Dr. Bill's ultimate marathon


I recently joined CURE as managing editor of books and special projects. While I have been in journalism for many years now, this is my first foray, as an editor, into the complex world of cancer. But as a daughter--well, that's a different story.

During one of my first staff meetings here, someone brought up the often-used analogies to describe the cancer experience: a battle, a journey, a roller coaster. But when I think of cancer, I always envision it as a marathon, admittedly, another well-worn metaphor. Perhaps that's because my father was an avid runner. He finished seven marathons in his lifetime, counted Chariots of Fire as one of his favorite movies (the theme song was one of his favorite songs), and he even founded a nine-mile running race in our hometown.

But in April 2000, my father's real marathon began when he was diagnosed with metastatic melanoma. The doctors figured it was from a large malignant mole he had removed from his leg 15 years prior, but that was only a guess. Melanoma can lie dormant for years before it resurfaces in places like lymph nodes, which is where my father's recurred. A small, seemingly innocuous lump on his groin.

My father was a doctor himself--an ophthalmologist--so he knew that his prognosis would not be good. And it wasn't; it was of the "get-your-affairs-in-order" variety. But, being a stubborn man, a first-generation Italian from Newark and the son of a steeplejack, Dr. Bill, as his patients called him, was just warming up. He had only begun preparing for what was going to be a grueling six-year run filled with fatigue, dehydration, pain and emotional exhaustion.

There were runner's highs, like when a limb perfusion appeared to work, followed by extreme lows, when the brain mets appeared. And then there were the second, third and fourth winds when promising new studies came out. On he went, plodding from surgery to chemo to radiation. From clinical trial to clinical trial. Along the course, family and friend had lined up to cheer him on, give him water and food or tend to his injuries. In June 2006, my father hit the wall. His melanoma could no longer be controlled. He was spent, and he wanted to enjoy the final leg of the race at a slow amble, absorbing the sights and sounds of the course and the gathering crowd. On November 11, 2006, he crossed the finish line at peace--surrounded by his biggest fans.


An update on the Cancer Genome Atlas for breast cancer


The final day of the San Antonio Breast Cancer Symposium began with an update from members of the working group of the Cancer Genome Atlas (TCGA) and International Genome Consortium (IGC) who are together embarking on a massive project to obtain broad scale gene sequencing, RNA profiles and functional protein information on breast tumors and to assemble a comprehensive database that can be immediately shared and "mined" to obtain important clues to the triggers of cancer and its vulnerabilities that can be exploited for therapy.

The efforts in the breast cancer component of this project will eventually involve over 1000 cases and a very large team of scientists, bioinformaticians and clinical consultants. The sheer amount of data generated (3 billion base pairs for each tumor genome just for starters) is mind-boggling. But special data analytical tools and high-powered computers are able to generate patterns – a glimpse of this was presented in a progress report on Sunday, revealing some new insights.

Most tumors contain several mutations, but only a few are commonly seen. The recurrent genetic abnormalities are presumed to be "drivers" – directly responsible for cancer behavior, while some are "passengers" – results of genetic instability and errors in DNA division and processing, but not affecting malignant potential. This is an important distinction, since drivers represent potential diagnostic markers and targets that are "druggable", and would only have been discovered through this extensive effort.

The numbers and types of mutation seen are distinct among the recognized classes of breast cancer based on hormonal and HER2 receptor status. Also, the consequences of these mutations on cell function appear to be similarly grouped. The expression of genes and their translation into protein, which are the actually workhorses of cellular structure and function, are not only affected by gene mutations but also by "epigenetic" alterations. These are not picked up by gene sequencing, but rather by detecting attachments to certain base pairs of DNA and the proteins that help organize DNA into a useful template that orchestrates when and where genes are expressed.

There is growing evidence that epigenetic changes may be the earliest events that set the stage for genetic mutations and modulation of the tissue microenvironment that help support cancer growth and spread. The field of epigenetic is rapidly growing and a few approved cancer drugs work through these mechanisms. At Sunday's session, a clearer map of epigenetic changes in the context of cancer subtypes began to emerge and this will undoubtedly provide a roadmap to better classification systems and treatment strategies.

What was special about this session is the power of collaboration and large numbers. The tiny pixels are starting to come together to provide a landscape – and we all hope this will be transformative.


Afinitor impresses in advanced hormone-positive breast cancers


One of the most highly anticipated presentations at this year's SABCS is BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2), a phase 3 study examining whether adding Afinitor (everolimus) to Aromasin (exemestane) in postmenopausal women with advanced estrogen-positive breast cancer would delay disease progression.

The study followed 724 patients with progressing breast cancer who have responded to previous hormone therapy for their cancer.

The BOLERO-2 trial was halted in February when it became apparent the Afinitor combination was better than Aromasin alone, much sooner than expected, said investigator Gabriel N. Hortobagyi, MD, director of the Breast Cancer Research Program at the University of Texas M.D. Anderson Cancer Center in Houston. Preliminary data were announced at a European meeting in September showing that with the addition of Afinitor, progression-free survival (PFS) improved from 2.8 months to 6.9 months.

