Chemotalk Newsletter

Chemotalk Newsletter, Vol. 95 March 1, 2016

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Jasmine in the air.  It's SPRING!


By Theodora Ross

Researchers announced in the New England Journal of Medicine that they had found that mutations in a gene called PALB2 greatly increase the risk of BREAST CANCER.  This is one of the biggest developments since the discovery in the 90s of the role of mutations in the BRCA1 and BRCA2 genes in breast and OVARIAN CANCER.

the response among patients has been predictable.  One woman's email to me summed it up: "I'd like to get an entire genome scan to rule out a hidden cancer diagnosis."

Genetic testing has revolutionized how we think about cancer, allowing us to make some decent predictions about who might get certain cancers and who might benefit from preventive treatments  Many know the story of Angelina Jolie, who used her family history to learn she had a BRCA1 mutation.  She chose to have a double mastectomy instead of waiting to see if she developed cancer.  We may not envy this choice, but we do appreciate the power that comes with taking evidence-based action against a deadly disease.  Many of us want that power for ourselves.

The problem is that many patients think genetic testing can tell us far more than it does.  Despite the exaggerated claims of some entrepreneurs and lab owners, we can't predict patients' cancer risk and advise them appropriately just by sequencing their genome.  At least not yet.

First, it's important to know the difference between sequencing a tumor and sequencing a germ line (which is what the woman who emailed me wanted).

The germ line genome is found in every cell of the body and encodes traits such as eye color and the tendency to develop diseases like cystic fibrosis.  It is the blueprint you inherited from your parents.

The tumor genome is like an ugly addition on top of the original construction.  It's acquired rather than inherited, and contains a mess of new mutations, a subset of which cause the cells to proliferate out of control and transform into a cancer.

Sequencing a portion of a tumor genome can sometimes tell us what went wrong and how the cancer might be treated more effectively.  For instance, testing people with MELANOMAS for mutations in their BRAF genes can influence treatment.  But it's unclear how many people would benefit from sequencing all the genes in a tumor; it, like full germ line sequencing, remains mainly a research tool.

Both tumor and full germ line sequencing suffer from the same problem: The whole genome doesn't make a lot of sense to us yet.  We have a very limited understanding of which variations in DNA contribute to disease development.  Most of your genome sequence looks the way Shakespeare does to a toddler - incomprehensive.

Conscientious doctors won't order a lab test that they can't understand, so they're unlikely to say yes to a patient's request for full genome sequencing.  And insurance companies shouldn't pay for a test if there isn't research backing up its use.

The genetic tests that are clearly valuable at this point for predicting cancer risk are those for the specific mutations that we understand.  But even then there can be other mutations in the same genes that are of unknown clinical significance.  So the best results come from sequencing the subset of genes that could potentially explain patterns of disease observed in the family tree.  If your family shows an increased incidence of certain cancers it makes sense to look for known mutations that increase the risk of those cancers.

For example, we recently saw a 25-year-old patient at our clinic with a strong family history of COLON CANCER.  His father had colon cancer, but had refused any kind of genetic testing.  When the son tested positive for a broken colon cancer gene, the rest of his family followed.  Those who tested positive now know they need to have frequent colonoscopies.  And most people with strong family histories of breast cancer should consider getting genetic counseling and, if recommended, testing for mutations in the gees such as PALB2, BRCA1 and BRCA2.

Family history doesn't just help us decide where to look for broken genes; if we find a mutation that could lead to cancer, the number of cancers in the family helps us determine what kind of risk that mutation might carry.  Some patients with BRCA mutations have a 40% chance of developing breast cancer by age 70, but of others, the chance has been estimated to be as huge as 87%.  It looks as if this is the case for PALB2 mutations as well.  According to the New England Journal of Medicine study by Marc Tischkowitz at the University of Cambridge and others patients with a broken PALB2 gene is no family history of breast cancer have a 355 chance of developing breast cancer, but if they had two or more family members with cancer, the risk rises to 58%.  This is significant when you're considering lie-altering preventive surgery or screenings.

Genetic testing is a process for many patients not a one-time event.  In the coming weeks, in light of the report on PALB2, as well as the emergency of sophisticated tests that can now analyze many cancer genes at one time, we'll advise former patients who tested negative for the BRA or other specific genes to return for more genetic counseling and potentially further testing.

One patient, who is now healthy but who dealt with a breast cancer diagnosis in her early 30s, emailed to ask if she'd been tested for the PALB2 gene when she had the BRCA test in 2007.  We found no mutations, an she seemed to be a genetic mystery.  My reply was easy: She hadn't been tested for PALB2, but she should now, along with any other new cancer genes. If she tests positive, we'll know more about the risk of her having a second cancer, and be able to test her family members.

For any patient who still wants to get his or her full genome sequenced, there is one good reason to do it: scientific curiosity.  Something of interest could come of it as the technology improves over time.  But it's worth doing only if a clinical trial is paying for it, or if you can easily afford it.  Getting the data can cost under $2,000, but having the data interpreted can cost in the hundreds of thousands.  It's a fine purchase, but definitely a luxury.  And bear in mind that the data that come back with raise more questions than they answer.  There is a good chance that mutations of unknown clinical significance will be found that will increase anxiety without illuminating any known risks.

