An update on the Cancer Genome Atlas for breast cancer

BY DEBU TRIPATHY | DECEMBER 11, 2011

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.

• For the Cure to a broken heart
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer
• Video blog: CLEOPATRA and pertuzumab in breast cancer

Video blog: Test could spare some DCIS patients from radiation

BY DEBU TRIPATHY | DECEMBER 10, 2011

Dr. Debu Tripathy discusses how a test, a variation of the Oncotype DX test, could help physicians decide on radiation therapy for their patients diagnosed with ductal carcinoma in situ (DCIS).

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer
• Video blog: CLEOPATRA and pertuzumab in breast cancer

Video blog: HER2-targeted agents

BY DEBU TRIPATHY | DECEMBER 10, 2011

Dr. Debu Tripathy explains the HER2 pathway's involvement in breast cancer and how new investigational drugs, including pertuzumab and TDM1, as well as combinations of new and approved drugs are targeting this pathway.

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: Complications with brachytherapy in breast cancer
• Video blog: CLEOPATRA and pertuzumab in breast cancer

Video blog: Complications with brachytherapy in breast cancer

BY DEBU TRIPATHY | DECEMBER 9, 2011

Dr. Debu Tripathy discusses a new study released at the San Antonio Breast Cancer Symposium that shows brachytherapy may cause more complications than once thought. Is it right for you?

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: CLEOPATRA and pertuzumab in breast cancer

Video blog: CLEOPATRA and pertuzumab in breast cancer

BY DEBU TRIPATHY | DECEMBER 8, 2011

With the announcement of the positive results of pertuzumab in metastatic breast cancer here at the 2011 San Antonio Breast Cancer Symposium, Dr. Debu Tripathy gives a breakdown of the trial and what it means for patients.

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer

Video blog: BOLERO-2 and Afinitor in breast cancer

BY DEBU TRIPATHY | DECEMBER 8, 2011

Dr. Debu Tripathy explains the updated results of the BOLERO-2 study, which looked at Afinitor (everolimus) and an aromatase inhibitor in metastatic breast cancer. How useful will this new drug be in metastatic breast cancer?

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer

Preventing late recurrences – New insights from San Antonio

BY DEBU TRIPATHY | DECEMBER 8, 2011

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.

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer

What to look for at this year's SABCS breast cancer meeting

BY DEBU TRIPATHY | NOVEMBER 30, 2011

This year's Annual San Antonio Breast Cancer Symposium has several presentations that could have immediate impacts on breast cancer care. Many of the details of results of clinical trials and other studies will not be fully disclosed until the time of the actual presentations, but the titles that have been posted offer some hints.

Several studies examining the effects of bisphosphonates on preventing recurrences of breast cancer will be presented for the first time or updated from previous presentations. So far, studies have yielded mixed results and these drugs are currently not recommended as adjuvant therapy - it is not clear yet if new information will tilt us toward new recommendations.

Also, the first large scale trial to be reported testing Tykerb (lapatinib) as adjuvant therapy for early stage HER2+ breast cancer will be revealed. While this may not change standards in the U.S., where Herceptin (trastuzumab) is the treatment of choice, there is also interest in combining the two drugs even though the combination study results are still pending.

Combining two hormonal therapies in metastatic breast cancer has not received much attention, so we are eager to see the results of a trial combining Arimidex (anastrozole) and Faslodex (fulvestrant) compared with Arimidex alone. In a similar vein, drugs that affect growth signaling have been shown to augment the effects of hormonal therapy, and updated results of the BOLERO II trial, showing improvements with the addition of the mTOR inhibitor Afinitor (everolimus) to exemestane for metastatic breast cancer will be presented. This strategy could very well be in practice soon as submission for FDA approval is planned. On the heels of the FDA's withdrawal of Avastin (bevacizumab) for metastatic breast cancer, two studies – one in combination with Herceptin in metastatic and one for patients on neoadjuvant (pre-operative) chemotherapy who are not responding will be presented, reminding us that the final chapter on this drug is still ahead.

On the diagnostic front, new information on molecular profiling to assess the risk of local recurrence of ductal carcinoma in situ (DCIS) may be helpful in planning surgery and radiation for this type of pre-invasive cancer that is being picked up more frequently with screening mammograms – a disease that rarely spreads and kills, but can recur in the breast and sometimes as a more dangerous invasive cancer. New information on markers that could help predict benefit from Herceptin and other biological drugs will also be presented.

Many advances in basic biology can be anticipated – the ones that are generating much interest (though still some way from clinical application) are further understanding of breast cancer stem cells and how they can be targeted therapeutically, new insights from full genome sequencing of breast cancers, and more details of growth factor receptor signaling pathways and how they vary among cancer cases, providing clues to vulnerabilities of cancer cells that can be exploited.

Overall, the agenda is very robust and we plan to continue our updates as soon as the news breaks.

Note: For full SABCS coverage, go to curetoday.com/sabcs2011.

