In June 2016, Lisa Geller was talking to her parents about where she wanted to be buried, and who would take care of her dog, Sadie. The 43-year-old had survived Hodgkin's lymphoma only to develop an aggressive endometrial cancer that wasn't responding to any treatments.
Geller's oncologist at the time, Don Dizon, MD, then at Massachusetts General Hospital in Boston, said he was "on the heels of putting her in hospice."
But Dizon had a Hail Mary: immunotherapy. Pembrolizumab (Keytruda) wasn't approved for Geller's cancer back then, but research suggested her tumor's genetic signature would make it particularly susceptible to the drug, and Dizon secured compassionate use from Merck.
Within just a few months of her first infusion, Geller's scans were completely clear -- and they have been ever since.
"It's such a dramatic shift in your life," says Geller, now 47, who is going on 4 years cancer-free.
Yet being a super-responder to immunotherapy means living in a specific type of limbo: not knowing if she'll relapse, if she should make a career leap, if she should get involved in a relationship, if she should stop taking the drug.
"I live what people consider a normal life," Geller told 51˶. "But that's on the outside. Inside is much different. I live in a constant state of anxiety waiting for the other shoe to drop."
A 'Magnet for Cancer'
Geller has been particularly unlucky when it comes to cancer. She was diagnosed with Hodgkin lymphoma in 2010 and eventually relapsed after her first treatment, so she had a stem cell transplant that wrapped up in 2013.
About 2 years later, Geller was diagnosed with endometrial cancer. She had a hysterectomy, but soon after developed a vaginal mass that was resected. It came back, along with other metastatic lesions, and Geller needed additional surgeries.
When another perineal lesion appeared in May 2016, a biopsy showed the tumor had become more aggressive. Luckily, it still had markers of mismatch repair deficiency: loss of expression of MSH2 and MSH6. Mismatch repair errors enable mutations to build up as the cell can't correct mismatched DNA bases that arise during replication, recombination, or other DNA damage, Dizon explained.
Additional genetic testing showed that Geller didn't have Lynch syndrome (indicated by a germline mutation in MSH2), but she did have a germline mutation in BRCA1 and somatic BRCA2 mutations.
"My body just feels like a magnet for cancer," Geller said.
Early research had signaled that mismatch repair mutations were particularly susceptible to anti-programmed death 1 (PD-1) checkpoint inhibitors, so Dizon reasoned that pembrolizumab -- which later won the FDA's first tissue-agnostic cancer drug approval, based on a genetic signature instead -- might have an effect.
After that first infusion, Geller's tumor shrunk by 30%, and within a few months, she was cancer-free.
of her mismatch repair and BRCA status may have made her cancer particularly susceptible to PD-1 blockade.
Life, Not Exactly Cured
Since then, Geller has "managed to piece my life back together," though it looks nothing like the one she had more than a decade ago. She'd been working as a lawyer at Skadden Arps in Washington, D.C., until she lost her job in 2009 -- just before her Hodgkin's diagnosis -- and decided to move back to Boston to be closer to family.
Now, Geller works as a college counselor at a boarding school in Bath, Maine, a job she took in 2013 after recovering from her stem cell transplant.
, Geller says she's coming to terms with not being as high-functioning as she was before cancer. "I read and write slower, my ability to think on my feet is a little duller, and it may take me a bit longer to process information," she writes, but says she has a better sense of herself. "I am focused more on the process as opposed to achievement. I am more empathetic. Most importantly, I am tougher and more resilient than I ever was when I thought I was so-called 'high-functioning.'"
The challenge for Geller is that having such a dramatic response to immunotherapy is new territory for medicine. The upper limit of her potential survival curve isn't known.
That means fear and anxiety are a constant background in her life. She writes that her fear of cancer returning is "indescribable -- the butterflies in my stomach every time I wait for my bloodwork to come back; the feeling of dread when I feel pain anywhere in my body; and the panic that runs through my body every time I think that the doctors I trust really can't tell me how long this will last."
When Geller came down with something last summer, for instance, she had an x-ray that showed enlarged lymph nodes.
"I thought, here we go again," Geller said.
Luckily, it turned out to be the flu.
The worries haven't eased with time. She doesn't sleep well. She thinks about how her parents, and her dog, might outlive her. Her dad is 87, her mom is 78, and Sadie is 6.
"I spend so much energy trying to operate like nothing's wrong," she said. "At night, it manifests into anxiety and it keeps me awake."
She feels that she's limited in terms of relationships, that her ordeal is "too much" for someone else: "too much of a risk for people to take a chance on, too emotional for one person to handle," she wrote on her blog. "And, to be told that I am 'too much' is more than I can handle at this point in my life."
It's easier to keep to her "insular world" -- her dog, family, and friends -- rather than letting in someone new, she says.
Stopping Treatment?
The question of stopping immunotherapy is one that weighs heavily. Every three weeks, she drives from Maine to Boston for treatment. She wonders if she even needs it, but says she'd never take that decision into her own hands.
"I will keep doing this until the doctor says it's OK to stop," Geller said. "I can't live with that anxiety.... As long as it's not causing side effects other than the fatigue and gastrointestinal issues that are manageable with medication, it's not doing anything to me. So why stop?"
Dizon, who now works at Brown University in Providence, Rhode Island, said in the years since he treated Geller, he's "starting to take cues from how we approach metastatic melanoma, trying to get to 2 years of immunotherapy and breaking treatment, then following the patient."
He even had one patient who had a complete response to immunotherapy and "decided to break his treatment after 22 months," said Dizon, who will have results from the patient's first follow-up scans soon.
Dizon said that patient had a different perspective from Geller: "He was seeing it as chains preventing him from getting on with his life."
For that patient, there's "some reassurance in the melanoma literature that even if folks start to progress off therapy, a proportion will re-respond. It's not like you close that door completely."
Truly Cancer-Free?
It's not often that a palliative care doctor gets to discharge a patient, but that's what Vicki Jackson, MD, of Massachusetts General Hospital, was able to do with Geller.
"My palliative care doctor basically told me not to come see her anymore," said Geller, who felt that her appointments with Jackson were "like therapy."
Since she's no longer Jackson's patient, she's been looking for another way to deal with the existential questions brought on by her situation and has recently started seeing a new therapist.
Though immunotherapy has extended life for many patients, super-responders like Geller are few and far between.
"Personally, I've seen this rarely," Dizon said. "But if you talk to any of us using immunotherapy, we have our own anecdotes where this actually happens."
That makes it harder for Geller to find her tribe: "I don't know other people who have experienced this. I don't know where to find those people."
She worries that those around her thinks she talks "about having cancer all the time. I don't think I talk about it at all. I have this distorted misconception that all I'm about is cancer."
Her concerns were suspended this summer when she went to a camp reunion where no one knew what she'd been through, and she did an experiment to see what life would be like truly cancer-free. She didn't talk about her last decade of cancer treatment.
"It was just odd because it's become my identity," she said. "It was just weird to be with people who don't know. I don't know if it's a good feeling or a bad feeling."