Prostatepedia

Conversations With Prostate Cancer Experts


Leave a comment

Small cell? Or neuroendocrine cancer?

AparicioDr. Ana Aparicio is an Associate Professor in the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas.

Prostatepedia spoke with her about rare but highly aggressive forms of prostate cancer.

Not a member? Join us.

How did you become involved in such a specialized subset of prostate cancer research?

Dr. Aparicio: I was very frustrated by the fact that we treat homogeneously a disease that we perceive in the clinic to be heterogeneous. It drives me crazy that different people walk into the clinic with different diseases and yet we do the same thing to each and every one of them. This ends up meaning that many large Phase III trials are an enormous resource expense. It’s difficult to advance the field. I had remarkable responses for patients with Yervoy (ipilimumab) and yet the Phase III trial was negative. I felt like that was wrong. We should be smarter about what we’re doing. We need to understand the heterogeneity of prostate cancer and incorporate that understanding into clinical trials. Otherwise, it’s going to take us 200 years to make a difference in this disease.

I think of it in the following way. I take all of the prostate cancers and peel away the most aggressive ones. I then look to see how that relates to the rest of the disease. If we peel back in that way, we will start to understand the disease.

So then the work you’re doing can potentially change not only how we treat patients, but also how we design clinical trials?

Dr. Aparicio: Yes.

What is neuroendocrine prostate cancer?

Dr. Aparicio: Neuroendocrine prostate cancer is a histological definition of a prostate cancer variant. The prostate is composed of glandular tissue. When a pathologist looks at your garden-variety prostate cancer under the microscope, she sees it is composed of groups of glands. That is why it’s called adenocarcinoma: adeno meaning of or relating to the glands, carcinoma referring to the cancer arising from epithelial tissue. It’s cancer and not normal prostate tissue, but you can still recognize the glandular structures. Prostate adenocarcinomas respond very well to hormonal therapies.

On the other hand, small-cell prostate cancers basically look like sheets of cancer cells under the microscope. There is no glandular formation of any sort. These are small, round cells that have small amounts of cytoplasm (the gel-like material surrounding the nucleus) so their nuclei look very prominent. Small-cell cancers often express neuroendocrine markers, which are a type of protein expressed by a number of different tissue types and in a number of different cancers. Neuroendocrine markers are in no way specific to small-cell prostate cancers, but because the small-cell prostate cancers express them frequently, the other name that is given for small-cell prostate cancers is ‘poorly differentiated neuroendocrine prostate carcinoma.’ Many garden-variety prostate adenocarcinomas (those composed of groups of glands) also express these neuroendocrine markers. Again, the word neuroendocrine is not specific to small-cell cancers. Small cell refers to sheets of cells that are small with little amounts of cytoplasm.

The presence of small-cell cancer morphology on a surgical specimen or a biopsy is often associated with atypical clinical features for prostate cancer and a poor response to hormone therapies.

Garden-variety prostate adenocarcinomas most often spread to the bone and make round sclerotic (hardening) or osteoblastic bone metastases that show on a CT scan like a white patch.

In contrast, small-cell prostate carcinomas are often associated with what we call lytic (relating to disintegration) bone metastases, which show on a CT scan like a dark, punched-out hole. And that’s when the carcinomas go to the bone because they often don’t even show up in the bone. Men with small-cell cancer morphology can have exclusive visceral metastases, meaning their cancer has only gone to the liver, lymph nodes, or lung. They might also have bulky tumor masses, including bulky and symptomatic primary prostate tumors or bulky liver or lymph node masses. While they don’t respond well to hormonal therapies, small-cell prostate cancers often respond to chemotherapy.

A problem we ran into was that we would often find these atypical clinical features that I just described, but under the microscope where we expected to find small-cell prostate carcinoma morphology to justify chemotherapy, we didn’t. What happens when we see those atypical clinical features, but the biopsy doesn’t show small-cell morphology? Our experience shows that those people don’t do well with hormone therapies. In other words, when we do a biopsy and we find small-cell carcinoma morphology, we know that those cancers need to have chemotherapy sooner rather than later, as opposed to treatment with hormonal therapy. They need early chemotherapy as well; so we coined the term aggressive variant prostate cancers, which are tumors that share clinical features with small-cell cancers but may have different morphologies under the microscope. When we do a biopsy, they might look like adenocarcinoma, but they behave like small-cell cancer.

Join us to read the rest of the conversation.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


1 Comment

Diagnosing Neuroendocrine Prostate Cancer

Prostatepedia spoke with Dr. Himisha Beltran, an Assistant Professor of Medicine at Weill Cornell Medical College in New York City, about diagnosing neuroendocrine prostate cancer.

