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Select Excerpts from the Interview
Tracks 2-3
DR LOVE: Can you present one of your own patients for whom you
obtained the Oncotype DX assay? DR TRIPATHY: I saw a 42-year-old woman who had a biopsy of a lump in
her left upper, outer breast, which revealed ER-positive, PR-positive, HER2-negative intermediate-grade cancer. She ultimately underwent a lumpectomy
and a sentinel node biopsy. All three of the sentinel nodes were negative, and
the tumor was 1.2 centimeters.
Before any additional testing, I outlined for her our general approach for balancing chemotherapy’s side effects with the projected benefits. We knew clearly we would recommend hormonal therapy. This would be a decision about how much benefit the chemotherapy would provide.
I had projected that her risk of recurrence was around 15 percent. We could lower that to maybe seven or eight percent with hormonal therapy and maybe by another two or three percent with chemotherapy. In her mind, at that point it was not something for which she would want to receive chemotherapy.
She was concerned about cardiovascular side effects of chemotherapy and leukemia. It became apparent to me that she had a clear threshold for which she was going to take chemotherapy, and I suggested that we obtain an Oncotype DX recurrence score. I don’t use this test for everybody. However, once it’s evident that the range of risk will matter to the patient and we may want a more precise definition of it, that’s exactly the kind of person who needs this test.
DR LOVE: What was this patient’s recurrence score?
DR TRIPATHY: She had a high Oncotype DX recurrence score of 33, which
corresponds to a distant recurrence risk at 10 years of more than 25 percent.
For this patient, therefore, we ended up using chemotherapy. She felt more
comfortable about the decision. She was obviously concerned and scared that
she was at a higher risk, but it gave her more resolve to move ahead with
chemotherapy.
DR LOVE: The relative risk reduction is estimated to be about 75 percent
for the patients with high recurrence scores, with three out of four relapses
avoided with chemotherapy in the higher-risk group (Paik 2006).
DR TRIPATHY: The benefit is dramatic in these patients and is probably
diluted in clinical trials. It could be that only a third of the patients benefit
and that they are actually getting a 75 percent reduction, as suggested in the
study (Paik 2006; [2.1]). These numbers may not hold up in larger
analyses. We shouldn’t take the 75 percent reduction too literally at this point,
but we can say that the benefit is not distributed equally across the population.
Track 4
DR LOVE: What endocrine therapy are you planning for this patient? DR TRIPATHY: We plan to use tamoxifen because she is premenopausal and
still having menstrual periods. Even if she stops having periods, I feel that
many of these women will still have ovarian function and continue to make
estrogen. Their disease needs to be treated with tamoxifen instead of an
aromatase inhibitor.
DR LOVE: Can you talk about the current clinical approach to both premenopausal
and postmenopausal women in the adjuvant setting?
DR TRIPATHY: Hormonal therapy is effective in all age groups. We used to
think it was mostly for older patients. Over the years, we have realized that
what matters is the hormone receptor content. Clearly, ER or PR positivity
indicates the possibility of a risk reduction with hormonal therapy. We now know that the optimum duration of adjuvant hormonal therapy is five years,
which provides around a 40 percent risk reduction in all age groups. The use
of tamoxifen continues to be the gold standard. For postmenopausal women,
however, the aromatase inhibitors are showing a marginal advantage, with a
20 to 40 percent additional risk reduction compared to tamoxifen. This translates
into an absolute improvement of between two and five percent in recurrence-free outcome over the next five years (Howell 2005; Thürlimann 2005).
DR LOVE: For a postmenopausal patient, generally, what’s your first-line
hormonal therapy in the adjuvant setting?
DR TRIPATHY: I will typically start someone off with an aromatase inhibitor.
I tend to use anastrozole as the drug of choice, but the other two aromatase
inhibitors — exemestane and letrozole — are in the same league.
Track 6
DR LOVE: What about the duration of therapy with adjuvant aromatase
inhibitors? DR TRIPATHY: One approach that has been evaluated is head-to-head comparisons
of tamoxifen to an aromatase inhibitor for five years (Howell 2005;
Thürlimann 2005). The other studies have been crossover studies. Patients
either take tamoxifen for two to three years and then cross over to an aromatase
inhibitor (Coombes 2003; Jakesz 2005), or after five years of tamoxifen
they cross over to placebo or an aromatase inhibitor for five years (Goss 2003,
2005).
On that basis, the ASCO Technology Assessment Panel recommended that an aromatase inhibitor be considered as part of adjuvant hormonal therapy for postmenopausal women. They recommend a duration of two to five years as long as there is a total of five years of any hormonal therapy. They also make the point that the effects of therapy beyond five years with an aromatase inhibitor are not known (Winer 2005). I generally recommend five years of an aromatase inhibitor. In fact, when I cross patients over after two to three years of tamoxifen, I still go ahead with a full five years of an aromatase inhibitor. When I’m using it instead of tamoxifen altogether, I use five years.
Track 10
DR LOVE: Can you summarize the recent trial results of trastuzumab in
the adjuvant setting for women with HER2-positive disease? DR TRIPATHY: It’s clear that trastuzumab reduces the risk of recurrence.
Four large randomized studies have all reported roughly equivalent reductions
in risk, cutting the risk of recurrence in half (Piccart-Gebhart 2005;
Romond 2005; Slamon 2005). These translate into large absolute reductions
because these patients generally have a high risk of recurrence. It looks as if
the recurrence risk is reduced by anywhere from 40 to 50 percent. Some of those studies are now showing mortality differences with longer follow-up
(Romond 2005).
The question is, what is the lower end of risk for which one would treat? We are seeing cardiac toxicity associated with trastuzumab as expected. We saw it in the metastatic setting, and we’re seeing it in the adjuvant setting. It seems to be different from the cardiotoxicity associated with chemotherapy. It tends to be more reversible and treatable.
In the adjuvant trastuzumab trials, no cardiac deaths were associated with trastuzumab, but clinical congestive heart failure rates of two to four percent were observed (Piccart-Gebhart 2005; Romond 2005; Slamon 2005). Most of these patients recover over time, but many of them have to stay on cardiac medications. It’s also becoming clear that older patients are at a higher risk.
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