WHEN I WAS 27, my husband and I welcomed our twins into the world. Their story began when they were born exactly two months early. Ten days later, in that same hospital, my mother started a new chapter in her life when she was diagnosed with ovarian cancer. I spent my days running between the floors of the hospital to visit my mother and my daughters. One generation up; one generation down — just two floors apart, but their stories were more closely connected than any of us understood. 

Not long after my mother’s initial diagnosis, we discovered that she was BRCA1 positive. Being positive for a mutation in this BRCA gene meant that she faced up to a 72 percent chance of developing breast cancer and up to a 44 percent chance of developing ovarian cancer over the course of her life. It also meant that there was a 50 percent chance that she had passed this genetic mutation on to me.

When my daughters were 4 months old, I decided to undergo genetic testing. My genetic counselor had me spend a lot of time gathering and outlining my family tree and my family’s health history. He explained my risk of carrying the gene mutation and drew my blood. Weeks later, he called and asked me to come into the office. My results were in. I took one look at his face and knew immediately that I, like my mother, am BRCA1 positive. 

Back when I first got tested, my daughters were so tiny that it was not possible to have a meaningful conversation with them about this diagnosis, but it definitely shaped our story going forward. Today I am blessed with three children: my 7-year-old twins and my 4-year-old son. I often think about whether they have inherited the same gene mutation I carry. I wonder how I can provide them with a framework for understanding how this genetic mutation has profoundly affected our family’s history. My family has many more BRCA obstacles yet to come. There is no doubt that my children will have questions. I knew I would have to find a way to answer them. 

I decided I would tell them a story — our story.

Whether around our dinner table or in the car on the way to soccer practice, my family loves to tell stories. In fact, my children love telling stories so much that they often create small picture books for my husband and me. Every day, I am in awe of their creativity and ability to learn through the stories they tell. It was from their works that I was inspired to create a picture book for young children, “Mom’s Genes,” that would help us start a much-needed conversation about our family’s health history. Because my children are still quite young, I knew I would have to approach this conversation slowly and in a way that they would understand. By lightly introducing the concepts of genetics and family health history, “Mom’s Genes” was meant to ignite that first conversation so that we could eventually dive deeper into these issues.

One day at breakfast, I told my children that Mommy had written a story. It was a wonderful experience to share the initial draft with them. They immediately started giving me detailed descriptions of what the illustrations should be. Sitting and sketching out ideas for “our story” became one of our after-school activities. All the while, I was introducing them to the story of their genes. As a result, they began recognizing and talking about genetic traits that they may have inherited from members of the family. Then, when the children were concerned about my frequent medical visits, the book helped me explain that my doctors know my family’s health history and use it to do plenty of checkups to keep me healthy. 

As genetic information and testing become more readily available, they will have a tremendous  impact on medical decisions going forward. Families with certain genetic mutations face many complex and personal choices, including how and when to share such information with their children. It is my hope that “Mom’s Genes” will help parents start conversations with their young children about their own families’ health histories and encourage their sons and daughters to be proactive about their health and wellness starting from a young age. 

Articles

Bookshelf

Families with certain genetic mutations face many complex and personal choices, including how and when to share such information with their children. Mom's Genes is here to help.

Starting a Conversation

THANKS TO RECOMMENDED SCREENING starting at age 55, the overall incidence of colorectal cancer declined over the past two decades. However, there is a sobering exception to the encouraging trend: Among those under 50, the rate has risen 51 percent since 1994, according to the American Cancer Society (ACS).

In an attempt to help reverse this trend, the ACS has issued an updated guideline that calls for screening to begin at age 45 for individuals at average risk of colorectal cancer. Previously, the accepted U.S. standard was to start screening at age 50. Despite the faster rise in colorectal cancer among younger adults, incidence rates among those aged 45 to 49 are actually lower than those of people aged 50 to 54. The ACS attributes this partly to the uptake of screening at age 50, which results in a higher rate of detection of the disease, including cases that are early and asymptomatic.

“(Implementing the ACS guidelines) is a way to prevent this disease from happening in younger persons,” Susan K Peterson, Ph.D., M.P.H., of the department of behavioral science in the division of cancer prevention and population sciences at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with CURE®. “(And it is) one way to potentially stem the occurrence of these cancers and the morbidity and mortality from them.” Screening can lead to removal of premalignant polyps before they turn into cancer, and to earlier detection of cancers that have already developed, improving health outcomes compared with later detection.

The ACS based its recommendation on colorectal cancer incidence rates, a computer model that demonstrated a benefit to screening beginning at age 45, and the expectation that this will lead to catching the disease earlier, just as it has for older adults. The guidelines, recently published in CA: A Cancer Journal for Clinicians, recommend the following:

• Adults aged 45 and older at average risk of colorectal cancer should undergo regular screening — either with a high-sensitivity stool-based test or a visual exam such as a colonoscopy, depending on patient preference and test availability or insurance coverage.

• All positive results on non-colonoscopy screening tests, such as fecal occult blood, should be followed up with timely colonoscopy.

• Average-risk adults in good health with a life expectancy of greater than 10 years should continue screening through age 75; for those 76 to 85, clinicians should individualize screening decisions based on patient preference, life expectancy, health status and prior screening history. Those over 85 should be discouraged from continuing colorectal cancer screening.

“The guidelines do not recommend only going (with) colonoscopy — which is oftentimes considered the gold standard of screening tests &mdash; so patients have a choice of what test they can use,” Peterson said. “Sometimes a colonoscopy can be a bit off-putting.”

Patients can be screened annually with a fecal immunochemical test or a high-sensitivity guaiac-based fecal occult blood test, both of which detect blood in the stool; every three years with a multitarget stool DNA test, which can detect not only blood in the stool but also abnormal DNA; every five years with CT colonography (a virtual colonoscopy using X-ray equipment) or flexible sigmoidoscopy (which examines the lower part of the large intestine); or every 10 years with a colonoscopy, which examines the entire colon.

To follow the new guidelines, the first step for patients is to find out if any relatives have or had cancer. “If you have a family history of colon cancer, you may benefit from being testing for an inherited gene mutation that indicates you have one of the known hereditary cancer syndromes,” Peterson said. Even if those syndromes are ruled out, having a first-degree relative who was diagnosed with colorectal cancer increases an individual’s risk, she said: “Everyone should know their family history, be aware of it and share that information with their doctors.”

In addition, patients’ discussions with their doctors should start before age 45 to at least determine when screening should start. Any middle-aged or younger individuals who have symptoms, such as abdominal pain, blood in the stool, narrowing of stools or fatigue, but are dismissed by a health care professional because of their age, should seek a second opinion.

“Talking about this, although uncomfortable, and becoming aware is really important,” Peterson said. “Boiling it down: This should be a wakeup call that if you are younger than 45 and are identifying symptoms that might be related to colorectal cancer, go see your doctor, and do not put it off.”

Diagnosis Cancer

A new American Cancer Society guideline recommends starting screening for colorectal cancer at age 45.

Screening Younger for Colorectal Cancer

MARK SAGLIOCCO / FILMMAGIC / GETTY IMAGES

SINGER ARETHA FRANKLIN, 76, died of advanced pancreatic cancer on Aug. 16 at her home in Detroit, with her family and friends at her bedside.

Franklin, who underwent surgery for neuroendocrine tumors, a rarer type of pancreatic cancer, in December 2010, kept her diagnosis private.