Not a member? Join us to read the entire conversation.

How is small-cell or neuroendocrine prostate cancer diagnosed? Biopsy? Imaging?

Dr. Himisha Beltran: Small-cell or neuroendocrine prostate cancer is diagnosed by tumor biopsy. The pathologist typically makes the diagnosis by looking at the morphologic features of the cancer under a microscope and may perform additional testing to look at expression of neuroendocrine markers or classical prostate markers to support the diagnosis.

One of the reasons why neuroendocrine prostate cancer was thought to be so rare was that doing metastatic biopsies on patients already diagnosed with prostate cancer was just not done in the clinic. It is only recently that we are recommending biopsies to look for neuroendocrine prostate cancer in select patients with aggressive clinical features and low PSA levels. Biopsies are also being considered to look for other emerging molecular targets. There are now several prostate cancer clinical trials targeting different mutations and alterations.

An obvious next step is to try to diagnose neuroendocrine prostate cancer noninvasively. Imaging is a noninvasive way to detect different cancers, but there hasn’t been any sort of imaging tool yet that can really identify these patients. We’re starting to see clues that there may be some molecular markers that are expressed that might help future research in this area. Another noninvasive approach we have been investigating is the use of liquid biopsies that include circulating tumor cells as well as circulating tumor DNA to see if there are clues that can help us identify these patients without a biopsy. This is still in research development.

 

 

 

 

 

Read the rest of Dr. Beltran’s comments on neuroendocrine prostate cancer.


1 Comment

Neuroendocrine Prostate Cancer

Beltran Himisha

 

 

 

 

 

 

 

Dr. Himisha Beltran, an Assistant Professor of Medicine at Weill Cornell Medical College in New York City, is keenly interested in developing research programs to study neuroendocrine prostate cancer.

We spoke with her about this aggressive form of prostate cancer.

Your research deals with a small subset of patients and is considered a specialized area of research. How did you become interested in neuroendocrine prostate cancer as opposed to another aspect of the disease?

Dr. Himisha Beltran: I take care of prostate cancer patients at all different stages of their disease. We know that not all patients with prostate cancer are the same and they may respond variably to the therapies that we use. My research has focused on understanding mechanisms of treatment resistance and identifying subsets of patients that may benefit from nonstandard approaches.

Neuroendocrine prostate cancer is one subtype within the spectrum of advanced prostate cancer that tends to look and act differently compared to your typical prostate cancer. They tend to be less responsive to standard therapies and often do not make PSA.

That is really what led me to neuroendocrine prostate cancers. I was struck by how some patients had tumors that looked very different under a microscope and acted very different clinically than others looked and acted. By understanding a small subgroup of patients, we can also better understand the entire group. That is really what precision medicine is about: identifying subgroups of patients that either have clinical, molecular, or other features that will help guide treatment. While my research is focused on a small subgroup of men, I think the impact potentially affects many more.

Let’s back up a bit and define neuroendocrine prostate cancer.

Dr. Beltran: Most prostate cancers consist of adenocarcinoma cells, which are derived from normal prostate tissue. They have more glandular prostate features. They express many prostate markers. When we say a cancer is neuroendocrine, we mean that the tumor looks less like a typical adenocarcinoma and has features that look more like neuroendocrine cells, which have a distinctive morphology under a microscope. Neuroendocrine cells tend to be smaller and may not express classical prostate markers such as the androgen receptor, which is the target of many of our drugs like Zytiga (abiraterone) and Xtandi (enzalutamide). These cancers also acquire other distinct molecular features.

What we’ve learned in recent years is that neuroendocrine prostate cancer rarely arises de novo; they most commonly develop in later stages of prostate cancer progression from a preexisting prostate adenocarcinoma as a way for the cancer cells to evade therapy. The tumors try to change their identity to develop new ways to grow. There is a spectrum as tumors progress from androgen-driven prostate adenocarcinoma toward an androgen independent neuroendocrine prostate cancer. Within this spectrum, the cancers may develop mixed or overlapping features, expressing some prostate markers but also acquiring new resistance markers.

Is there any way to predict who is going to develop treatment resistance?

Dr. Beltran: By studying the clinical and molecular features of patients, how cancers evolve with time, and how these features affect the biology of the cancer, we now have better insights into mechanisms of response and resistance to specific therapies. This growing knowledge sets the stage for biomarker development.