Researchers announced updated results at the San Antonio Breast Cancer Symposium, and after a year follow-up PFS had improved from 3.2 months in the Aromasin arm to 7.4 months in the Aromasin and Afinitor arm, an improvement of about 57 percent. Response rates also doubled from 25.5 to 50.5 percent, which included complete and partial responses, as well as stable disease lasting at least six months. Side effects in the combination arm included oral mucositis, rash, diarrhea and fatigue.

Data also suggest a survival benefit, but researchers were quick to caution that survival results arenot expected for another year. Hortobagyi says it may be another year before survival data is available.

Afinitor inhibits mTOR, a protein that helps regulate the growth of cancer cells and blood vessels. Aromasin is a commonly used drug in hormone-positive cancers that inhibits the enzyme aromatase, blocking its conversion to estrogen, the hormone that drives tumor growth in certain breast cancers. It's believed that some cancers that are resistant to hormonal therapy have an over-activation of the mTOR pathway. By using an aromatase inhibitor in combination with Afinitor, researchers hope to overcome that resistance.

At last year's symposium, results of a study suggested that women with metastatic disease taking Afinitor and tamoxifen live longer. Two other BOLERO studies are looking at whether Afinitor benefits women when combined with Herceptin (trastuzumab) and Taxol (paclitaxel) or vinorelbine. Afinitor is currently approved to treat advanced kidney cancer.

Novartis, the drug's maker, is expected to submit Afinitor to the FDA for use in advanced breast cancer within the next few weeks in light of the positive results.

You can read about the study in the New England Journal of Medicine.


Fertility takes center stage at SABCS


In an educational session that kicked off this year's San Antonio Breast Cancer Symposium, Teresa Woodruff, PhD, noted that survivors experience depression and anxiety because of sterility. Adult survivors of childhood cancer are often afraid to begin dating because they don't want to have that conversation with someone at an early stage in the relationship but are uncertain as to when to initiate it. Young men and women have the same concerns, but these concerns are heightened among young breast cancer patients.

Fortunately for me, I was already married when I learned that I had cancer. I was also the mother of a wonderful two-year-old boy named Ryan, who remains the best and brightest light in my life. That said, at 35, I was devastated when my oncologist told me that I wasn't going to be able to have more children. I had always thought I would have two or three kids and the thought of Ryan being an only child, with no sibling to grow old with, made my heart ache. It still does.

Lance Armstrong announced publicly that he banked his sperm – that was one of the first public acknowledgements that cancer treatment can cause sterility and patients should do something to preserve their fertility before treatment.

In regards to the logistics of preserving one's fertility, men have an easier time, but not all men have been offered sperm banking. There needs to be better patient navigation in adequate time to ensure that men are able to father future generations. Options for women have been available for some time, but are not always used. Navigation is more difficult – Women have to go from cancer care to reproductive endocrinology and then back to cancer care again which is difficult, and quite honestly, scary and stressful.

Woodruff suggested that patients and doctors know that fertility conversations should happen, but she isn't convinced that all newly diagnosed patients are thinking about fertility, even if it is more widely known. What about you? Did your healthcare team bring it up? Were you given a chance to fully understand your options?


Preventing late recurrences – New insights from San Antonio


At the first set of scientific sessions of the San Antonio Breast Cancer Symposium, there was a common theme to many of the presentations. This revolves around the long natural history of hormone receptor-positive breast cancer – what this means is that the risk of recurrence persists for many years – up to 15 to 20 years after surgery.

While chemotherapy, hormonal therapy, and Herceptin in the case of HER2+ cancers, can lower these risks and are standard therapies, the question is what should be done after all treatment is completed? More than half of all the recurrences occur after five years.

Two presentations examined gene signatures obtained on the tumor and showed that genes associated with tumor growth seem to predict early recurrences within a few years, and those that relate to active hormone receptor signaling might indentify those with risk of later recurrences. This needs to be further verified, but it still does not tell us what additional treatment might help.

There are studies that are looking at 10 years of hormonal therapy with aromatase inhibitors compared with the standard five years, but those studies will not yield results for a couple of years. More follow-up from previously as well newly reported trials examining bisphosphonates to prevent recurrences were presented - these are still not showing clear results, with the exception of the ABCSG-12, which is showing a third fewer recurrences with the use of Zometa (zolendronic acid) for three years in premenopausal patients treated with ovarian blockade but without chemotherapy, along with either Arimidex (anastrozole) or tamoxifen. However, the other trials suggest a benefit in the subset of postmenopausal women who are in a "low estrogen environment," where bone turnover is more active.

It is interesting that Dr. Gnant, who presented the ABCSG trial, felt that Zometa was the new standard for care, at least for patients meeting the criteria of that trial, while the commentator, Dr. James Ingle from Mayo Clinic was not as convinced. Still, the whole session pointed to the need to take a very long-term (15- to 20-year) look at outcomes to test new drugs that can improve upon what hormonal therapy does. Also, newer tissue tests can help decide who might be at risk for longer-term recurrence and may be in need of additional treatment.


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