The Monday before she died, a source told the Associated Press that the Queen of Soul was “seriously ill” and her death was “imminent.” Franklin entered hospice care just days before her death.

“In one of the darkest moments of our lives, we are not able to find the appropriate words to express the pain in our heart,” her family said in a statement. “We have lost the matriarch and rock of our family. The love she had for her children, grandchildren, nieces, nephews and cousins knew no bounds. … We have felt your love for Aretha, and it brings us comfort to know that her legacy will live on.”

People Report

SINGER ARETHA FRANKLIN, 76, died of advanced pancreatic cancer on Aug. 16 at her home in Detroit, with her family and friends at her bedside.
 

Aretha Franklin Died of Advanced Pancreatic Cancer

When Laura Brashier received a diagnosis of stage 4 cervical cancer at age 37, her life came screeching to a halt. She was prepared for the possibility of a hysterectomy, extensive radiation and chemotherapy — and even the reality of never being able to bear children. What she wasn’t prepared for, however, was how to adapt to her “new normal” after the cancer was gone.

“The interesting thing about cancer is that here you are, just trying to survive, and life around you goes on,” Brashier says. “People go about their business, and you’re over on the sidelines, just watching. Eventually, you really have that desire to jump back into that mainstream.”

Being single often includes dating, but that is an uncomfortable and often taboo topic for people affected by cancer.

“Some of the most frustrating things that cancer patients deal with, when it comes to dating, are struggling with body image and self-esteem,” says Sarah Paul, LCSW, manager of the child, adolescent and young adult program at CancerCare, a national organization dedicated to providing free, professional support services to anyone affected by cancer. “(Appearance) changes are usually the first things that happen when you’re undergoing cancer treatment, and a lot of dating apps and websites focus on that first look.”

Just as patients in treatment struggle with whether to add a line about their diagnosis in their profile or post an older picture to mask hair loss, survivors of cancer often find it difficult to put themselves out there. They grapple with questions about when to reveal their survivorship or any longer-term side effects of their past treatment.

Brashier, whose lifesaving radiation left her unable to have intercourse, is no stranger to these insecurities. After years of avoiding the conversation when friends and family asked her why she wasn’t dating, she decided to look online. “I thought, ‘Everything’s online nowadays,’” she says. “‘I wonder if there’s a dating site.’”

Her search uncovered a vast assortment of websites catering to a variety of people; however, she found nothing designed for others like her. She was shocked. “There are thousands of us on the planet,” Brashier says. “We live in these bodies we don’t always have control over, and people never talk about it.”

So, on a mission to solve what she calls the unspoken epidemic of cancer patients and survivors struggling with living life in quiet solitude, she started her own website.

Brashier launched RomanceOnly.com in 2011. With the tagline “intimacy…without intercourse,” the website now connects 14,000 users across 126 countries based on a geographic radius they choose and general interests, Brashier says.

Notably absent from each user’s profile: the reason for joining. After all, the point of the site is to remove the need to explain oneself when trying to navigate dating after a lifechanging diagnosis. “We don’t ask,” Brashier says. “The fact that they’re even on the site is a huge applause.”

Six years before the launch of RomanceOnly, Darryl Mitteldorf, LCSW, embarked on a similar mission. After founding Malecare.org, selfdescribed as “America’s leading men’s cancer survivor support and advocacy national nonprofit organization,” in 1997, Mitteldorf saw another opportunity to make a difference: connecting people with cancer not only on a peer-to-peer support level but also on a romantic level.

“I just started learning how single cancer survivors really struggled to find purpose in life,” Mitteldorf says. “I saw a need for an arena for people to meet each other where they didn’t have to explain themselves over and over and over again … to meet other people who understand.”

Thus, CancerMatch.com was born. Since launching in February 2005, it has grown to serve over 1.3 million members, Mitteldorf says.

Similar to RomanceOnly, CancerMatch trusts that its users are there for the right reasons and never verifies whether the diagnoses shared on profiles are actually legitimate. Mitteldorf describes CancerMatch as selfpolicing: A disclaimer at the bottom of the site urges, “Remember — report ANYONE who asks for money or makes you feel uncomfortable in any way.”

“We obviously can’t verify that people have cancer. We’re not asking for doctors’ notes,” he says. “But people (who may be dishonest) are relatively easy to spot — they don’t know what their treatments really are or what their side effects may be. And those people get reported back to my team, and we delete those profiles instantly, as well as track their IP addresses to make sure they don’t sign on again.”

Any platform brings risks, Mitteldorf says: “From Facebook on down, all of these sites have people trying to scam others … but what’s really nice, though, as far as I know, is that out of over a million users, we haven’t had a single real issue.”

RomanceOnly charges $9.99 per month; CancerMatch is sustained by donations made to MaleCare.org. “It’s entirely free,”Mitteldorf says. “There’s no advertising or anything like that. It’s just there for people to use.”

On both sites, users determine their own level of privacy and anonymity. For example, they don’t have to post pictures, and many use fake names. Over time, after they begin to form a connection with someone, they can decide to disclose more. “The depth of your profile can’t be read by just anyone,” Mitteldorf says. “Both people have to say ‘I want to meet you’ or ‘I want to message you.’” In addition, both sites emphasize that users aren’t required to seek romantic relationships. CancerMatch’s homepage urges potential users to “build your own network of contacts,” “meet or mentor,” “join, create or lead your own support group” and “meet new friends and, maybe, even fall in love.”

“We aren’t meant to be alone,” Brashier says. “We’re meant to have companionship. Even if you don’t want to date and you end up meeting a friend, it’s just a place to talk with someone who can relate to how you’re feeling.”

Despite the growing user bases of websites designed for people with cancer, public awareness remains relatively low. As Brashier states, “People just don’t want to talk about it.” Even so, within the cancer community, the interest is there. In a 2012 discussion board on StupidCancer.org, a nonprofit organization that focuses on young adult cancer advocacy, research and support, one member started a discussion titled “Dating.” “I think there should be a Match. com-like section of StupidCancer.org dedicated to singles who had/have cancer and are searching for relationships,” the post reads.

Over the course of six years, a steady flood of comments has followed.

“I agree totally. Dating is hard … even harder with the triviality of online dating sites,” says one user.

“Yes, I agree!” says another. “It seems like every time I meet new people, my cancer somehow gets mentioned or comes up in the conversation. That’s usually the end of it.”

In 2014, Elle Green* — at the time, a recently single, 30-year-old breast cancer survivor &mdash; wrote a blog post on FirstDescents.org titled “Back in the Game: Dating After Cancer.” She mused about the unique difficulties of finding love as a survivor: “OkCupid has a lot of search criteria to help you find your ideal match, but I was pretty sure ‘cancer survivor’ wasn’t one of them.”

In addition to voicing concerns about scaring people away before they got to know her and how to handle the revelation of her mastectomy scar (“the right time for this conversation is somewhere between the first date and the moment where you see each other naked”), Green sums up the reality of dating after cancer in one simple sentence: “I find that there’s a weird tension between wanting to share in the name of authenticity and wishing you didn’t have to in the first place.”

“In general, it’s hard to meet people, even without cancer,” Paul says. “Dating can be really challenging … in a culture that’s focused less on commitment and more on casual dating. So, for someone who’s diagnosed with a serious illness and might be looking for something more … if they make a connection with someone and they do choose to disclose (their diagnosis), they’re being completely vulnerable.”

