Andrew J. Roth

When faced with cancer or any other difficult situation in life, one of the best medicines can be to hear stories and advice from others. This was the key point Susan M. Domchek, M.D., made in her closing remarks during last night’s “In Our Genes: An Evening of Storytelling” event in New York City.

The event was put on by the Young Leadership Council (YLC) of the Basser Center for BRCA, part of Penn Medicine’s Abramson Cancer Center, and featured three speakers who told their stories of learning they — and in one case, a loved one &mdash; were positive for a BRCA mutation.

Each speaker’s story relied on humor to lighten the mood — a crucial part of the equation, according to Domchek, the executive director of the Basser Center.

“Any time you deal with a hardship, you have to find some humor and they certainly showed us that tonight,” she said in an interview with 

The first speaker of the night was Caitlin Brodnick, a comedian and a writer for Glamour.com, who lives in New York City. Brodnick told her story of family members passing away and always thinking she or her siblings were next.

“As I was growing up, I had family members that were dying of cancer and my father is the only surviving person in his family,” Brodnick said to the audience of about 50.

Her father, though, didn’t view cancer as an inevitability and enrolled as a test patient for the BRCA gene at Johns Hopkins University. He found out that he was positive for the mutation, and Brodnick herself was tested soon after — she had it too. Brodnick was 25 years old at the time and had just become engaged.

“I believe the percentages have changed slightly, but then they told me, in my lifetime, I had an 87 percent chance of cancer,” Brodnick said. “That made me go 100 percent insane.”

In 2013, Brodnick drew inspiration from Angelina Jolie and decided to undergo a double mastectomy to reduce her risk of cancer.

“When Angelina came out and said she was going to have the surgery, I [thought], ‘One of the sexiest women in the world has chosen to take this in her hands and take control, maybe I can do it,’” she said.

Brodnick then chronicled her three surgeries to remove tissue and reconstruct, subsequent swelling and recovery. She drew laughs from the crowd as she spoke about how she was able to choose the appearance of her nipples and likened the entire situation to ‘renovating’ her body and the HGTV show “Fixer Upper.”

Brodnick concluded by thanking her audience and joking that she usually only performs in small clubs with just a few people in attendance.

The second speaker of the night was Jon Steinberg, the CEO of Cheddar, a media company, and former executive of DailyMail.com and BuzzFeed. Steinberg began by simply telling the audience how difficult it was to be on stage talking his and his wife’s story with BRCA.

“I do four hours of live TV a day, but for some reason this is very nerve-wracking for me,” Steinberg said. “I haven't really talked about this.”

Steinberg found out that his wife, Jill, was positive for the BRCA1 mutation in 2010 from a 23andMe test. While at work, he Googled around to learn more and immediately knew that it was bad news. The subsequent days and weeks were a bit of a blur, Steinberg admitted, but it became apparent that a mastectomy was the best option for his wife.

“I knew right away that I thought that Jill should do it,” he said, but knew that it was her decision ultimately. “And then what I struggled with a little bit was that it was her body, it was her.”

Steinberg said that his wife’s journey with surgeries was remarkably similar to that of Brodnick, the previous speaker. It took several operations to get it all right and it was a struggle for Steinberg to know what to say.

“You tell your wife that you love her, because you do love your wife — I love my wife &mdash; and you tell your wife that she's beautiful to you,” he said. “You feel like it's never enough. You feel like it's never convincing. You never quite know how she feels about her new body in this context.”

Steinberg also discussed the struggle of weighing two bad things — a mastectomy and cancer.

“Whenever you get into a situation where you're weighing terrible things, they say you're not supposed to do that, but inevitably you do do that,” he said. “I don't have a conclusion on how to think about that, but it just is something that I think goes through your head.”

Steinberg created an analogy to air travel and waiting to hear how long a flight will be delayed.

“Do you want to rebook the plane ticket immediately because you just don't trust Delta or do you like your odds of sitting on that plane?”

Steinberg and his wife have become closer as a couple, he said, because they always decide get off that plane and buy the next ticket.

Finally, Steinberg brought up stories of people he’s known in his professional life who have gone through cancer.

“It's almost shocking to me how strong and enduring and how much of a fighter some people can be,” he said. “You have to be so absolutely tireless and ferocious and be unwilling to ever give up as you face this situation.”