We have to have patience with the pace of research.  We can now use genetic information to prevent breast, ovarian and colon cancer in many patients and we will get better at this.  In the meantime, most people should focus less on the high-tech future of genetic testing and more on the low-tech history of their family trees.  Those who don't know their own family histories, because of adoption, secrecy, loss or estrangement, should take comfort in the fact that we are one big family.  Data in aggregate from many families, fathered together in studies like Dr. Tischkowitz's, will eventually teach us how to manage our risks, how to treat disease and how to save lives.

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Background:     Ocrelizumab (OCR) is a humanized monoclonal antibody that selectively targets CD20+B cells. In a randomized, double-blind, placebo-controlled Phase III study (ORATORIO), OCR significantly reduced disease activity in patients with primary progressive multiple sclerosis (PPMS).

Objectives:     To evaluate the efficacy of OCR in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing (Gd+) lesions at baseline.

Methods:    A total of 732 patients were randomized (2:1) to receive OCR 600 mg or placebo (PBO) as two 300 mg intravenous infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression (CDP) events occurred. Key eligibility criteria included age 18-55 years, diagnosis of PPMS (2005 revised McDonald criteria), Expanded Disability Status Scale (EDSS) score of 3.0-6.5, and documented history of elevated immunoglobulin index and/or presence of oligoclonal bands in the cerebrospinal fluid. Although not powered for comparisons, prespecified subgroups included age (¾ 45 vs > 45 years), sex, body mass index (< 25 vs „ 25), weight (< 75 vs „75 kg), region (US vs rest of world), treatment history, MS symptom duration, and disease activity (EDSS score ¾ 5.5 vs > 5 and presence/absence of T1 Gd+ lesions) at baseline. Efficacy of OCR on „ 12- and „ 24-week CDP, change in total T2 lesion volume at 120 weeks, and other secondary efficacy outcomes was evaluated in the subgroups with presence and absence of T1 Gd+lesions at baseline.

Results:    Compared with PBO, OCR significantly reduced the relative risk of 12-week CDP by 24% (hazard ratio [HR], 0.76; p= 0.0321) and 24-week CDP by 25% (HR, 0.75; p=0.0365). T1 Gd+ lesions were present at baseline in 27.5% of OCR-treated patients vs 24.7% of PBO-treated patients. In patients with and without T1 Gd+lesions at baseline, respectively, OCR reduced: the risk of 12-week CDP by 35% (HR, 0.65; 95% CI, 0.40-1.06; p=0.0826) and 16% (HR, 0.84; 95% CI, 0.62-1.13; p=0.2441); the risk of 24-week CDP by 33% (HR, 0.67; 95% CI, 0.40-1.14; p=0.1417) and 19% (HR, 0.81; 95% CI, 0.59-1.10; p=0.1783); and total T2 lesion volume by -3.8% (95% CI, -7.0 to -0.5) vs +12.0% with PBO (95% CI, 7.2-17.1; p<0.001) and by -3.1% (95% CI, -5.0 to -1.1) vs +6.1% with PBO (95% CI, 3.3-9.0; p<0.001).

Conclusion:     In this subgroup analysis of patients with or without T1 Gd+ lesions at baseline, OCR reduced clinical and MRI disease activity compared with PBO.

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by Ashley Boynes-Shuck

There are several cancers linked to rheumatoid arthritis due to the disease itself and the medical treatments. Most recently, a link was established between RA and CERVICAL CANCER, which is often caused by HPV.

The majority of cervical cancer cases are caused by the human papillomavirus virus (HPV) ‹ or so we thought.  Lately other links have been investigated and among them, rheumatoid arthritis (RA).  Now, RA has been shown to be associated with cervical cancer.

And scientists are now faced with the question of what came first, the cancer or the RA? And did RA biologic treatment perhaps worsen or cause the cervical cancer?

Researchers hope to uncover the answers to these questions as they strive to better understand the complex, puzzling link between autoimmune inflammatory conditions and various forms of cancer.  The overall risk of RA patients developing any form of cancer is at least 10 percent higher than that of the general population.  This risk can increase or decrease based on a number of factors including genetics, lifestyle, environment, medications, and coexisting conditions.

A recent study out of Sweden provided evidence that, at least in female RA patients, biologic drugs (in particular, TNF-inhibitors) could be to blame for a rise in virus-related cancers such as cervical cancer, as well as an increase in cervical dysplasia.  Female patients with rheumatoid arthritis who¹ve never been on any type of biologic showed no significant difference from the general population when it came to risk for cervical dysplasia. However, the study showed that younger women with RA who relied on anti-TNF therapy, also called T-cell inhibitors, were at an increased risk for cervical dysplasia and/or cervical cancer.