Green agrees. “When you’re dating at age 30, most people have not experienced something like cancer,” she says. “For me, it actually got harder once I wasn’t in active treatment anymore, because there were no external signs of my cancer history. When you’re bald, it’s evident. But when you have hair and you look ‘normal,’ it becomes trickier, because you have to decide when to tell someone.”

Removing those initial anxieties makes a world of a difference, according to Brashier and Mitteldorf. “The CancerMatch experience dissolves awkwardness,” Mitteldorf says. “You never have to apologize for the way you feel when you’re dating a person with another cancer diagnosis. … You don’t have to have the ‘I have cancer’ talk. You never even have to bring it up.”

Adds Brashier: “It’s about finding a community of people who understand what you’re going through, a community that can relate to your new normal.”

Although many patients and survivors feel that a dating website designed specifically for people with cancer can help in their search for love, others worry about overidentifying with their diagnosis. “Some struggle with feeling that people only see them as a cancer patient or a cancer survivor,” Paul says. “Embracing your survivorship is such a beautiful thing, if that’s your choice. But for some people, after they finish treatment, they’re ready to pick up and move on and leave that part of their life behind, which is also completely fine.”

Above all, Paul urges anyone considering jumping back into the dating scene during or after treatment to stay true to themselves, take it slow and prioritize making connections with others, whether romantic or not. “Improving your social surroundings and your support system can really improve your quality of life in general,” she says. “Whether it’s dating, whether it’s joining a support group … that connection makes a difference in healing.”

Brashier and Mitteldorf agree — they’ve seen it firsthand. “I’ve gotten so many emails from people who have partnered up and even gotten married through CancerMatch, and it’s been enormously gratifying,” Mitteldorf says. “Support groups are about hope; CancerMatch is about happiness.”

“I thrive on the positive emails that people send me,” Brashier says. One, now highlighted as a Success Story on the RomanceOnly website, reads: “After one and one-half years of driving 150 miles one way and three hours the other every weekend, Sheila and I decided we wanted to move closer to one another, as we just love being together. Our unique intimate relationship is beyond anything either of us thought possible. … We both really thought we’d be alone forever, and instead we’ve decided to be together forever.”

Features

Some online dating sites are specifically for people affected by cancer.

In Sickness and in Health: Dating Apps in the Cancer World

When GARY HARTSTEIN was diagnosed with stage 3 kidney cancer, there were no approved drugs to help prevent recurrence after treatment. - PHOTO BY RYAN DEARTH

When Gary Hartstein found blood in his urine in January 2017, he was alarmed, especially when he had difficulty urinating. Within a week, the urologist at his local New Jersey hospital ordered a CT scan and found a racquetball-size tumor. During surgery, the doctor removed Hartstein’s kidney and the 9-centimeter mass and found that the tumor had been pressing into blood vessels, causing clots. Pathology revealed renal cell carcinoma (RCC). Hartstein was told his cancer was stage 3 and was relieved to hear that doctors had removed it all.

Both his New Jersey doctor and another from New York City, who gave a second opinion, said there was nothing more to do. The 52-year-old nonprofit program manager was declared cancer-free. “There was certainly a risk of it returning,” Hartstein says, but the doctors told him there was no proven additional medical strategy to prevent recurrence or disease spread, and the standard of care was to monitor his condition.

Less than a year later, in November 2017, the Food and Drug Administration (FDA) approved the first and only adjuvant, or post-surgical, maintenance therapy to help prevent recurrences of the disease: Sutent (sunitinib), a targeted drug for adults with a high risk of their cancer coming back after a kidney removal (nephrectomy).

The most common treatment for early-stage RCC, a category that generally includes stages 1 through 3, involves removing part or all of the affected kidney and then monitoring for further signs of disease. The surgery can be curative if the cancer is restricted to the kidney. Giving Sutent as an adjuvant treatment, or safeguard against disease progression, is not a popular choice: Just one study showed it to be effective in prolonging the time without evidence of disease, also known as disease-free survival. There hasn’t been any proof yet that Sutent as adjuvant therapy extends a person’s life, known as overall survival. If there is a high risk of recurrence and the cancer is not metastatic, patients can consider entering a clinical trial testing other adjuvant targeted drugs, immunotherapies or both.

Sutent and similar drugs can also be used by patients who, at diagnosis, have stage 4 RCC that is metastatic — it has spread to other parts of the body. For those who will not undergo surgery, the drugs may be given as a first drug to treat the cancer. To treat any sites of disease that remain after that, patients might get more Sutent or one of several similar drugs: Nexavar (sorafenib), Torisel (temsirolimus), Afinitor (everolimus), Avastin (bevacizumab), Votrient (pazopanib), Inlyta (Axitinib), Cabometyx (cabozantinib) and Lenvima (lenvatinib).

The drugs work by interfering with the growth of blood vessels that feed tumors or inhibiting the activity of proteins that help drive cancer cell growth. Sutent does both. Known as a tyrosine kinase inhibitor, it blocks the activity of a protein known as VEGF, or vascular endothelial growth factor, and other proteins that transmit signals from different growth factors.

But in recent big news, Sutent is showing promise as an initial treatment for most patients with metastatic kidney cancer — regardless of whether they’ve been deemed eligible for surgery. The CARMENA study revealed that patients with operable metastatic disease who took Sutent alone did not have worse longevity than those who underwent kidney removal and then took Sutent. That means that most surgery-eligible patients with metastatic disease can safely skip the procedure and simply take Sutent.

This is likely to change the standard of care, which was previously informed by older data showing that nephrectomy improves survival in patients with metastatic disease, even though it doesn’t remove all disease.

Hartstein learned that he had small lung nodules in June 2018, several months after his surgery. He had moved to Lakewood, Colorado, and continued to get baseline scans. His new doctor, who found the nodules, ordered a biopsy and confirmed metastatic cancer.

Progressing from stage 3 to stage 4 is common for patients with RCC. A subset who have no evidence of cancer on initial CT scans just after surgery will later develop signs that can be seen via imaging. This likely happens because the cancer is at first microscopic, below the threshold for detection. “It takes about a billion cancer cells to make a 1-centimeter mass seen on a CT scan,” says Matthew Galsky, M.D., a professor of urology, medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai and director of genitourinary medical oncology at the Tisch Cancer Institute in New York City.

It can take months to years for those microscopic cancer cells to be detected, and that’s why some doctors recommend that certain patients with a high risk of recurrence consider adjuvant treatment following surgery.

Patients with the greatest risk of recurrences that are metastatic have tumors that are large, extend beyond the kidney or have spread to nearby lymph nodes, says Lauren Harshman, M.D., assistant professor of medicine at Harvard Medical School and co-director of the kidney cancer program and a senior physician at Dana-Farber Cancer Institute in Boston.

Until recently, there was no FDA-approved drug for adjuvant RCC therapy in patients with earlier-stage disease, and even though Sutent got the green light, doctors say it’s not commonly given for that purpose. “The general level of enthusiasm for this in the community is not extremely high,” says Eric Jonasch, M.D., a professor in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center in Houston.

Those who do take Sutent after surgery get the same one-year regimen that is given for metastatic treatment: 50 mg a day orally for four weeks on and two weeks off. “Whether that will be tolerable is a question,” Jonasch says. “If you look at the clinical trial data, you see that a significant number of individuals are reducing their dose or coming off.” That’s because of side effects, which can include diarrhea, fatigue, high blood pressure, hand-foot syndrome, mouth sores and gastrointestinal upset.