That theme of relentlessness followed through to the final storyteller of the night. Jessica Queller, a TV writer who has written for “Gossip Girl” and “Supergirl,” told her story of learning she was BRCA positive and her struggle to become pregnant.

Throughout her 20s, Queller’s life was going according to plan. At 31, though, life screeched to a halt: Queller’s mother was diagnosed with terminal cancer and passed away, and then she herself found out that she was BRCA positive and had a double mastectomy. The clock was still ticking, though, as she still wanted to get pregnant — her childhood dream &mdash; but knew she had to have her ovaries removed by the age of 40.

“One thing they don't often tell you about the BRCA mutation is [that] it takes all the fun and whimsy out of life,” she said.

BRCA took away a lot of things in her life, but Queller refused to let it take away her vision of being a mother.

At age 37, Queller was single and writing for “Gossip Girl.” Every month for eight consecutive months, she would go to a fertility clinic to get inseminated — none resulted in pregnancy. The most likely cause of the unsuccessful inseminations, her doctor said, was stress. She then quit her job and focused on “doing nothing but fertility treatments and yoga.”

Eventually, the artificial insemination did work and her daughter is now seven years old.

“Now, I am living both of my dreams: I am a mother and I am some version of a Bohemian artist person and my daughter is a wild child, who likes to stay up with me till midnight every weekend,” Queller said. “She prefers dessert for breakfast and she often dances on the roof of my friend Rosemary's car whenever she can get away with it.”

“The BRCA gene tried to knock the whimsy out of my life, but I am proud to say it didn't get the best of me.”

The Basser Center for BRCA had the goals of raising funds — tickets were $150 at the door &mdash; through the “In Our Genes” event, but also to provide education, inspiration and conversation.

Another goal of the event, and possibly the most important one, Domchek said, was to create and build the sense of community among BRCA mutation-positive individuals and their loved ones.

“BRCA1/2 are the best known inherited cancer susceptibility development genes, but there are others and there will only be more as we go,” Domchek said.

“BRCA1/2 is ahead of the game of having this group of individuals who, starting at 25, knew what their risk was and then figured out how to take that on and deal with it.”

Articles

Last night's "In Our Genes: An Evening of Storytelling" was an event that not only raised money for research in BRCA-related cancers, but also aimed to raise the spirits of individuals who have been affected by the gene mutation.

'In Our Genes' Event Raises Research Funds, Builds Community for Those at Increased Risk of Breast and Ovarian Cancers

With immunotherapy, androgen receptor (AR)-targeted agents and targeted therapies on the horizon, the treatment paradigm for patients with triple-negative breast cancer (TNBC) is rapidly shifting, says Hope S. Rugo, M.D.

spoke with Rugo at the 2016 Lynn Sage Breast Cancer Symposium.

What's currently known about the efficacy of immunotherapies in TNBC? What makes TNBC unique?

Rugo is a professor of Medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.

We don't really know that TNBC is unique, actually. We know that the mutational load of TNBC is higher than other subsets—you increase mutations and resistance over time. If mutational load correlates with neoantigens and the immunogenicity of the cancer itself, that may be what makes it uniquely sensitive. We know some of those tumors are basal-like. If you look at the non-HER2 enriched tumors, that may be another group that is resistant with a lot of host immune response where there can be a unique response to checkpoint inhibition.

What other agents are on the horizon in TNBC?

We're all disappointed with standard chemotherapy. We're past that and we want something else.

There have been a lot of studies that have focused on a variety of targeted agents with relatively disappointing results. There are a few areas of great excitement.

One is the area of immunotherapies. These are cytotoxic agents that are targeted by an antibody to a specific antigen. There's CDX-011 (glembatumumab vedotin), which is looking at monomethyl auristatin E (MMAE) toxin to glycoprotein NMB, which is overexpressed. It's overexpressed on many subsets of breast cancer, but researchers saw a signal in the TNBC group in their original trial. They're studying that more now in a larger phase 3 trial. The problem is that the expression is not very frequent. It may matter whether you're looking at metastatic tumor tissue or archived tissue from the early stage setting.

There's also been great interest in the drug sacituzumab (IMMU-132), a Trop-2-targeted toxin. That drug has shown nice single agent responses, some of which are quite durable in TNBC. There's a larger single agent cohort trial going on and there are plans for larger randomized trials.

What does the toxicity profile look like for these targeted agents?