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer

Is pink demystifying and destigmatizing breast cancer?

BY DEBU TRIPATHY | OCTOBER 11, 2011

This month, I have seen more pink on the football fields across the country that I have ever seen before. I know that many wonder whether the "pinkification" campaign is really working and whether it is a fair way to raise awareness. Does this simply go to running the operations of organizations that raise money, or does it really trickle down to help those with breast cancer?

As I pass my 20-year anniversary as a breast cancer clinician and researcher, it is clear that the basic science and clinical trial output is at an all-time high. Whether or not this is due to increased awareness or to fundamental breakthroughs in science cannot be clear discerned, but in the last two decades, breast cancer specific journals and general journals have increased their publication quantity and quality exponentially. The impact of these findings on earlier detection, less invasive options for surgery, better assays to make medical decisions and newer life-saving treatments are very tangible.

However, we are stuck in some areas without progress:

> Advanced metastatic disease is no more curable than it was 20 years ago. Although these patients are living longer and better lives, the improvements are not very dramatic.

> Disparities in outcome based on ethnicity and income continue, while narrowed in some areas.

> We are still overtreating some patients and undertreating others - new assays are just starting to get implemented, but we have a long way to go in our quest to "personalize" medicine.

> Medical prevention, while effective, has side effects. Because of this, we tend not to prescribe these drugs to those at risk, and also do not know how to estimate risk very well.

So at this point, the progress report is mixed, but mostly positive. After all, breast cancer awareness is not only moving the field forward, it is about demystifying and destigmatizing breast cancer.

While research is not moving fast enough, the public has a much better understanding about breast cancer - the importance of research funding, clinical trial participation, supporting a recently diagnosed employee, modifying their risks and getting objective information to help guide treatment should they be diagnosed.

Whether you are a fan of structured awareness and pink ribbons or not, there is no mistake that our society, as it so often does, is becoming fluent in the subject matter of the month.

• For the Cure to a broken heart
• An update on the Cancer Genome Atlas for breast cancer
• Video blog: Test could spare some DCIS patients from radiation
• Video blog: HER2-targeted agents
• Video blog: Complications with brachytherapy in breast cancer

Drug approvals: Are we in a new age yet?

BY DEBU TRIPATHY | AUGUST 28, 2011

With all the news of cancer drug shortages and the FDA's controversial decision to withdraw approval of Avastin (bevacizumab) for breast cancer, we are also getting some positive developments.

Just recently (on Aug. 26), the FDA granted accelerated approval to Xalkori (crizotinib), the newest member of an emerging generation of "niche" drugs. These are drugs that work in very defined subsets of patients, based on certain biological characteristics.

In the case of Xalkori, this is confined to the approximately 3 to 9 percent of patients with non-small cell lung cancer (NSCLC) who carry a chromosomal translocation that results in overexpression of the ALK protein (anaplastic lymphoma kinase). In fact, the approval of this drug is accompanied by the approval of a gene-based test to detect this translocation in tumor tissue. This approval comes on the heels of the approval of Zelboraf (vemurafenib) just eight days earlier for advanced melanoma, and again, only for the subset who harbor a mutation in the BRAF gene, and also approved with a diagnostic kit called the cobas 4800 BRAF V600 Mutation Test. In this case, the mutation is more common, seen in about half of all melanomas.

The big question is whether these two approvals herald the new age of personalized drugs. The now old story of Herceptin that many regard as one of the first targeted therapies, was spread out over 17 years from discovery of the gene to drug approval (or 11 years if you go from the discovery of HER2 amplification in breast cancer).

The new generation of drugs is being developed in a just a few years based on our exponentially growing body of data on mutations carried in cancers and new clinical trial designs that rapidly test drugs and verify biomarkers that predict response. Moreover, they seem to be quite effective with a higher percentage of patients responding, but not to the point that permanent cures are expected.

One can only hope that we are truly in the new era – and there are several indicators that this is the case. The Cancer Genome Atlas (TCGA) program is one of several worldwide that is collaboratively sequencing tumor genomes. Drug companies are investing more effort into biomarker analyses and integrating them earlier in the clinical trial process. Healthcare reform is demanding that drugs have a larger impact and that they not be used indiscriminately. Finally, the public's expectations are rising – they want more information about their cancers and access to clinical trials.

While it is possible that the initial wave of "low-hanging fruit" of "druggable" gene targets will soon be exhausted, it is more likely that we will have more targets and drugs than we can test. The bottleneck will really be in the patient clinical trials and how quickly and widely they can be deployed and fully enrolled. There will still be negative trials and other disappointments, but perhaps we are entering a new era where the bar of success is being raised.

• When the cancer comes back
• Two new drugs approved, one pulled from the pipeline
• Emerging treatment option for myeloma presented at hematology meeting
• The big news from the American Society of Hematology
• Studies highlight progress in lymphoma, pose more questions