Doctors may also hesitate to recommend Sutent in this scenario because just one clinical trial, S-TRAC, showed a positive effect. “S-TRAC is the only trial in the history of kidney cancer that showed a one-year improvement of disease-free survival versus placebo in very high-risk patients with stage 3 disease. It did not show an overall survival advantage, though the authors argue that the data need to mature,” says Chris Wood, M.D., deputy chairman of the department of urology in the surgery division at MD Anderson.

Although one of Galsky’s patients completed a year of Sutent adjuvant therapy, Jonasch and Wood say that none of their patients have taken it under these conditions. “It’s super toxic at doses recommended. It’s very expensive. It showed a one-year difference in (disease-free survival, or the time from treatment until disease progression,) but no difference in overall survival. If you don’t live longer, what good is it?” Wood asks. “If I had stage 3 kidney cancer, I wouldn’t take sunitinib.”

Some researchers theorize that this type of adjuvant therapy works by slowing down already existing microscopic metastases, thereby delaying the diagnosis of progression, but with no prospect of improving survival. Many believe there’s a need for drugs that exert a greater impact on metastatic disease, suggesting that these medications would also work better as adjuvant drugs, generating more cures and longer life.

Before the FDA approved Sutent, a survey by the Kidney Cancer Research Alliance asked 450 patients at all stages of RCC under what conditions they would use some kind of adjuvant therapy. The results, presented at this year’s American Society of Clinical Oncology Annual Meeting, revealed that 54.7 percent of respondents would be willing to take an adjuvant drug to delay or prevent recurrence — even in the face of toxicities: 24.2 percent only if there were a proven overall survival benefit; 16.9 percent if the drug was associated with moderate toxicity; and 13.6 percent regardless of toxicity level. Meanwhile, 28 percent of respondents said they would need more information before making a decision, 8.2 percent reported they would only use an adjuvant therapy if there was no toxicity, and 3.8 percent stated they would not use such a drug.

LAURA LOUGHLIN didn't like the idea of watching and waiting after her initial treatment for kidney cancer. - PHOTO BY DEIRDRE RAKUS

After Laura Loughlin was diagnosed with stage 3 RCC and had a kidney and a 24-centimeter tumor removed in 2016, she thought she was cancer-free. Doctors planned to employ active surveillance, with scans every three months. A few weeks later, they noticed thyroid nodules, which turned out to be cancerous. Although Loughlin realizes that, given the short span between her surgery and the diagnosis of metastatic cancer, she probably would not have benefited from adjuvant Sutent, she doesn’t like the idea of watching and waiting. Still, without any approved adjuvant treatments at that time, doctors did not recommend additional therapy after she received radiation for the nodules. “That’s the hardest part of all for me. I felt like I actively stopped fighting,” says the North Grafton, Massachusetts, information technology project manager. “The idea of doing nothing gives me pause.”

On the other hand, Loughlin recognizes that, had she taken Sutent, her life might have been quite different due to side effects. “I’ve had two good years, where if I was taking Sutent, I might have had a different quality of life,” she says.

SUTENT VERSUS CLINICAL TRIALS FOR ADJUVANT THERAPY

Without a benefit in overall survival, and 30 to 40 percent of patients coming off Sutent early because of toxicity, doctors and patients should consider whether it’s the best treatment for them, says Harshman. It may be better to monitor the disease, treating just if the cancer recurs, which would avoid toxicity for patients who may never have a recurrence.

Multiple clinical trials are looking at different targeted and immunotherapy agents as adjuvant treatments. “Adjuvant therapy has been the holy grail of kidney cancer research,” Wood says.

Harshman agrees, noting that researchers have been conducting randomized trials of potential adjuvant RCC therapies for more than 30 years with little success. She hopes that will change with the PROSPER trial, of which she’s the principal investigator. Its approach is “adjuvant therapy with a twist,” she says, because it will give some drug therapy prior to surgery — a strategy that is novel in RCC but effective in other cancers, such as breast and bladder. Patients in the control arm receive surgery only, and those in the study arm receive doses of the immunestimulating therapy Opdivo (nivolumab) before kidney surgery and for nine months after. “(The agent) revs up cancer-fighting T cells while the tumor is in place, so they can better recognize the micrometastatic cancer once the primary tumor is removed,” Harshman says. Opdivo then continues to help the T cells propagate, so they can recognize and kill microscopic cancer cells that have spread outside the kidney and surgical field.

Those with high-risk non-metastatic kidney cancer have a particularly compelling reason to consider enrolling in clinical trials of adjuvant therapies: “If their disease comes back, we don’t have many treatments for them,” Harshman says.

Deciding on a treatment approach after a stage 2 or 3 RCC diagnosis depends on personal preferences, and patients need to be aware of each option’s pros and cons, according to Harshman. Adjuvant Sutent, she says, is for patients who are highly motivated to do everything they can. Those who don’t want intervention unless it’s absolutely necessary choose active monitoring with scans, with treatment given just if the cancer returns.

“There’s a group of patients who say, ‘If there’s nothing proven in this setting and the potential (that) I may have been cured with surgery alone, I’d rather not proceed with anything,’” Galsky notes.

Enrolling in a clinical trial of the newer immunotherapies is something of a risk, because there’s no guarantee of being placed in the treatment arm rather than the control (placebo or standard-of-care) arm. Still, this may be a chance worth taking, according to Galsky. “(Trials are) clearly the most important option in this setting right now, as we have gone decades without adjuvant therapies with a definitely proven benefit,” he says. The new class of immunotherapy drugs known as checkpoint inhibitors has benefited those in the metastatic setting and led to major changes in treatment; for a large portion of patients, they are better tolerated than VEGF tyrosine kinase inhibitors, he adds.

However, it’s too early to predict any promise in the adjuvant-treatment clinical trials now in progress, says Jonasch, and results may be years away. In the meantime, the S-TRAC data on overall survival with adjuvant Sutent could mature and provide more insight.

Given the controversy with adjuvant Sutent data, the lack of an overall survival benefit, and potentially significant toxicities that decrease quality of life, Harshman generally encourages her patients to pursue the ongoing clinical trials or close surveillance.

Survivor and patient advocate DEBORAH MASKENS advises others not to let anxiety shape their treatment decisions. - PHOTO BY COURTESY OF DEBORAH MASKENS

Deborah Maskens of Guelph, Ontario, Canada, also has advice for patients with RCC who are making treatment decisions. Diagnosed with metastatic RCC in 1996, Maskens is now a patient advocate. She co-founded Kidney Cancer Canada and is the only patient on the National Cancer Institute’s Renal Task Force.

Maskens urges patients who worry about watching and waiting to not allow anxiety to shape their decisions, and, if necessary, to seek treatment for the distress. They should also look into their individual chances of recurrence and consider getting second opinions. After that, she says, patients can decide for themselves whether the potential side effects of treatment and the logistics involved with specific clinical trials are worth it. It’s a trade-off, she says, with no right or wrong answer.

Sutent, meanwhile, seems poised to make its greatest immediate contribution to care not as an adjuvant treatment but as an initial one for those with metastatic RCC. The results from the CARMENA trial are making waves in the RCC community.