Those have chemotherapy-related toxicities. Nothing unexpected: diarrhea, nausea, hair loss or thinning and low blood counts. These are pretty easily controlled.

We've given CDX-011 at our institution and certainly patients have toxicity, but we just have to be proactive about it. This is true of any agent—if you're proactive, patients will do pretty well.

We tend to think of these drugs as having less toxicity than chemotherapy, but compared to, say, weekly paclitaxel, the toxicities are just different.

How you view the state of AR antagonists to treat TNBC today?

We've seen some responses with Xtandi (enzalutamide) as well as older AR antagonists. It will be interesting to see how we determine which patients will benefit. There is a gene signature that's been developed, but it will be fascinating to see if that signature will help us find the patients who could be treated with AR antagonists. Of course, there are AR agonists that are being tested as well.

If we can identify that group of patients, it could potentially be an adjuvant regimen. That would be exciting, to prevent recurrence in patients who generally have less chemotherapy-sensitive disease.

The toxicity is quite modest. Most patients tolerate them quite well—physicians should watch for nausea and monitor liver enzymes. The toxicity profile is absolutely better than chemotherapy. Taking a pill will be easier than taking an immune checkpoint inhibitor, too. The idea of combining AR-targeted agents with checkpoint inhibitors is also exciting.

We need to treat smaller and smaller populations as we understand that there are subsets of TNBC that respond differently to other subsets. We've been hesitant to jump into that realm without significant data, but studies moving forward will be forced to do that.

What do you think the future looks like, overall, in this area?

There are a lot of exciting things going on. Moving forward, what we need to do are trials in collaboration—allowing for multi-site leadership. This will allow us to come to an answer  faster. It's critical. There are international efforts going on in this regard.

We also need multi-arm studies, where we enroll patients into neoadjuvant and metastatic settings with tissue analysis and circulating cell-free DNA. These are critical paths for the future. The time where we're going to do a single study lead by a single individual and have some sites participate—that's going to be less advantageous. There has been a lot of interest, as well, from pharmaceutical companies in supporting new approaches to trials.

CURE spoke with an expert on the future of treating triple-negative breast cancer, including the potential for immunotherapy, targeted therapy and AR-targeted agents.

Expert Discusses What's on the Horizon in Triple-Negative Breast Cancer Care

With encouraging current data for for androgen receptor (AR) antagonists, future results may make it so that the agents have a spot in the treatment paradigm for many patients with breast cancer, Tiffany A. Traina, M.D., said at the 2016 Lynn Sage Breast Cancer Symposium.

Triple-negative breast cancer (TNBC), which is a heterogeneous disease, houses a group of patients who may benefit from AR antagonists. “There is a subset — that is larger than we initially thought &mdash; that upwards of almost 50 percent women with triple-negative breast cancer may have this androgen-driven subtype,” Traina, from the Memorial Sloan Kettering Cancer Center (MSK), said in an interview with 

. “We now have three phase 2 studies that show signal of activity for targeting androgen in that subset.”

The first agent described by Traina was bicalutamide, which was first approved in 1995 to treat prostate cancer. This agent was evaluated in the phase 2 TBCRC011 trial for patients with AR-positive, ER/PR-negative metastatic breast cancer.

Twenty-six patients on the TBCRC011 trial were AR-positive and received bicalutamide at 150 mg daily. The primary endpoint on the trial was clinical benefit rate. Though there were no CRs or PRs on the trial, 19 percent of patients (five patients) had SD for at least six months. An additional 8 percent of patients (two patients) had SD of less than six months.

In a whole transcriptome analysis of the results presented at the 2014 San Antonio Breast Cancer Symposium, Traina and her colleagues came to several conclusions: (1) RNA expression variation was consistent with basal-like breast cancer, (2) AR-positive tumors were noted beyond the luminal AR subtype and (3) there was clinical benefit seen beyond the luminal AR subtype.

Overall, Traina said in her presentation, TBCRC011 was proof-of-concept that bicalutamide had activity in AR-positive metastatic TNBC. An ongoing study at MSK is looking at the agent in combination with the CDK4/6 inhibitor palbociclib for women with AR-positive metastatic breast cancer (

The second-generation AR inhibitor Zytiga (abiraterone acetate) was evaluated in a phase 2 trial of postmenopausal women with ER-positive metastatic breast cancer. A total of 297 patients were randomized to receive Zytiga and prednisone (89 patients) ; Zytiga, prednisone and exemestane (106 patients); or exemestane alone (102 patients). The primary endpoint of the trial was progression-free survival (PFS).

