Cancer

Cancer. It’s been called “The Big C,” but the more we study it, the more it resembles hundreds of little c’s, each with its own unique molecular makeup. The differentiation exists both among patients with cancers in the same site (the various sub-types of breast cancer, for example) as well as within a single patient. This latter phenomenon is referred to as “intra-patient tumor heterogeneity,” and it has profound implications for the future of cancer treatment, including the viability of so-called “targeted therapies” receiving so much attention and hope.

Many cancer tumors tend to be chaotic mixes of different cell types, some more aggressive – and therefore more dangerous – than others. Chemotherapy and the emerging category of more specific “targeted therapeutics” work by acting on a known characteristic of a particular cancer cell type, like accelerated replication rates or a specific genetic mutation.  But in a complex tumor, not all cells will exhibit that specific characteristic, or at least not do so at the same time. Also, it is possible for cancer cells to adapt and become resistant to a particular therapy, in a partially analogous way in which evolution works on a macroscopic scale.

A recent opinion piece published online in the journal The Scientist points out that intra-patient heterogeneity can also involve treatment-relevant difference between the primary tumor and metastases, as well as among metastases. Written by Stanford Cancer Institute Director Beverly Mitchell, MD; David Rubenson, associate director for administration and strategic planning; and Daniel S. Kapp, MD, professor emeritus of radiation oncology at Stanford, the article discusses these matters in detail and lays out many of the significant scientific and clinical questions surrounding the potential for treating cancers with targeted therapies. This fall, the Stanford Cancer Institute will convene an international symposium to discuss these questions and a range of related issues.

Information on the symposium, titled “Intra-patient Tumor Heterogeneity: Implications for Targeted Therapy,” will soon be available on the Stanford Cancer Institute website.

Previously: Director of the Stanford Cancer Institute discusses advances in cancer care and research

Stanford scientists have shown that it’s possible to simultaneously screen for dozens of cancer-associated mutations from a single blood sample using a multiple-gene panel. The research is published today in the Journal of Clinical Oncology (subscription required).

As I describe in my release:

Gene panels allow researchers to learn the sequences of several genes simultaneously from a single blood sample. It stands to reason that screening for mutations in just a few select genes is quicker, easier and cheaper than whole-genome sequencing. The technique usually focuses on fewer than 100 of the approximately 21,000 human genes. But until now, few studies have investigated whether homing in on a pre-determined panel of suspects can actually help people.

The researchers, medical oncologists and geneticists James Ford, MD and Allison Kurian, MD, used a customized 42-gene panel to investigate the presence of cancer-associated mutations in 198 women with a family or personal history of breast or other cancers. The women had been referred to Stanford’s Clinical Cancer Genetics Program between 2002 and 2012 to undergo screening for mutations in their BRCA1 or BRCA2 genes. They found that the panel was  a useful way to quickly screen and identify other cancer-associated mutations in women who did not have a BRCA1/2 mutation. From our release:

Of the 198 women, 57 carried BRCA1/2 mutations. Ford and Kurian found that 14 of the 141 women without a BRCA1/2 mutation had clinically actionable mutations in one of the 42 genes assessed by the panel. (An actionable mutation is a genetic variation correlated strongly enough to an increase in risk that clinicians would recommend a change in routine care — such as increased screening — for carriers.)

Eleven of the 14 women were reachable by telephone, and 10 accepted a follow-up appointment with a genetic counselor and an oncologist to discuss the new findings. The family members of one woman, who had died since giving her blood sample, also accepted counseling. Six participants were advised to schedule annual breast MRIs, and six were advised to have regular screens for gastrointestinal cancers; many patients received more than one new recommendation.

One woman, with a history of both breast and endometrial cancer, learned she had a mutation that causes Lynch syndrome, a condition that increases the risk of many types of cancers. As a result, she had her ovaries removed and underwent a colonoscopy, which identified an early precancerous polyp for removal.

The study shows that gene panels can be a useful tool that can change clinical recommendations for individual patients. It also indicates that patients are willing and eager to receive such information. As Ford explains in the release:

Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information.

Previously: Whole genome sequencing: the known knowns and the unknown unknowns,  Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside and Blood will tell: In Stanford study tiny bits of circulating tumor DNA betray hidden cancers.

Blood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there’s another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don’t) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

…

“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

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Cervical cancer is the third most common cancer among women worldwide, and Mongolia has one of the highest incidence rates in Eastern Asia. Prevention and early detection programs are essential to counteract its prevalence, especially in developing countries.

However, women encounter barriers to knowledge and access to cervical cancer screening services in Mongolia – a country with low population density. The urban–rural divide, lagging healthcare reform, and cultural differences are cited as core factors leading to lack of awareness and treatment.