The trial looked at whether to remove part or all of the kidney in patients with operable metastatic RCC at the time of diagnosis, before giving Sutent. In the study, 450 patients were randomly assigned to receive the medication either with no surgery or after nephrectomy. It’s the patients who are in fairly good health, with no metastases in the brain, liver or bone, who are typically considered good candidates for nephrectomy, but “CARMENA threw that into question,” Wood says.

The trial showed that those receiving Sutent alone did not have a worse overall survival rate compared with those who had surgery and then Sutent. “The results were the opposite of what we all expected,” Harshman says. That’s partly because years ago, a trial in metastatic RCC evaluated interferon, an older generation of immunotherapy, with or without nephrectomy, Harshman says. That study’s results showed a six-month benefit to surgery plus interferon. “Once we had the more effective targeted therapies, we still performed cytoreductive therapies (partial or total kidney removal), but without proof (that) it was still needed,” she says.

Furthermore, historically, kidney cancer is one of the few cancers for which surgery is done on the organ despite the presence of metastatic disease, Galsky says. He compares it to fighting a forest fire and working hard to remove the tree that started the fire, rather than attacking the spreading flames. Metastatic RCC treatment is done this way for three reasons: The appearance of tumors on scans is so characteristic that biopsy and removal are done at the same time; based on the anatomy, the tumor is often large, but the metastatic burden is small; and symptoms may necessitate the removal of the kidney.

The CARMENA trial diminishes enthusiasm for routinely removing kidney tumors, but Galsky says he still feels there’s a role for surgery in certain symptomatic patients. “That decision needs to be individualized,” he says, and Harshman, Wood and Jonasch agree.

This was the case for William Feazel, whose metastatic kidney cancer was diagnosed in 2013, when he was 58. The civil engineer from Prairieville, Louisiana, had abdominal pain and a fist-size tumor on his right kidney causing thromboses, blood clots into the venal artery. “Because the mass was so large, it was working its way into the major blood vessel. It had to come out,” says Feazel. Not long before the CARMENA results came out, doctors had already begun to more carefully select patients with metastatic RCC for kidney surgery.

“We’ve already started to move toward a risk-based and common sense-based approach toward cytoreductive nephrectomy,” says Jonasch. The goal is to prevent harm in those individuals who should not undergo kidney removal. “The vast majority of physicians I know and work with still think there’s a role for nephrectomy,” says Wood. “If you don’t dive down into the data, you can get swept up with the message that patients don’t need surgery.”

Surgery should never be taken lightly, so it’s important to select patients who are likely to do well. Any surgery comes with risks; plus, it affects treatment timing. Patients have to heal from surgery and may end up waiting 30 or more days to start systemic treatment, knowing they have metastases. “How much those delays play into outcomes, I don’t know,” Galsky says.

Whether a patient’s cancer is metastatic or not, at some point the disease could spread. Again, the best course of treatment is an individual decision. Loughlin is among those who like the idea of enrolling patients in studies.

“I find the clinical trials exciting,” she says. “I think a clinical trial is a chance to get the best treatment there is. There are a lot more treatments now than five to 10 years ago. I’m encouraged. A trial is a chance to help. My reality is that I’m stage 4. I’ll do anything I can to help others not get to stage 4.”

The online version of this article differs from the version that appeared in print. This version includes added details about a survey conducted by the Kidney Cancer Research Alliance, which more fully communicate its findings.

Targeted drugs are controversial in early-stage kidney cancer, but play a more important role in treating advanced disease.

A State of Flux for Kidney Cancer

Type “revolutionary new cancer” into your favorite search engine and you can almost hear the hype machines engage.

Headlines promise revolutionary vaccines, tests, drugs and imminent clinical trials. But despite the many extraordinary advances in this golden age of oncology, few are truly revolutionary. Then there is CRISPR, a technology that has emerged only in the last decade, empowering us to edit the genetic code of almost any living thing. The technology, which uses software to mimic a geneediting process that bacteria use to fight off viruses, can make a gene stop working, repair damaged DNA, or even insert an entirely novel piece of DNA. Science, the flagship journal of the American Association for the Advancement of Science, published a special issue this August on revolutionary technologies. CRISPR led off its short list.

Testing of CRISPR in humans is just beginning, but the possible uses of the technology are vast, with an array of potential benefits, pitfalls and ethical implications. CRISPR is already being used by a food company to give bacterial cultures used in cheese and yogurt more immunity against viruses. In the future, the technology could be used to create better crops or livestock, make synthetic copies of microbes used to manufacture drugs, modify the fertility of pest species so they become less prevalent, eliminate diseases in animals, people or societies, or even design babies with specific characteristics, such as enhanced intelligence or height, in some cases creating traits passed on to future generations.

LUKAS DOW, Ph.D., uses CRISPR to build genetic models of cancer on which medicines can be tested. - COURTESY CORNELL / PHOTO BY ROBYN WISHNA

While genetic engineering has been feasible in the laboratory for some time, CRISPR makes it comparatively easy. “We never really had tools that were powerful enough to do it in a reasonable time frame at a reasonable expense,” says Lukas Dow, Ph.D., assistant professor of biochemistry in medicine at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. That explains why, in the time it typically takes someone to earn a Ph.D., CRISPR has not just emerged but infiltrated labs worldwide. Its capabilities for genetic manipulation are more sophisticated than even those celebrated in last year’s biggest cancer news, the FDA’s approval of Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), known as chimeric antigen receptor (CAR)-T cell therapies. These expensive but powerful medicines use genetic engineering to enhance the human immune system by training T cells to selectively seek and destroy cancer. That’s a revolution, too, yet the engineering itself is much less refined than CRISPR technology.

“There is so much anticipation and expectation that some people seem to have formed the impression that CRISPR is already curing diseases and in the clinic,” says Michel Sadelain, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center in New York City. Sadelain hopes it won’t be long before that happens. He is constructing what could be the first U.S. trial using CAR-T cells designed with the help of CRISPR, scheduled to begin in 2019. “There is no doubt that CRISPR is a major advance,” says Sadelain, “but there is still a whole body of work to do on its safety.”

CRISPR has had, and will continue to have, growing pains. Early concerns about precision, called off-target effects, have been allayed as techniques improve and more assessment data is collected. “We have been lulled into the view that editing is small and local and controllable,” Allen Bradley of the Wellcome Sanger Institute in England told the journal Nature Methods in July. “(T)he reality of DNA repair in a cell is much more complex.”

MICHEL SADELAIN, M.D., Ph.D., has made it his life's work to engineer human immune cells. - COURTESY MEMORIAL SLOAN KETTERING CANCER CENTER

In June 2018, two articles sharing study findings in Nature Medicine said that the anticancer gene P53 often prevents CRISPR from successfully editing human cells, and when the technology does make an edit, it may be in cells that lack P53. When those edited cells multiply in the body, their malfunctioning P53 increases the risk that cancer might develop.

Scientists who work with CRISPR say that part of the reason for the research was to reveal any such complexities and increase understanding of how the technology works.

Still, the studies hit the mainstream media, including an article in the New York Post with the headline “Futuristic gene-editing technology may cause cancer.”

“That really couldn’t be further from the truth,” Dow says with a sigh. “There’s been a lot of hype about CRISPR’s potential to cure disease. Some people even say (it could) cure all disease. The same hype cycle drives fear.”

Because fungi fight bacteria, we discovered antibiotics, which may be the most important medical breakthrough of the 20th century. Because bacteria are under constant attack from viruses, we now have CRISPR, perhaps the most intriguing medical breakthrough of this century.