Trial data showed that while overall response rate (ORR) was higher among those receiving Zytiga, prednisone and exemestane (12.1 percent) compared with exemestane alone (6.3 percent), the benefit was not statistically significant. Similarly, the clinical benefit rate was higher with Zytiga, prednisone and exemestane (22.7 percent) compared with exemestane (12.7 percent), but again the data were not statistically significant.

The median PFS with exemestane alone was 3.7 months, compared with 4.5 months with Zytiga, prednisone and exemestane and 3.7 months with Zytiga plus prednisone.

Most recently, Xtandi (enzalutamide) was evaluated in the phase 2 MDV3100-11 trial presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. In this study, single agent Xtandi was evaluated in patients with advanced AR-positive TNBC. The primary endpoint of the trial — the largest prospective trial of an AR inhibitor in TNBC &mdash; was clinical benefit rate at 16 weeks.

Among the 75 evaluable patients at a median age of 50 years, the CBR was 35 percent (26 patients) at 16 weeks and was 29 percent (22 patients) at 24 weeks. Further, six patients had a CR or PR (response rate, 8 percent) and median PFS was 14.7 weeks in the evaluable population.

In the intent-to-treat population (118 patients; those who received more than one dose of Xtandi), the median age of patients was 57 years. The 16-month CBR was 25 percent and the 24-month CBR was 20 percent. The response rate was 6 percent. Median PFS was 12.6 weeks. Median overall survival was 12 months.

Using the PREDICT AR biomarker test, the median PFS was 16.1 weeks in the positive group versus 8.1 weeks in the negative arm. In those who received zero or one prior therapies, the median PFS was 40.4 weeks in patients with PREDICT AR-positive tumors versus 8.9 weeks in those with negative tumors.

Overall, 61 percent of patients (72 patients) experienced a treatment-related adverse event (AE) with one AE being serious. The most common related AEs were fatigue (30 percent), nausea (22 percent), and decreased appetite (11 percent).

Xtandi, Traina said, is the most promising agent in this space and is currently being explored in a “definitive” phase 3 trial (named ENDEAR), which will evaluate the agent in combination with paclitaxel or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC.

Outside of that, there are other trials in metastatic TNBC evaluating Xtandi with or without a PI3K inhibitor (

); a novel CYP17 inhibitor and AR antagonist (

). In the adjuvant setting, Xtandi is being evaluated in a feasibility study (

) and in the neoadjuvant setting with paclitaxel (

Traina emphasized that an AR antagonist could make a huge difference to patients’ quality of life. “Using a hormonal strategy versus what chemotherapy is so much easier for our patients,” she said. “The side effect profile for taking a hormone pill a day where you don't lose your hair, you're not sick to your stomach, you're not vulnerable to infection — it's really great quality of life.”

Anti-androgen therapies may eventually be used to treat some patients with breast cancer, according to Tiffany A. Traina, M.D.

Anti-Androgen Therapies May Find New Home in Breast Cancer

Combining and sequencing novel targeted therapies, such as CDK 4/6 inhibitors and PI3K inhibitors with anti-hormonal therapies will be a key factor in helping patients with hormone receptor (HR)-positive breast cancer overcome drug resistance. Then, physicians can focus on optimizing treatment for these patients, says William J. Gradishar, M.D.

Gradishar addressed this topic in a presentation at the Lynn Sage Breast Cancer Symposium hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  

Gradishar is the deputy director of the Lurie Cancer Center Clinical Network and director of the Lurie Cancer Center’s Maggie Daley Center for Women's Cancer Care in Prentice Women's Hospital.  

sat down with Gradishar to discuss his talk.

Can you provide me with a brief overview of your talk?

The talk focused on HR-positive breast cancer and the strategies that have been employed to enhance the effect of standard anti-hormonal therapy and the strategies to overcome resistance that develops.  

This has taken us into the realm of combining endocrine therapies with targeted therapies: mTOR inhibitors, such as Afinitor (everolimus), and CDK 4/6 inhibitors such as Ibrance (palbociclib) and others that are in development.  