To address the rising burden, a national cervical cancer screening program was implemented in August 2012 by Mongolia’s Ministry of Health (MOH) facilitated by a grant from the Millennium Challenge Corporation.

Gendengarjaa Baigalimaa, MD, the 2013-14 Developing Asia Health Policy Fellow at Stanford’s Walter H. Shorenstein Asia-Pacific Research Center in the Freeman Spogli Institute, has been evaluating the effects of that program. She serves as a gynecological oncologist at the Mongolian National Cancer Center (NCC). Her early findings show that awareness of cervical cancer has increased, and more women and girls are now getting screened. Gendengarjaa recently talked about her research.

What does your “typical” patient look like at the NCC and how has your work informed your research?

Patients typically arrive at the NCC with an advanced stage of disease – 70 percent of these women have progressive forms of cervical cancer. Of course it is not easy to work with patients who are this far along, especially if we are unable to offer full palliative services. As the only cancer center in the nation, just 10 gynecological oncologists are available to take on the high demand for treatment services. Healthcare providers and policymakers designed the Mongolian Cervical Cancer Program to address the alarming incidence rate. My research analyzes behavioral change before and after the introduction of the national screening program, bearing in mind my experiences with my own patients.

What does the national cervical cancer screening program facilitate?

Before the program was implemented, regular cervical cancer screening did not exist in Mongolia. The program diffused and strengthened primary care screening services (Pap test) as well as prevention programs. Gynecological doctors from the NCC were systematically dispatched to the 338 soums or districts throughout the nation. They trained local doctors and midwives on how to administer the Pap test. The program coordinated two initiatives: a pilot HPV vaccination program for girls aged 11-15 years from four select areas and a Pap test program for women aged 30-60 years. The women and girls who participated are urged to get screened every three years thereafter. Health education campaigns were also broadcast on select television and radio programs targeted at women and girls.

Comparing a survey taken at the program’s outset in 2010 to your survey at the program’s conclusion in 2013, what behavioral changes have been observed?

Our preliminary results have shown increased knowledge about risk factors and screening services. Women in both rural and urban areas are now more informed about cervical cancer risk factors. Awareness of the need for a Pap test increased from 15.3 percent in 2010 to 45.3 percent in 2013. The respondents also reported being more educated about the suggested frequency of visiting a doctor, and the availability of services outside of Ulaanbaatar. Due to increased knowledge, 54.2 percent of the women surveyed confirmed that they had attended cervical screening services.

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Leukemia research was the focus of a recent Google Hangout hosted by the California Institute for Regenerative Medicine; included in the conversation were Stanford’s Ravi Majeti, MD, PhD; Catriona Jamieson, MD, PhD, with the University of California San Diego; and Karen Berry, PhD, DVM, a CIRM science officer. In the words of CIRM blogger Kevin McCormack, “Between the three of them they painted an optimistic look at the state of stem cell research into leukemia, the progress we are making, and the obstacles we still have to overcome.”

Majeti, whose works focuses on a potential leukemia treatment using an antibody to a protein called CD47, begins talking around the 10-minute mark.

Previously: Blood cancers shown to arise from mutations that accumulate in stem cells and Leukemia prognosis and cancer stem cells
Related: Cancer roundhouse

Last September, Scope/Inspire contributor Jessica Rice wrote about her experience being diagnosed with terminal lung cancer; as a follow-up to Rice’s piece, one of our physicians shared her thoughts on communicating with seriously ill patients. Rice, who also chronicled her journey on http://stageiv.wordpress.com, passed away last Friday. We’re re-publishing this entry in her memory.

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Since becoming ill, I’ve learned that I have the innate ability to make doctors very uncomfortable – squirmy, even. It’s surprising because I had assumed medical professionals with decades of experience have fielded every possible question a patient might ask.

But I suppose I’m not a typical patient. In November 2011, I was diagnosed with stage IV lung cancer (bronchioloalveolar carcinoma, a subset of adenocarcinoma) with extensive spread to the mediastinal and hilar lymph nodes. At the ripe old age of 30, I joined a very exclusive club of young, non-smoking women with this rare cancer.

What I’m discussing with these doctors is no picnic. While there’s a sprinkling of terminally ill 30-somethings out there, we’re not a common sight in most oncology offices.

My biopsies were immediately tested for genetic mutation and found to be ALK+. Crizotinib had received FDA approval a few months earlier, so it was the logical first course of action. The pill was successful for three months before two things happened: toxicity set in, and my cancer grew resistant. Next, I tried two different chemo cocktails; both failed. I joined the LDK378 trial in November 2012 and had an excellent response. Unfortunately I experienced very painful side effects which led to dose reductions below protocol. I was likely getting booted from the trial and taking a break when I had a seizure this past June.