The new technology takes advantage of a natural immune response of the same name that bacteria use to fend off viruses. The mechanism was first seen in E. coli in 1987. You may recall that nucleic acids — DNA and RNA &mdash; are each made from just four molecules. Scientists assign each of these a letter, so your genetic code can be read as a 3 billion—character string of just these four letters. Viruses are also constructed largely of RNA or DNA, and they do damage by hijacking the DNA of their host. Inside bacteria, CRISPR works to ward off these viral interlopers, even saving samples of viral DNA, like mug shots, to allow the bacteria to recognize future intruders.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. It refers to palindromes, or repeating patterns, of DNA that are found in most single-celled organisms known as archaea and in nearly half of bacteria. The palindromes are like bookmarks for the virus snippets that the bacteria capture and keep “on file” so they are able to recognize any dangerous viruses that come along later. When the bacteria detect such a virus, they send a Cas (CRISPR-associated) enzyme to destroy it by cutting it up.

Our limited ability to decipher DNA meant that we didn’t even notice these curious palindrome patterns in bacterial DNA until the late 1980s. It took another 20 years to see the purpose in the pattern. Now that scientists understand how bacteria use CRISPR to repel viruses, they are harnessing the technique for use in the lab and clinic. In the decade since the technology emerged, CRISPR techniques have proliferated, spurring a host of research, investments, patent battles and sci-fi scenarios.

CRISPR’s importance in cancer is fundamental. The disease is first and foremost a corruption of the body’s DNA, a cruel hitch in our genetic code. In the past 20 years, our ability to read that code has expanded exponentially, driving many advances in treatment and understanding. CRISPR now makes it feasible to write, and rewrite, that code.

To do so, scientists use computers equipped with special software to indicate what they would like to accomplish with CRISPR and are given instructions on the materials they should mix in a test tube to get the desired reaction. According to MIT Technology Review, to use the technology on people, several methods have been proposed that will be tested in clinical trials: gels or creams that go on the skin; drinks or foods; ear injections; CRISPR-engineered skin grafts; and a technique like that used in Kymriah and Yescarta that removes cells from a patient, engineers them in a lab and reinfuses them.

Dow’s lab focuses on gastrointestinal tumors, primarily colon and pancreatic cancers, and searches for the genetic drivers of disease. There can be thousands of mutations in a tumor, but many of them have little or no role (so-called passengers). What mutations drive a tumor to form and grow? What makes it susceptible to a drug and then able to evolve resistance to that drug?

“If you take apart a car and want to understand what every component of the engine does, it’s very difficult, because often you just take a piece out and it stops working,” Dow says. Tumors are the same way. For several decades now, cancer scientists have been painstakingly building genetic models of cancer in mice and yeast and from cancer cells themselves. They’ll simplify a cancer by knocking out noncritical parts — something akin to the air conditioner. Then they’ll systematically remove and restore other genes to try to figure out whether they might be the cancer’s spark plug or accelerator.

“It’s a way for us to home in on the individual parts of a very complex machine and find out exactly what those things do,” says Dow.

CRISPR allows that work to proceed far more quickly and with much more precision. “By building these more accurate models, our hope and our goal is that we will build systems that are more predictive of human disease,” Dow says. Being able to predict response or resistance patterns means that researchers can more precisely target drugs: “The goal has always been to develop better treatments with the hope of getting curelike responses.”

Cancer is a disease of enormous complexity. In 2000, Douglas Hanahan, Ph.D. (who developed one of the first mouse models of cancer), and Robert Weinberg, Ph.D. (who discovered the Ras cancer-causing gene), published “The Hallmarks of Cancer.” One of the most cited papers in oncology, it outlined six biological processes defining cancer; in 2011 they updated it to 10. In 2018, a group of Australian cancer researchers looked at CRISPR research through the “Hallmarks” lens and found active CRISPR research in all 10 areas of interest. “This system has the potential to dramatically accelerate progress in cancer research,” they concluded.

CRISPR feels so powerful right now because it comes on the heels of a tremendous effort to sequence cancer genomes. Researchers now have easy access to the complete genetic code of thousands of tumors of nearly every cancer type. “We now know in many different tumor types all of the mutations that occur,” says Kathryn O’Donnell, Ph.D., assistant professor at the University of Texas Southwestern Medical Center Department of Molecular Biology and Simmons Cancer Center in Dallas. “Finding the ones that really matter — sifting the drivers from the passengers &mdash; is really important.”

KATHRYN O'DONNELL, Ph.D., uses CRISPR to speed up research into how lung cancer develops and grows. - O'DONNELL: COURTESY UT SOUTHWESTERN

O’Donnell’s lab focuses on mechanisms of tumorigenesis in lung cancer, and CRISPR cuts months, even years, off discovery timelines. Not too long ago, the development of a mouse model might have taken researchers years of collaboration. Now it can be accomplished in months.

Some of O’Donnell’s work right now focuses on an overactive cell surface protein in lung cancer called Protocadherin-7, encoded by the PCDH7 gene. Using CRISPR to knock out that gene in a lung cancer mouse model shows a significant reduction in tumorigenesis. Now O’Donnell and her colleagues are trying to figure out how to turn this knowledge into a target for potential therapy. It can be tough to balance her excitement with her necessary critical thinking. “We as scientists need to be cautious and cautiously optimistic,” she says. “I think more research is needed, and we always need to be rigorous and careful as we proceed.”

Genetic engineering has long been the dream of cancer researchers. In the early 1990s, Sadelain began his life’s work of engineering human T cells while he was a fellow at the Massachusetts Institute of Technology in Cambridge. His advisers found his vision without merit, and it took twoand- a-half years to achieve even limited proof of concept. With CRISPR, he says, he could now teach a high school student how to engineer a batch of T cells in an afternoon.

Kymriah and Yescarta are both created using a retrovirus to introduce the desired genetic modification to the T cells. Though powerful enough, the technique has limited precision. Genes won’t even necessarily wind up on the same chromosome. That works well enough; the successes with T cell engineering so far show that. But location does matter to genes. Genes work in a context, and that context is their chromosome, their neighborhood. If you insert the same genes in different places, they don’t work in the same way, explains Sadelain. In fact, there are rare cases of genetic insertion leading to leukemia because it occurred next to a critical growth gene.

Sadelain has been working with CRISPR to better target the modification. “We expected to find chromosomal position effects, and we did,” he says. But they were pleasantly surprised to discover just how big a difference it made: In a mouse model of acute lymphoblastic leukemia, CAR-T cells generated by CRISPR “vastly” outperformed the conventionally generated CAR-T cells at every dose level. The next question is, will it work the same way in humans?

Meanwhile, Khalid Shah, Ph.D., director of the Center for Stem Cell Therapeutics and Imaging at Brigham and Women’s Hospital in Boston, wants to use CRISPR to help cancer cells to kill cancer.

Some cancer cells that circulate in blood have a selfhoming tendency that causes them to return to tumor sites. Harnessing this behavior could deliver a Trojan horse inside the walls of a difficult-to-reach tumor. Working with mice, Shah and his colleagues used CRISPR to edit these brain and breast cancer cells, inserting molecules that would initiate cell death. The mice showed a “marked survival benefit.” Shah hopes to bring that technique to clinical trials in humans in the next three to four years.