We are interested in identifying patients before they develop neuroendocrine prostate cancer. We are investigating the genomics and other molecular features of tumor biopsies and applying this to noninvasive approaches such as liquid biopsies— looking at cancer cells or DNA from cancers that may be detected in the blood. If we can identify patients, we can also select patients most likely to benefit from a neuroendocrine type of regimen.

Join us to read the entire conversation.


Leave a comment

Advances in Medical Oncology

PetrylakDr. Daniel P. Petrylak, Professor of Medicine and Urology at Yale School of Medicine, has been a pioneer in the research and development of new drugs and treatments to fight prostate, bladder, kidney, and testicular cancers.

Prostatepedia spoke with him about advances in medical oncology for prostate cancer.

Not a member? Join us.

What are the current points of controversy and/or trends in the field of medical oncology for prostate cancer?

The first controversy is over localized disease. There are really two forms of prostate cancer. There is the nonaggressive form that is not going to be lethal and that you’ll die with and not from. Then, unfortunately, there is the lethal form of the disease that kills about 30,000 men a year in the United States. The controversy is how do you treat these patients? How do you decide who to treat and who not to treat?

For advanced metastatic disease, there are controversies over the right treatments, the right sequences of treatments, when to use other hormones, and when to use other chemotherapies. There are a lot of questions that need to be answered.

Unfortunately, prostate cancer has always been behind other tumors. If you look back to the 1990s, there was about five times less funding for prostate cancer than breast cancer. We were behind in funding compared to other tumors, but have made significant strides in increasing money available for research.

We’re catching up in the area of personalized medicine. We didn’t really have markers a couple of years ago. But now we’re beginning to see markers—whether that be with BRCA mutations, BRCA-like mutations, or AR-V7—employed in the treatment of advanced metastatic disease to help select therapies. These approaches are in the advanced stages of development and have yet to be approved by the FDA. Those are the major controversies.

Subscribe to read the entire conversation.


Leave a comment

Prostate Cancer Treatment Advances

Pp_July_2017_V2_N12_ThumbIn July, Prostatepedia is talking about advances in urology, radiation therapy, oncology and immunotherapy for prostate cancer.

Not a member? Join us to read the conversations.

Dr. Oliver Sartor, one of the leading researchers in advanced prostate cancer today, has the following to say about this month’s conversations.

Three of the biggest areas in prostate cancer right now are: 1) the use of the checkpoint inhibitor PD-1 to treat men with mismatch DNA repair defects, 2) the use of either PARP inhibitors or platinums to treat mismatch DNA repair defects, and 3) better imaging techniques.

Within the next year or two, we’ll be able to define a subset of patients who will benefit from the PD-1 inhibitors that Dr. Charles Drake discusses in his conversation on immunology. I anticipate that PD-1 inhibitors may be meaningful for around 10% of men.

The FDA recently approved Keytruda (pembrolizumab) for those with mismatch DNA repair mutations, which applies to a subset of prostate cancer patients. This story will be meaningful to watch as testing for these mutations becomes more prevalent.

As Dr. Daniel Petrylak alludes to, there are now a variety of rapidly moving clinical trials looking at the combination of three DNA repair defects—BRCA1, BRCA2, and ATM. Data to support the use of PARP inhibitors in men with this combination of repair defects is rapidly evolving. This practice remains unproven in prostate cancer, though, despite promising preliminary data published by Dr. Joaquin de Mateo in the New England Journal of Medicine in 2016. [See Prostatepedia June 2016 for a conversation with Dr. Mateo about his work.]

But I do want to make sure that Prostatepedia readers are aware that if you have metastatic prostate cancer and a DNA repair defect—like BRCA1, BRCA2, and ATM—there is some reasonable preliminary data to support using carboplatin. We have a manuscript at press right now that shows that if you have an inherited BRCA2 mutation, there is better activity if a carboplatin plus a taxane are administered as opposed to just giving you a taxane alone. Thus carboplatin appears to be an option for men with certain DNA repair alterations.

Advances in imaging are also discussed in several of the conversations that follow. PSMA imaging is moving quickly. Axumin (fluciclovine F18) is the new imaging technique on the block with FDA approval. I think that in using these newer imaging techniques we will be able to define oligometastatic disease groups more and more efficiently. The consequences will be less therapy that just sets patients up to fail and, hopefully, more therapy that, if targeted to those lesions, will have a meaningful effect.

Stay tuned: the prostate cancer field is evolving really fast right now. I believe some men with advanced disease will potentially have molecularly targeted therapies available to them within the next several years.

Subscribe to read our July conversations on advances in treatment.