Don S. Dizon

The holy grail in women's oncology is early detection. This is most painfully true for ovarian cancer, where symptoms often suggest that the disease has already advanced. Unlike the mammogram or pap smear, there is no way to screen the general population for ovarian cancer. For women with ovarian cancer, the protein CA-125 can be followed in a majority of women with advanced disease. That is, for women whose CA-125 was elevated at diagnosis, it can be a good way to tell how she is responding to treatment and her overall status once treatment is completed. A rise in the CA-125 can herald that cancer has returned about 8 months before signs or symptoms would otherwise arise. Given that a blood test can be used to follow the woman with ovarian cancer, it has been a challenge to find a test that may help us find women with ovarian cancer while still early. There are a number of other proteins that have been touted as a marker for ovarian cancer, including proteins called HE4, CA72-4, MMP-7, and CA15-3. The question has been: do these add to the usefulness of CA-125? Could they be better than CA-125?

 At the 2009 American Association for Cancer Research Meeting (AACR), an abstract was presented by Daniel Cramer from Harvard Medical School/Brigham & Women's Hospital, on behalf of researchers nationwide involved in a large screening trial for prostate, lung, colon, and ovarian cancers, called the PLCO screening study.

 In the first part of the study, investigators screened more than 50 markers from the blood of three groups of women: those with ovarian cancer with serum taken at the time of diagnosis (n=160) versus women without any cancer (n=160) versus blood taken from the general population (n=480).  The proteins that fell out with the greatest accuracy were CA-125, HE4, CA72-4, Transthyretin, HK6, B7H4, MMP7,and CA15-3. In the second part of this study, the blood samples from women who were part of the PLCO study, who had blood drawn months to years prior to a diagnosis of ovarian cancer, were used to test these proteins with proposed screening panels of markers (ie, a group of markers that were suggested to be more accurate than single protein levels). The end result was fairly sobering: the panels did not do much better than the CA-125 alone. However, they made two important observations: other markers (HE4, CA72-4, and MMP-7) seemed to increase the performance of CA-125 and the measurement of values over time seemed to help too. These observations may some day help to formulate a screening strategy, but for now, measurement of these values off a study cannot be recommended (particularly in light of the PLCO trial which reported that screening did pick up ovarian cancer, although in a significant proportion the disease was advanced at diagnosis. Whether or not screening improves survival has yet to be answered.

 For more on this, check out the AACR media page at: 

www.aacr.org/home/public--media/aacr-press-releases.aspx?d=1317

Articles

The holy grail in women's oncology is early detection. This is most painfully true for ovarian cancer, where symptoms often suggest that the disease has already advanced.

So Close and Yet so Far...

I was interviewed this past week on a study to be published in the 

. This study was based on an analysis of women treated in Denmark who had undergone surgery for breast cancer in whom either isolated tumor cells (ITC) were found in lymph nodes (technically, node-negative) and women in whom microscopic metastatic disease (N1mic) was found (technically, node-positive). The authors showed that while the overall 5-year axillary recurrence rate was low, less than 2% of the population which included over 2500 women), the 5-year disease free survival (5yDFS) was signficantly shorter in women with any evidence of cancer in the lymph nodes. In women with node-negative disease the 5yDFS was 86% but in those with ITC it was 77% and in those with N1mic it was 76%. Of more interest was the finding that adjuvant systemic therapy reduced the risk of recurrence by 33% in women with ITC and by 50% in women with N1mic. 

 In the interview I suggested that this study questioned the dogma that ITC were nothing that warranted agressive treatment and would lead oncologists to question the value of chemotherapy, or in fact, to treat even the smallest amount of disease in the node as a node-positive patient. However, my friend and colleague, Michael Linver, also interviewed, suggested that it would raise the concern that more women would be subjected to toxic treatment for very little gain. 

 In truth, the decision to use adjuvant chemotherapy for breast cancer has become more and more personalized, and not one factor is able to distinguish those who should get chemotherapy and those who should not. As important as the status of the lymph nodes is what the tumor itself looks like. Large tumors, high-grade cancers, hormone receptors, and even HER-2/neu status are all used to determine which patients "should" undergo chemotherapy- and these decisions may be made independent of the nodal status. Afterall, a woman whose tumor is 2.5 inches wide, ER-negative, would still be recommended for chemotherapy on the size and hormone receptor status alone; negative, ITC, or N1mic would not dissuade my recommendation in such a case. Even more than histologic and receptor status, we are going in to a changing world of breast oncology. Genomics has introduced us in to a new lexicon of tumor characterization where gene expression defines the tumor type, not histology. Hence, we now speak of luminal and basaloid tumors, both of which carry their own prognostic indications. 

 So, while the study is interesting and inserts more controversy and thought in to the question of who should get chemotherapy, in reality the discussion has already taken steps beyond this. We now have the capacity to look at a tumor's own genes, and this information will probably be the most powerful information a medical oncologist can rely on when counselling a patient with newly diagnosed breast cancer.

 Here is a link to the article, which appeared yesterday in 

http://online.wsj.com/article/SB10001424052970203496804574346624109995500.html

I was interviewed this past week on a study to be published in the New England Journal of Medicine. This study was based on an analysis of women treated in Denmark who had undergone surgery for breast cancer in whom either isolated tumor cells were found in lymph nodes and women in whom microscopic metastatic disease was found.

Breast Cancer: To Treat or Not to Treat

Oophorectomy is a fairly routine procedure in women with cancers of the gynecologic tract, performed as part of surgical staging. For women with breast cancer and are premenopausal, oophorectomy can even reduce risk of relapse, especially in those who are hormone receptor positive. For women with BRCA gene mutation carriers, an oophorectomy is the surest way to reduce the risk of ovarian cancer. But for all others, an oophorectomy should be considered an elective procedure and new data suggests it is one that requires a careful balance of risks and benefits.

Two papers have been published that raises potential concerns regarding the risks of an oophorectomy. In one study from the John Wayne Cancer Institute, almost 30,000 women enrolled as part of the Nurse's Health Study, which is observational in nature, looked at long-term outcomes following women who underwent total abdominal hysterectomy (TAH) with oophorectomy (BSO) versus those who underwent TAH with ovarian conservation. They reported that over a 24 year period those who underwent BSO were at a higher risk of death from all causes (HR 1.12, 95%CI 1.03, 1.21), fatal and nonfatal MI (HR 1.17, 95%CI 1.02,1.35), and BSO was also associated with an increased risk of lung cancer (HR 1.26, 95%CI 1.02-1.56). Of more concern was the finding that, in no circumstance, was BSO associated with a survival advantage. The second from Montreal was a case-control study involving 422 women with lung cancer compared to 577 controls. They found that after controlling for other factors such as smoking, early medically induced menopause was associated with an increased risk of lung cancer (OR 1.92, 95%CI 1.22, 3.01).

What explains this increased risk is not clear. Yet the publication of these articles this year raise serious questions about the long-term implications of early surgical menopause. As such, these risks must be taken in to account for any woman undergoing surgery for a non-malignant indication. If hysterectomy is indicated, oophorectomy should not and cannot be considered as a routine part of the procedure and frank discussion is warranted.

1.  Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z, Shoupe D, Berek JS, Hankinson S, Manson JE.  Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. 

2.  Koushik A, Parent ME, Siemiatycki J.Characteristics of menstruation and pregnancy and the risk of lung cancer in women. 

Oophorectomy is a fairly routine procedure in women with cancers of the gynecologic tract; performed as part of surgical staging.