Additionally, this study found that while simply having rheumatoid arthritis alone appears to increase a female patient¹s risk of developing cervical dysplasia, the young women being treated with a tumor necrosis factor inhibitor were at higher risk of dysplasia further developing into cervical cancer.

³In an analysis of 34,984 women with RA not taking biologics, rates of cervical intraepithelial neoplasia were 53 percent higher and another type of cervical cancer, CIN2+, were 39 percent higher than in the general population,² reported Dr. Hjalmar Wadstrom of the Karolinska Institute in Stockholm, in a press statement. ³However, women in whom a TNF inhibitor had been initiated had a 36 percent higher rate of CIN2+ and had double the risk of invasive cervical cancer compared with women with RA who were biologics-naïve.²

The authors, however, caution that this casual link may not be a matter of concern just yet.  In order to stay safe, suggests that, ³if you are between ages 21 and 29, you should get a Pap test every 3 years. If you are between ages 30 and 64, you should get a Pap test and HPV test together every 5 years, or a Pap test alone every 3 years. If you are 65 or older, ask your doctor if you can stop having Pap tests.²

Women who are immunocompromised, as are many with rheumatoid arthritis, should discuss more frequent screenings with their OB-GYN.

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By Andrew Pollack

A federal advisory committee cleared the way for the first approval of a CANCER drug that would be used to treat patients before surgery to remove their tumors.

`   The advisory committee to the Food and Drug Administration voted 13 to 0, with one abstention, that Perjeta, a Genentech drug approved last year for late-stage BREAST CANCER, could also be used at the disease's earliest stage. Such pre-surgery treatment might help make some inoperable tumors amenable to surgery, or make tumors small enough to allow for breast-conserving surgery rather than complete removal of the breast.

Moreover, the approval could serve as a model for a new path to quicker approval of cancer drugs.

"This is an historic moment," Dr. Mikkael A. Sekeres, an associate professor at the Cleveland Clinic who served as the chairman of the advisory committee, said immediately after the vote.  "We are supporting the rapid movement of a highly active drug for metastatic cancer to the first-line setting, with the hope that women with earlier stages of breast cancer will live longer and better."

The F.D.A. still has to formally approve Perjeta for the new use but officials indicated it was likely to do so.

Perjeta, like the older Genentech drug Herceptin, is approved to treat only so-called HER2-positive tumors, which account for about 20% of all breast cancers.  Pre-surgery treatment would be approved for only a minority of those patients, with large tumors or other features that increase the risk.

Genentech, which is part of the Swiss company Roche, estimates that 15,000 American women a year would be eligible for preoperative treatment with Perjeta, out of about 220,000 new cases of early-stage breast cancer.

Preoperative treatment, known as neoadjuvant therapy, is already fairly common for breast cancer and some other cancers, although the drugs are used off-label.

Approval of Perjeta -- which would be the first neoadjuvant drug approval for any cancer, not just breast cancer -- would presumably make it easier to obtain insurance reimbursement.  It would also allow at least some women to gain access to Perjeta years earlier than they might otherwise.

Cancer drugs are typically tested first in patients with late-stage disease that has spread beyond the primary site.  Because those patients are closer to dying than those with early disease, it takes less time to tell if a drug is improving survival.  Also, side effects are less problematic for someone with little left to lose.

But metastatic breast cancer is virtually incurable.  Bigger gains come from treating early-stage disease, typically after surgery, which is known as adjuvant therapy.  In that use, drugs can prevent the return of the cancer, effectively curing the patient.

But it can take years to determine whether adjuvant therapy is preventing recurrences or prolonging lives.  Herceptin was not approved for adjuvant use until eight years after it was approved for late-stage cancer. Data on the postsurgery use of Perjeta is not expected until this year.

"Our current path to approval in early breast cancer is far too slow," Dr. Jose Baselga, physician in chief at the Memorial Sloan-Kettering Cancer Center, said on behalf of Genentech.

So the F.D.A. issued a draft proposal last year that would allow pre-surgery treatment to be used as a basis for approval rather than postsurgery treatment.

Genentech's main neoadjuvant trial involved only about 400 patients treated for a mere 12 weeks.  About 39.3% of patients who received Perjeta plus Herceptin and taxotere had what was called a complete pathologic response, meaning no invasive cancer was detected in their breast tissue or in any removed lymph nodes.  For patients who received only Herceptin and taxotere, only 21.5 percent had a complete pathologic response.

Despite their positive vote, some members of the advisory committee expressed concerns.

It is not clear whether a drug that increases the rate of pathologic complete responses will actually prolong lives or reduce recurrences.  For that reason, the F.D.A. would give so-called accelerated approval to Perjeta, subject to confirmation with more data later.

Also, one of Perjeta did not increase the percentage of women in the trial who decided to switch from mastectomy to lumpectomy.  There were concerns that Perjeta, which is known generically as pertuzumab, could raise the risk of damage to the heart.

Using Herceptin and Perjeta together for 9 to 18 weeks before surgery would cost $27,000 to $49,000, according to Genentech.  And preoperative treatment would not eliminate the need for drugs after surgery.

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Until next month...


And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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