“Cellular based therapy — CAR-T cell therapy, cancer cell therapy &mdash; may become the norm in the next 20 years,” Shah predicts.

CRISPR may also help realize the long-held dream of early cancer diagnosis by detecting miniscule amounts of tumor DNA in a patient’s blood serum or urine.

But most patients who benefit from CRISPR technology won’t get such paradigm-breaking treatments and probably won’t even know. Their doctors will make simple decisions, informed by CRISPR, to guide treatment at an early stage. If it hasn’t happened already, it probably will soon, and it may even go unnoticed by patients. It won’t be long before every branch of cancer research is built on conclusions derived from CRISPR clues.

If CRISPR clears the safety bar set by clinical trials, many more exciting developments could usher in a new era. CRISPR has encouraged blue-sky thinking about treatment for many cancer types. Several trials are already under way in China, where T cell—engineering drugs created with CRISPR have been used in patients. One lab has even repaired a gene in embryos that otherwise would have caused Marfan syndrome, providing “proof of principle for the technical feasibility of gene therapy,” the researchers stated in a paper explaining the findings.

“CRISPR enables precision genetic engineering,” Sadelain says. “That allows you to do more precise experiments, more precise engineering, and we all hope that it’s going to make more precise medicine.”

We’ve never been completely comfortable with genetic engineering as a society, and that’s probably as it should be. Our modest accomplishments continue to set off loud debates across a range of human enterprises: medicine, war, conservation, agriculture, religion.

CRISPR raises the stakes, moving us from mostly speculative fiction to scientific reality. What changes can we make? What changes should we make? What changes dare we make? Might a monster someday be created? “Genetic engineering and claims about genetic disease and genetic problems have a deep, dark history,” says Arthur Caplan, Ph.D., the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University. “Genetics has been the subject of gross and horrific abuse. We can’t ignore that fact.”

While many people believe humans have no business messing with genetic code, Caplan is not one of them. “I don’t worry about the slippery slope. I think eliminating and preventing diseases makes a lot of sense. I think it would be almost impossible to argue against it.”

But CRISPR is particularly challenging because of the rapid pace of discovery it’s enabling. “Speed is important, but speed kills,” he cautions. While some people worry that bioethics may slow progress, Kaplan doesn’t agree. In fact, history suggests that ethical prudence has significant value. In September 1999, scientists at the University of Pennsylvania broke several ethical guidelines, leading to the death of a patient in an early gene therapy clinical trial. That put the field on hold for 10 years, says Caplan.

He believes CRISPR is a long way from proving that it can efficiently and reliably edit embryos. Consider the Chinese Marfan repair: At what point do we allow that embryo to come to term? Caplan has some thoughts about what shortcuts not to take: “You have to demonstrate that you can do it safely in animals,” he says. “The offspring have to be healthy. And you do have to be able to show that your tool is as accurate as you say it is.”

Caplan would like further safeguards to backstop CRISPR’s rapid rise. A global registry of genetic engineering efforts is needed, because the technology is already widespread. And he hopes that journal editors will not reward rash or racing behavior. A bioethics framework should also strengthen mechanisms for emergencies and desperate measures, tools that can benefit some cancer patients. “We’ve done that with drugs; we should be able to do it with gene editing,” he says. We also need to settle some outstanding business questions. Two major institutions are already embroiled in an epic patent dispute over CRISPR techniques. As more companies and institutions add their incremental improvements, freely using the technology could become more difficult.

And then there is the cost: Even the doctors involved in CAR-T cell research were stunned when Novartis set its initial price point for Kymriah at nearly a half million dollars. CRISPR may bring prices down, but will it be a meaningful price cut?

“Do not tell me about helping humanity until you tell me how you are going to make it affordable,” says Caplan. “Justify your prices. Tell me how you got to them.” And he suggests that this accounting should probably recognize that these discoveries are largely built upon generous public funding of genome mapping. “Paying twice never made me happy,” he says.

CRISPR technology can edit the genetic code of most living things. How will it be used to prevent and treat cancer, and what are the ethical considerations?

Evolution Revolution: CRISPR in Cancer Care

MELISSA MELI didn't undergo fertility preservation before cancer treatment because of the expense. - BEN HIDER

When Melissa Meli received a diagnosis of breast cancer earlier this year, her boyfriend’s mother was the first person to suggest — gently &mdash; that she look into freezing eggs before starting chemotherapy that could make her infertile. Meli’s oncologist agreed, and a few days later, Meli met with a reproductive specialist while her boyfriend was deployed. Aside from having breast cancer, Meli, who is under 40, was in good health, and the doctor said fertility preservation would take just a few weeks.

Then Meli was taken to another room, where a staff member at the clinic outlined the associated costs: $11,000 to retrieve the eggs and $1,000 per year to store them, none of which was covered by insurance. A possible grant might cover $4,000 to $6,000, and paying out of pocket would bring a small discount. Meli, a singer and actress who lives in New York City, didn’t have the money. Furthermore, she and her boyfriend hadn’t decided if they would have children.

“We thought about asking people to help with the money,” she says, “but that felt like too much pressure to eventually have a child. I was afraid if I started a GoFundMe to raise money that I would feel beholden to my family and friends to have children. It would put a lot of pressure on us, and I decided not to do it.”

These are the choices that many younger patients with cancer face — going into debt, raising money or forgoing fertility preservation. That’s because few insurance plans cover these procedures, even in states with infertility mandates. A host of nonprofit organizations and advocates are working to change these laws, state by state, in a movement that is gaining momentum.

Each year, approximately 70,000 adolescents and young adults between ages 15 and 39 receive cancer diagnoses, but not all undergo treatments that affect fertility. According to the 

, between 20% and 70% of patients with cancer are rendered infertile every year.

One study from the University of Pennsylvania found that women who underwent in vitro fertilization (IVF) after treatment were five times more likely than those who’d never had chemotherapy to have a cycle canceled due to a complete lack of ovarian response to fertility drugs. Patients can bank sperm or eggs for future use — if they can afford it. For men, the relatively simple process costs less than $1,000, but storage takes another $150 to $400 per year. For women, the price tag for the procedure is $10,000 to $15,000; storage, $300 to $500 per year. Even the initial consultation can be costly.

Meli, who received her insurer’s preapproval for her appointment with the fertility specialist, was still charged more than $1,000.

The lack of insurance coverage for people like Meli troubles Dr. Eden Cardozo, who works in reproductive endocrinology and infertility at Women & Infants Hospital in Providence, Rhode Island. “We were getting referrals from oncologists,” Cardozo says. “But we were finding that patients were canceling appointments or not showing up, and when we looked more carefully, we realized they didn’t have any coverage to see a fertility specialist. It would be several hundred dollars to come for the initial consult, and so they weren’t even getting through our doors.”

These initial appointments are crucial whether or not patients pursue fertility preservation, according to Cardozo, who is also an assistant professor at the Warren Alpert Medical School of Brown University. “There’s literature that shows that even just having that initial consult results in reduced long-term regret,” she says. “It improves physical and psychological quality of life. Even if all they do is come have that initial meeting, it’s so important for these patients to know that somebody is looking out for them on the other side of cancer and to give them hope that they can have a family and there is a future for them on the other side of this.”

The impact of those high costs cannot be underestimated, says registered nurse Rosemary Semler, a fertility nurse at Memorial Sloan Kettering Cancer Center in New York City who meets with young cancer patients every day. “It’s devastating for patients who can’t afford preservation,” she says. “The uncertainty is difficult. There is no way to predict the effects of treatment, and patients have no idea if they will be able to attempt natural conception.”