My MRI showed five brain tumors, along with small lesions I affectionately termed “brain lint.” After two CyberKnife sessions, a few tumors shrank, a couple grew, and five more sprouted from that innocent looking brain lint. It was time for whole brain radiation.

Through all this I’ve worked with more than a half-dozen doctors and surgeons. Some have impressed me, a couple seemed lacking in one area or another, and one even managed to capture my heart. Regardless, I’ve unintentionally made all of them uncomfortable at one time or another.

It could be my tough questions.

I consider myself a down-to-earth, logical creature; looking at the facts and hearing the truth is strangely comforting to me. This is why I recently asked, “What will dying be like if it’s the brain tumors that kill me? Will it be sudden, like a seizure with an uncontrollable brain bleed?” I had asked this question long ago in relation to lung cancer, but it now seems more likely that the brain tumors will lead to my demise.

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But how do you really feel? Over on KevinMD.com, Anoop Kumar, MD, reflects on his personal and professional experiences with cancer. The emergency physician cares for people with acute complications from cancer and related treatments. In the post, Kumar describes his journey through the death of his grandmother when he was in seventh grade, the bursting of a dam of emotional supression later on, and the continued leaking of grief as he confronts his confusion, sadness and loss around the event.

Inspired by a 2010 article in The Guardian, Kumar urges readers dealing with hardship to “be positive. Or be negative. Or be confused. But whatever you are, be yourself.”

Previously: Becoming Doctors: Stanford med students reflect and share experiences through podcasts

We’ve partnered with Inspire, a company that builds and manages online support communities for patients and caregivers, to launch a patient-focused series here on Scope. Once a month, patients affected by serious and often rare diseases share their unique stories; the latest comes from cancer survivor Danielle Ripley-Burgess.

I consider myself one of the lucky ones.

A diagnosis of stage III colon cancer at age 17 probably sounds like a pretty tough blow and not lucky at all. Not to mention a second diagnosis of stage I colon cancer at age 25 and subsequent surgeries and hospital stays to combat my genetic disease, Lynch Syndrome.

Yet despite the extensive medical record over the past decade, I still consider myself extremely lucky when compared to other survivors.

You see, I’m not alone in my fight. Although colon and rectal cancer most often appear in those over age 50, it can happen in young people. In fact, it is happening – and those of us diagnosed under age 50 make up the fastest growing demographic to be diagnosed.

Screening recommendations for colon cancer don’t typically apply for those of us still washing our faces with acne cream, going prom-dress shopping or planning our weddings. But when we walk into a doctor’s office with symptoms like severe abdominal pain, cramping, bloating and rectal bleeding, we need to be taken seriously.

A fellow survivor named Meaghan, stage I colon cancer at age 26, initially assumed her bleeding and pain came from past pregnancies. The emergency room staff concurred and offered her pain pills and suggested a high-fiber diet. Not until she returned to urgent care in extreme pain did a CT scan discover her tumor. Another friend, Melissa, knew that “college stress” couldn’t be the only cause of her pain and blood in the stool. Melissa fought tooth-and-nail for a referral, yet doctors wouldn’t send her to a specialist. Luckily, her mom called a gastroenterologist who had a last-minute cancellation. That appointment discovered her stage III rectal cancer at age 20 and saved her life.

I consider myself lucky because unlike many survivors also diagnosed “too young,” I never got the runaround from physicians. I was never told I had irritable bowel syndrome, prescribed antidepressants, instructed to simply change my diet or denied medical exams.

My gastroenterologist took aggressive steps and sent my 17-year-old behind straight into a colonoscopy the day he learned of my bleeding. I spent only minutes in his office but as soon as the stool test detected blood, he didn’t cut corners. My dad’s insistence on him treating me as if I were his teenage daughter led to the discovery of my tumor just days after the appointment. I was treated based on my symptoms – and not my age.

The hands-on approach from every member of my medical team not only saved my life from colon cancer twice, but it set me up for survivorship. Now, I have a long life ahead of me.

No, colon cancer doesn’t often occur in teenagers. But it can. And thankfully, my symptoms influenced my doctors’ recommendations and treatment – not my age.

Danielle Ripley-Burgess, a two-time colon cancer survivor, is director of communication for advocacy organization Fight Colorectal Cancer. She was Miss October in the 2009 Colondar, an educational calendar of young colon cancer survivors that raises awareness of colorectal cancer. She writes about the topic of cancer as a blogger for Huffington Post and on her blog, Semicolon Stories. Last Friday, she was among a group of colon cancer survivors that NBC’s TODAY show interviewed for a segment about Colorectal Cancer Awareness Month.

