on scans, the false positive hypothesis may be justified. If, on the other hand, a test returns positive and the value rises, a false positive is less likely.

I am incredibly grateful for the negative result and the way that it shifted Jesse's prospects for long-term survival. But merely receiving a single positive result flooded us with uncertainty that cannot be easily dissipated. I felt relieved by the negative result, but at the same time, I also felt something closer to grief.

As a medical anthropologist who has studied new genetic technologies and their impact on patients and society, I am very familiar with how scientific advances such as Signatera can have unintended consequences for patients and caregivers. Thirteen years ago, my colleague Stefan Timmermans and I introduced the concept of patients-in-waiting to describe how new genetic technologies create new categories of patients who are not quite sick yet nevertheless not healthy. The cases we wrote about include people who undergo genetic susceptibility testing for cancer or Alzheimer's disease.

CtDNA testing had not yet been developed at the time of our study, but if it had, it would have offered us an ideal case. Jesse's Signatera result instantly switched him from being a cancer survivor to a patient-in-waiting whose cancer might never be considered fully eliminated. It was a subtle shift, one that was imperceptible to friends and relatives who were understandably ecstatic to hear about the negative result. Yet simply receiving the lone positive result opened the door to a persistent new type of uncertainty. This, then, was the source of my grief: the loss of an easier time in which I knew less and had less reason to worry.

Jesse's oncologist had warned him before ordering the first Signatera test that the wait following a positive result can be distressing. Despite our best efforts, the news cast a dark shadow over our summer. Had Jesse never undergone ctDNA testing, on July 2 we would have celebrated two years with no evidence of disease — after which, his oncologist had advised us, his survival odds would increase substantially. Instead, I spent the two-year mark consumed by apprehension over a looming recurrence.

Of course, it wasn't a recurrence, or at least isn't one yet. But as a caregiver, I found that the worry, fear, and uncertainty were not that much different than they were with actual disease — just as Stefan and I found in our interviews with parents whose children had been diagnosed through newborn screening with genetic anomalies of ambiguous significance.

I don't regret this knowledge, and neither does Jesse. It has enabled us to move up his scans and consider therapeutic options that were not previously on the table.

But we have also lost something here. When a person becomes a patient-in-waiting, their world is irrevocably altered. Every patient-in-waiting stands in for a life interrupted, a blissful innocence lost.

With applications for both surveillance and monitoring the efficacy of ongoing treatment, Signatera and other ctDNA assays are poised to change the landscape of cancer management. As the biomedical sciences continue their inevitable onward march, we must remember these ambiguous losses as well the triumphs.

Mara Buchbinder is professor and vice chair of the Department of Social Medicine at the University of North Carolina at Chapel Hill.

Stage IV Breast Cancer Treatment Options

So the treatment of stage IV breast cancer is complicated and has changed a lot over the course of even the last few years. Most patients with stage IV disease-- disease that's spread beyond the breast or surrounding lymph nodes-- won't be curable. It'll be treatable, and sometimes treatable for years or even decades, but probably not curable. And so each treatment decision has to be made with an understanding of, what are the patient's goals? What are their other limitations? How is this treatment going to impact their quality of life?

For different types and subtypes of breast cancer, there are different treatment options. Chemotherapy is one of the things that we use, chemo or drugs that classically travel through the bloodstream and kill rapidly dividing cells. So that includes cancer cells, but it also includes other cells. So chemotherapy is not without its side effects. But can be really beneficial for the patients who have aggressive stage IV cancer and require it.

We also have a growing number of targeted therapies for metastatic breast cancer, which has been really exciting, because more targeted therapies allow us to treat the breast cancer a little bit more focused with fewer side effects, because we're killing off cancer cells as opposed to normal cells. And immunotherapy, treatments that kind of harness the patient's own immune system to fight the cancer more effectively, is another kind of class of drugs that is also starting to make its way now into the breast cancer space.

Maintaining quality of life with stage IV cancer is a really important question. So I think, for doctors, it's very important to have honest conversations with patients about what in their life is most important to them and what do they feel like the cancer is limiting them from doing so that we can then help them figure out how to manage that. ","publisher":"WebMD Video"} ]]>

Hide Video Transcript

JANE MEISEL

Search This Blog

Lung Cancer