Grants are available through Livestrong (livestrong.org/what-we-do/program/fertility), Heart Beat (ferringfertility.com/paying-for-treatment/save-on-your-medication/ heart-beat-program) and other financial aid programs for young adults, but these resources are limited. The funds are a “huge help,” Semler says, but, especially for adolescents and young adults, the remaining $7,000 or $8,000 can still be “prohibitively high.”

Financial problems are cited as the biggest obstacle to fertility preservation for women, but there are other roadblocks, too. “Many times, we see patients who ultimately don’t pursue fertility preservation,” Cardozo says. “Often, it’s because it isn’t financially feasible, but sometimes they don’t have the time prior to their cancer treatment, it’s too emotionally overwhelming with everything else going on, or they’ve already completed their family building.” Sometimes, early on, a patient doesn’t realize that fertility preservation is an option. According to American Society of Clinical Oncology guidelines, oncologists should initiate this discussion with patients. However, many doctors are unaware of this or reluctant to bring up the issue when they think the patient can’t afford it.

This phenomenon has been dubbed “wallet biopsy” by Joyce Reinecke, executive director of the Alliance for Fertility Preservation, a group that strives to connect patients, oncologists and fertility specialists, and a founding member of Stupid Cancer, Resolve and the Coalition to Protect Parenthood After Cancer. “The wallet biopsy happens when there’s an assessment made, whether it’s conscious or not, about which patients can afford these services,” Reinecke says. “This assessment informs whether they have the conversations. I don’t know that fertility preservation is discussed in a thorough or supported way with these patients, or in a way that makes the patients feel like these are real options for them.”

When Cardozo realized that patients weren’t making it into her office because they didn’t have insurance coverage, she decided to take action. She and Dr. Ruben Alvero, director of the Women & Infants’ Fertility Center, met with the hospital’s legal and communications teams to draft a bill that would make it mandatory for insurance companies to pay for fertility preservation for patients who are likely to become infertile due to cancer treatment. Cardozo championed the bill, even testifying before the Rhode Island House of Representatives and Senate, until it passed and was signed into law in July 2017.

Meanwhile, as Cardozo and her team worked on changing the law in Rhode Island, Melissa Thompson led the charge in Connecticut.

MELISSA THOMPSON helped pass a fertility preservation bill in Connecticut - PHOTO BY DANIELLE ROBINSON CALLOWAY

In 2015, just after giving birth to her first child, Thompson learned she had breast cancer. Fertility preservation was important to her, and, even though she needed to start chemotherapy, she decided to freeze embryos. The night before her egg retrieval procedure, the insurance company called to say the $12,000 fee would not be covered. Her doctor removed 22 eggs the next day, and weeks later — in the midst of chemotherapy &mdash; Thompson put the $12,000 charge on her credit card. “I was cornered,” Thompson says. “I needed to do it, and I couldn’t fathom why it wouldn’t be covered. By the time I was healthy enough to look at my appeals letter, the time period to file had closed.”

Connecticut has a mandate stating that infertility treatments must be covered for people struggling to get pregnant. However, at the time, the definition of infertility involved a healthy individual who could not conceive or sustain a successful pregnancy during a one-year period.

Because Thompson was not healthy and had not been trying for 12 months to conceive, she was not covered. However, if she had not retrieved eggs and had tried to get pregnant after finishing chemotherapy, the procedure would have been covered but likely unsuccessful. That didn’t make sense to her.

After making a few calls, Thompson got in touch with Matt Lesser, a state representative and cancer survivor who had introduced the bill in 2014. Thompson and Lesser worked together to change the law. Their bill passed and was signed into law in June 2017.

“It was an unbelievable experience and one of the proudest moments of my professional career,” says Bryte Johnson, the Connecticut director of government relations and advocacy for the American Cancer Society Cancer Action Network, who supported the bill. “You’re lucky to see advocacy power like that once in your career. Melissa Thompson took a bill that never went out of committee and got it through the entire process without a single no vote. That’s unheard of. There’s something to be said for unstoppable tenacity.”

THOMEEKA SPEAKS had insurance coverage for her fertility preservation under a bill passed in Rhode Island. - PHOTO BY PETER GOLDBERG

The passage of these laws and similar ones in Maryland and Delaware was helped along by numerous nonprofit groups and individual advocates: the Alliance for Fertility Preservation, Resolve, the American Society for Reproductive Medicine, the American College of Obstetricians and Gynecologists, the Ulman Cancer Fund for Young Adults and Shady Grove Fertility in Maryland, the Oncofertility Consortium at Northwestern University in Illinois, and patient advocate Christie Gross in Delaware.

Many are members of the Coalition to Protect Parenthood After Cancer, a group of nonprofit organizations that work behind the scenes to gain support for bills like these and planned to meet in early September to set priorities for 2019. Although advocacy has been successful in these four states, others lack such legislation. Similar laws have been proposed in several, and even at the federal level.

According to Erin Kramer, the government affairs manager of the American Society for Reproductive Medicine, Rep. Rosa DeLauro, D-Conn., and Sen. Cory Booker, D-N.J., introduced a federal bill (HR 5965 and S 2960) that would require insurance plans that cover obstetrics to also cover infertility treatments such as IVF. However, Kramer isn’t optimistic about such bills passing in the current political climate.

Kramer says opposition has been voiced at the state and federal levels by antiabortion groups, which testify against these bills on the grounds that life begins at conception. “Some organizations are opposed morally to reproduction with medical assistance,” Kramer says. “There are bills pending in Congress that would declare life beginning at conception, and this could impact embryos that have not yet been transferred to a woman’s body, and fertility preservation could get wrapped up in this issue.”

There has also been resistance from insurance carriers. According to the New England Journal of Medicine, lobbyists claim that IVF techniques are experimental or that infertility coverage should not be mandated because the condition is not life-threatening.

Kramer counters that these techniques have been used for 40 years. Plus, insurers cover many other non-life-threatening procedures for survivors of cancer, such as breast reconstruction.

Some critics argue that this coverage would significantly raise insurance rates. However, the Maryland Health Care Commission found that, in 2017, there were 2,000 people in Maryland who could become infertile due to medical treatment, and fertility preservation coverage for those patients would cost each insurance holder an extra 24 cents per month.

Not all insurance plans refuse or oppose this coverage. For example, Blue Cross Blue Shield of Rhode Island has covered fertility preservation services since before laws were enacted. However, Blue Cross Blue Shield policies vary by state.

After the law was enacted in Connecticut, Sen. Alice Forgy Kerr, a Republican, introduced a similar bill in Kentucky, with support from Thompson.

“Kentucky has the highest rates of cancer in the country, and it’s a conservative state. I wanted to go to a place where the political values and processes were different than Connecticut,” Thompson says. “What we’ve seen is that, at the core of the legislation, there is a commonality and a shared humanity that sees no party or side of the aisle. This bill is about protecting a vulnerable population, looking toward the future and giving young people the opportunity to live the life they’d hoped for.”

The bill passed the Kentucky Senate and the House Health and Family Services Committee but was not called to the House floor for a vote before the session ended. Thompson is hopeful for its passage in the coming year.

A new movement aims to secure insurance coverage for patients who undergo fertility preservation before cancer treatment.

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