Additionally, there has been a lot of work and interest in looking at PI3K inhibitors because that pathway is amplified and mutated in patients with estrogen receptor (ER)-positive breast cancer. The strategy would be to look at a combination of anti-hormonal therapy and a PI3K inhibitor and see if that improves response and translates into a better overall outcome. We are also evaluating drugs that affect epigenetic phenomena using HDAC inhibitors, such as entinostat.  

What are the challenges associated with treating patients after disease progression?

To date, we know that adding an anti-hormonal therapy adds time to when the disease progresses. We're hopeful that as we go forward some of these other drugs may have the same effect. Some of these drugs are being investigated in early-stage breast cancer to see if similar strategies might translate into a better overall outcome.

It's inevitable that patients with metastatic disease will develop progressive disease. All of the therapies we have —even beyond anti-hormonal therapy &mdash; despite good responses, the disease figures out a way of working around the treatment. There are a number of reasons why that may occur: the tumor can evolve, mutations can develop, bypass pathways can become more dominant, and subclones of tumor cells may be more responsive to one therapy versus another. This speaks to the issue of having more strategies when progression happens.  

So you want to have more effective therapies before resistance develops?

The hope would be that by having other agents that can be combined with anti-hormonal therapies, that you may be able to suppress or delay those resistances. The ultimate goal with anti-hormonal therapy is to continue it as long as possible because compared with chemotherapy, it's much better tolerated. 

Yes. As an example, if you combine Ibrance with an anti-hormonal agent like an aromatase inhibitor, the time until the disease progresses is significantly longer — by about 10 months &mdash; compared with those who just get the anti-hormonal therapy. That's before there are these resistance mechanisms are developing.  

You mentioned CDK 4/6 inhibitors, PI3K inhibitors and HDAC inhibitors. Is toxicity a big concern with combining these agents?

We have data that show us when patients have been exposed to other agents, we can still further delay time to progression. We can achieve an initial enhancement or one that happens when a patient has been exposed to more than one other anticancer therapy.  

Toxicity is a concern because anti-hormonal therapy alone is pretty well-tolerated. I'm not suggesting that by combining an anti-hormonal agent with something else that you'd make it prohibitively toxic, but you do change some expectations. For instance, Ibrance added to an anti-hormonal therapy is going to cause neutropenia, which is not typical of anti-hormonal therapy by itself. Clinically, it won't be a significant, but you have to check them. Afinitor can cause mouth sores. These wouldn't be typical of what we'd see with just anti-hormonal therapy.  

With this change in toxicity, you want to be sure that the upside is much, much bigger — how responsive the tumor is and how long until the disease progresses &mdash; to make those side effects worthwhile.

The questions that are still unanswered are: What do you do when a patient who has had a CDK 4/6 inhibitor, will they respond to an alternative CDK 4/6 inhibitor? We don't know the answer to this. Will they benefit if you stay with the CDK 4/6 inhibitor and switch anti-hormonal therapies? We don't know the answer to this either.  

We don't have a lot of data regarding changing the class of targeted therapy either. Right now, the only two approved drugs in this setting are Ibrance and Afinitor, but there are dozens being evaluated.   A good problem we may have is that if these drugs prove to be effective, how do we optimally use them? That's where the questions about sequencing come in.  

Based on what we've talked about, what do you hope treatment looks like for HR-positive disease in coming years?

There's an obvious other piece of this. We've talked about efficacy and toxicity, but there's also an increase in the expense that goes with adding targeted therapies to standard anti-hormonal therapies. A combination in this space could cost $10,000 or $20,000 per month. That would be the cost to the system. 

Though we freely toss around the term “precision medicine,” we're still practicing relatively crude medicine. The promise of precision medicine is that we'll identify specific signatures in an individual patient at a specific point in time to help dictate the therapy we think is best for them. Rather than checking drugs we've tried off of a list, we hope to have an objective reason to choose any drug for a given patient. With new assays, we can order these treatments but we need to show that they’re making a difference in patient outcomes.

Optimizing treatment for patients with HR-positive breast cancer means that researchers must first find a way for patients to overcome drug resistance, says William J. Gradishar, M.D.

Andrew J. Roth

'In Our Genes' Event Raises Research Funds, Builds Community for Those at Increased Risk of Breast and Ovarian Cancers

Expert Discusses What's on the Horizon in Triple-Negative Breast Cancer Care

Anti-Androgen Therapies May Find New Home in Breast Cancer

Strategies Needed to Overcome Drug Resistance in Breast Cancer Subset

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