Breast Cancer Update Issue 7, 2007

CHARLES L VOGEL, MD: My experience with the arthralgias associated with the aromatase inhibitors has been highly variable. Approximately 30 percent of my patients have to be switched to another therapy or discontinue the aromatase inhibitor. Aman Buzdar and I had an agreement not to agree. He told me, “It is a class effect. If you get it with one aromatase inhibitor, you will get it with another.” I absolutely do not agree because I have seen patients respond to a second aromatase inhibitor.

Breast Cancer Update Think Tank Issue 2, 2008

DANIEL F HAYES, MD: Many of us underestimated the issue of aromatase inhibitor-associated arthralgias during the early clinical trials and when they were first reported. Increasingly in practice, many of us are beginning to see arthralgias as a major issue.

In a prospective trial we have in our consortium of breast cancer pharmacogenomics, COBRA, we found in the first 100 patients we put on a randomized trial comparing exemestane to letrozole that 15 percent of patients quit taking the drug because of joint symptoms.

In a study by Morales and colleagues reported in the Journal of Clinical Oncology, they assessed tendon synovial changes serially with MRI and observed carpal tunnel thickening in many patients who were receiving the AIs and in fewer patients who were receiving tamoxifen.

We don’t know why this happens, but physicians need to be aware of it. I have seen a few patients who started out at baseline with low-level carpal tunnel syndrome and ended up requiring surgery. That may have happened anyway, but it seemed as if it was hastened by the aromatase inhibitor therapy.

Breast Cancer Update Issue 5, 2008

NANCY E DAVIDSON, MD: Lynn Henry published data from the first 100 patients in a clinical trial evaluating the pharmacogenomics of adjuvant exemestane and letrozole, and a large proportion saw a rheumatologist because they crossed a predefined symptomatology threshold.

The findings are all over the map, and no single explanation for these symptoms is clear to me. What to do about them is also complicated, and one purpose of our study is to determine whether it is possible to predict which aromatase inhibitor a patient will tolerate better or perhaps to identify patients who are more prone to these musculoskeletal symptoms.

I believe these symptoms were underreported in the large, randomized aromatase inhibitor trials. Now that we are paying attention to this side effect, we are recognizing that the problem is critical to address because compliance is important with these drugs.

Breast Cancer Update Issue 5, 2007

JACK CUZICK, PHD: Not surprisingly, we see somewhat but not enormously higher rates of arthralgias with anastrozole than with tamoxifen in the ATAC trial. The rate is 30 percent with tamoxifen and 36 percent with anastrozole, so the effect is real, but it’s a small effect compared to the fact that arthralgia is not uncommon in the early postmenopausal years anyway.

So, to some extent, the aromatase inhibitors are being blamed for some arthralgias that they don’t cause. They do increase the risk, but a lot of arthralgias will occur anyway. We will learn more about that from the IBIS-2 study because we’ll be comparing anastrozole to placebo, and there’s no doubt that a fair amount of arthralgia is occurring in the placebo arm.

D Cella et al. Quality of life of postmenopausal women in the ATAC (“Arimidex”, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer. Breast Cancer Res Treat 2006;100(3):273-84.

These are the first HRQoL data to become available that cover the entire 5-year treatment period in the primary adjuvant setting for an aromatase inhibitor.

Although it was not necessarily expected, results from the 5-year HRQoL analysis are broadly similar to those of the 2-year analysis. For both the anastrozole and tamoxifen treatment groups, the good HRQoL of patients at baseline was maintained and perhaps even improved overall throughout the treatment period...

Vaginal discharge was less frequently bothersome with anastrozole but vaginal dryness, decreased libido, and dyspareunia were more frequently bothersome with anastrozole compared with tamoxifen. HRQoL should play a role in informed consent and patient-reported data of this nature add important information beyond the traditional end points to be considered when making decisions about therapeutic options and appropriate supportive measures.

C Derzko et al. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy. Curr Oncol 2007;14(Suppl 1):20-40.

Clinical evaluation of AI therapy-associated signs and symptoms of urogenital atrophy, vaginitis, dyspareunia, and loss of sexual interest demonstrates several similarities with natural age- and menopause-related gynecologic events associated with diminished estrogen levels. Management of these events through a combination of lifestyle modification, counseling, and hormonal and non-hormonal interventions can therefore improve quality of life significantly for patients...

In view of recent findings raising concerns over elevated circulating estradiol levels in breast cancer patients on AI therapy who are using transvaginal estrogenic preparations, non-hormonal therapies including regular application of vaginal moisturizers and lubricants are recommended and certainly should be first-line therapy. In addition, pelvic therapy for pelvic tone awareness and pelvic floor exercises (for example, Kegel exercises) and lifestyle modification are preferred and should be considered early.