Stand-up comic Tig Notaro brought her unique brand of comedy to Stanford early this week, and she didn’t disappoint the standing-room-only audience of students, faculty, staff and community members gathered on campus.

Notaro, a fairly successful stand-up comic before 2012, exploded on the national scene when she greeted an audience at the Largo in Los Angeles with the words, “Thank you, thank you, I have cancer, thank you, I have cancer, really, thank you.” She then told the audience: “Tragedy plus time equals comedy. But I don’t have the benefit of time. So I’m just going to tell you the tragedy and know that everything is going to be okay.”

In that now legendary comedy set, Notaro went on to share the tragedy of her bi-lateral breast cancer diagnosis, the unexpected early death of her mother, and the ending of a romantic relationship: all within a four-month span. Well-known comedian Louis C.K. was in the audience that night, and he tweeted: “in 27 years doing this, I’ve seen a handful of truly great, masterful standup sets. One was Tig Notaro last night at Largo.”

During her Stanford performance, which was sponsored by the Stanford Storytelling Project, the Stanford Arts Institute and ITALIC, Notaro gave a hilarious impression of a TSA agent trying to pat her down in the front. Notaro chose not to have reconstructive surgery after her bi-lateral mastectomy, so the agent had a hard time deciding if Notaro was a man or a woman. Laughing, Notaro said, “I had small breasts before, and I would joke about them all the time… how small they were.” Pausing for a moment, she grinned and said, “You know, I think my breasts heard me and decided to get revenge.” Notaro’s statement, and the audience’s responding laughter, illustrated what Louis CK has said about her comedy: “It is an amazing example of what comedy can be. A way to visit your worst fears and laugh at them.”

In a Q&A session after her performance, Notaro said using comedy to deal with her cancer was a “godsend. I hadn’t planned to talk about it as part of my act, but it just came out.” And today, she says, she’s glad it did. “I get letters every day from people who have been diagnosed with cancer, or people who have lost a loved one to cancer. If my comedy can help just one person who has to travel the same journey I have traveled, it is worth it.”

Jacqueline Genovese is assistant director of the Arts, Humanities and Medicine Program within the Stanford Center for Biomedical Ethics.

Previously: Saying thank you with art: Stanford undergrad pens one-woman play on cancer
Photo courtesy of Tig Notaro

UPDATE: This entry has been corrected from a previous version, which incorrectly implied that these scans were used for cancer screening.

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Sometimes, getting a clear picture of the tumors in a newly-diagnosed cancer patient requires exposing the patient to potentially harmful ionizing radiation, which can be particularly harmful to young patients who are still growing. Now, researchers from Lucile Packard Children’s Hospital Stanford have developed a technique to scan for tumors that takes radiation out of the equation, lowering the young patients’ risk of later developing secondary tumors.

From our release:

The new method… is a modification of magnetic resonance imaging that employs a novel contrast agent to find tumors. The MRI-based method is as effective as cancer-detection scans that use ionizing radiation — specifically, positron emission tomography-computed tomography — the researchers found.

Although whole-body PET-CT technology provides essential information for detecting cancer, it has one big drawback: A single scan exposes the patient to as much radiation as 700 chest X-rays.

…

To find tumors via MRI, the Stanford team used a new contrast agent consisting of nanoparticles of iron. Injections of these iron nanoparticles are approved by the Food and Drug Administration to treat anemia, and the researchers obtained FDA permission for the experimental use. The nanoparticles are retained in the body for many days. On MRIs, they cause blood vessels to appear brighter, providing anatomic landmarks. The nanoparticles also cause healthy bone marrow, lymph nodes, liver and spleen to appear darker, making tumors stand out.

The images generated from the experimental MRIs provided comparable information to the PET-CT scans that study subjects received as part of their care. The PET-CTs detected 163 of 174 total tumors in the 22 patients; the MRIs found 158 of 174 tumors. The two methods had similar levels of sensitivity, specificity and diagnostic accuracy.

The method is described in a paper published today in The Lancet Oncology. “I’m excited about having an imaging test for cancer patients that requires zero radiation exposure,” senior author Heike Daldrup-Link, MD, associate professor of radiology at Stanford and a diagnostic radiologist at the hospital, told my colleague. “That is a big deal.”

Previously: Questioning whether physicians are equipped to care for childhood cancer survivors and Five days instead of five weeks: A less-invasive breast cancer therapy
Image by Jessica Donig