Breast Cancer Update Issue 4, 2008

MICHAEL GNANT, MD: The ABCSG-12 trial, evaluating adjuvant endocrine therapies in premenopausal women, addressed both the issue of endocrine therapy and the use of bisphosphonates. The bone substudy data reported in 2004 revealed that the bisphosphonates completely reversed bone loss from aromatase inhibitors. We then increased the trial size from 1,250 to 1,800 to answer the antitumor question regarding bisphosphonates.

We administered four milligrams of zoledronic acid every six months, for a total of seven infusions over three years. At five years of follow-up, we observed only 137 disease-free survival events. We saw a 36 percent improvement in disease-free survival, translating to at least a nonsignificant trend toward better overall survival. That’s an accomplishment usually observed with interventions such as taxane chemotherapy. We observed that efficacy with an acceptable side-effect profile.

More importantly, we also saw benefit in various event subcategories, including locoregional recurrence, contralateral breast cancer and distant metastasis outside of the bone (such as liver or lung disease). That’s something most of us did not expect.

When we started the trial in 1999, nobody was aware of osteonecrosis of the jaw (ONJ). When the first reports were published, we made an effort to educate physicians and patients. We identified three suspected cases and examined the original dental films. We did not find evidence of a single case of confirmed ONJ. This is in line with what is known about that dose and frequency of administration of zoledronic acid.

Basically, all the reports suggest that ONJ with IV bisphosphonates occurs with more intense regimens or higher-dose schedules. I would say that ONJ is not a problem in the adjuvant treatment setting. I believe it’s prudent for patients to see a dentist prior to initiating bisphosphonate therapy to ensure that they don’t have any major problems.

DM Reid et al. Guidance for the management of breast cancer treatment-induced bone loss: A consensus position statement from a UK Expert Group. Cancer Treat Rev 2008;34(Suppl 1):3-18.

In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use...

Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss.

Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis.

Breast Cancer Update Issue 3, 2008

JOHN F FORBES, MD: The data on bone fractures from the long-term follow-up of the ATAC trial are informative and pleasantly surprising. For a number of years, we’ve been aware of the increased risk of fractures associated with the aromatase inhibitors compared to tamoxifen. What was surprising was that upon completion of the treatment, no difference was detectable in the risk of fractures with anastrozole compared to tamoxifen.

It is interesting that no detrimental carryover effect is evident here. Almost as soon as you stop the treatment — within one year — the difference is gone. I believe we need to be a little cautious about leaping to safety reassurance at this point, however, because the types of fracture risk may vary: Hip fractures may well be different from vertebral fractures. These are different types of bone, and I believe we need much longer follow-up to be sure that there isn’t some unsuspected, longer-term effect on hip fractures.

The bone substudy in ATAC was designed to evaluate the effect of anastrozole on bone density and potential longer-term strategies to correct it. We learned that women who started out with a normal bone density may develop osteopenia but will not develop osteoporosis.

Breast Cancer Update Issue 3, 2007

ANTHONY HOWELL, MD: The important clinical point from the bone data in the ATAC trial was that if the patients started treatment with a normal bone density, none of them became osteoporotic over the five years. In addition, we’re seeing a lot of data on the effectiveness of bisphosphonates in preventing bone loss associated with therapy.

The most important data remain those from the Austrian study, which was published in the Journal of Clinical Oncology in 2007. They show that zoledronic acid at four milligrams administered every six months completely abrogated the bone loss from goserelin with either tamoxifen or anastrozole.

Breast Cancer Update Issue 5, 2007

ROWAN T CHLEBOWSKI, MD, PHD: I believe it’s clear now that almost no one needs annual bone mineral density testing. I expect the recommendation will be every two years. In addition, if the baseline test is normal and insurance issues exist, I believe you can wait longer. As for prophylactic bisphosphonates, the question is, where do you draw the line? Some clinicians might choose to initiate bisphosphonates at a T-score of -1.5, based on Coleman’s data, and that’s probably reasonable.

R Weitzman et al. Critical review: Updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients — May 2006. Crit Rev Oncol Hematol 2007;62(2):148-52.

It is recommended that patients be encouraged to receive a dental examination prior to initiating bisphosphonate therapy and, if possible, complete any necessary dental procedures (eg, tooth extraction) prior to initiating bisphosphonate therapy. Patients should receive regular dental visits during bisphosphonate therapy.

Patients should be encouraged to practice good oral hygiene and minimize possible jaw trauma. If possible, patients should avoid dental surgery during treatment with bisphosphonates. If exposed bone is observed or reported in the oral cavity at any time (suspected ONJ), refer the patient to a dental professional immediately.

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