DR PAPISH: This patient is the 45- year-old premenopausal wife of a physician in our community who presented with a left breast abnormality that she felt on examination. She underwent mammography, which was negative, but an ultrasound revealed a seven-millimeter nodule at approximately five o’clock. She ultimately underwent an excisional biopsy for a 0.7-centimeter, poorly differentiated, invasive ductal carcinoma that contained approximately 25 percent high-grade DCIS.

The tumor was strongly ER-positive (90 percent on IHC), PR-positive (80 percent), and HER2-positive (amplified by FISH). She subsequently underwent bilateral breast MRIs, which were negative. Her family history is negative for breast cancer and ovarian cancer, but she is of Ashkenazi heritage and underwent both BRCA1 and BRCA2 testing for the three Ashkenazi genes.

DR LOVE: John, if this woman turned out to be BRCA1- or BRCA2-positive, would you approach her local breast cancer therapy any differently?

DR MACKEY: When we see a patient who is BRCA1-positive, we often have the discussion that they’re at quite high risk of local recurrence or a second primary cancer. Even though this is a small tumor, the woman should be given the discussion regarding prophylactic mastectomy, as well as perhaps a completion mastectomy on the affected side.

DR PAPISH: She then underwent a re-excision and sentinel node biopsy. The re-excision revealed a residual two-millimeter area of just high-grade DCIS with no other invasive tumor. Three sentinel lymph nodes were negative by IHC and H&E.

DR LOVE: What was her attitude? Was she more of the proactive, “I want to do everything possible,” or was she more concerned about toxicity?

DR PAPISH: There was a clear-cut difference between the patient and her husband. She is a long-distance runner. She was very worried about anything that might impact on her cardiovascular health. She truly did not want to receive any aggressive therapy if it were not warranted. However, she’s bright enough to understand that if it were needed, she would accept it.

DR LOVE: Aman, would you bring up the use of the Oncotype DX assay in this woman?

DR BUZDAR: The tumor is relatively small, and the risk in this woman of this breast cancer causing a problem is relatively small. But if she has one breast cancer, she has at least a 0.6 percent risk of developing contralateral breast cancer on a yearly basis, and she’s young. She may have another 30 or 40 years of lifespan left. So that also has to be taken into account.

DR LOVE: So how did you approach this patient?

DR PAPISH: We discussed the Oncotype DX assay. My bias was that with a poorly differentiated tumor and borderline but HER2-positive amplification, we would probably see a high or a high-intermediate recurrence score. The recurrence score was 16 (6.1).

DR LOVE: Her recurrence score was 16, which is low risk. What did you decide to do?

DR PAPISH: She was started on tamoxifen and breast irradiation. We had previously discussed that if the recurrence score from the Oncotype DX assay was low, we would use hormonal therapy.

I explained that I had a bias about possibly using an aromatase inhibitor and ovarian ablation but did not feel strongly that it needed to be done at the moment. She’s perimenopausal, so she clearly would not be a candidate for an aromatase inhibitor alone at present. They have an appointment next week, and her husband still thinks he may want her to have chemotherapy. But I think the patient is very comfortable with hormonal therapy.

DR LOVE: If you’re thinking about chemotherapy, potentially you also might be talking about trastuzumab.

DR PAPISH: The tumor is FISH-positive, but I don’t know whether the Oncotype DX assay trumps the HER2 positivity in the sense that we have a relatively low recurrence score. I would presume that if she had an increase in genes coding for HER2 positivity, she would have had a higher recurrence score and certainly a more proliferative tumor.

DR LOVE: John, I’m curious. Is it possible that the HER2 positivity is from the DCIS?

DR MACKEY: There’s generally a high degree of concordance between the HER2 status of DCIS and invasive disease. In general, the two travel together. However, when one does FISH, the person who’s reading it should be trained enough to score only the invasive nuclei, as opposed to the in situ component.

DR LOVE: Andy, what would you say to this woman?

DR SEIDMAN: I think we need to be cognizant of what the real benefit is and lead with the data rather than the emotional response. I would absolutely give this woman tamoxifen and talk to her about participation in a trial of ovarian function suppression.

DR LOVE: You’re going to knock down the relapse rate a little bit with trastuzumab. Of course, following an anthracycline base, we’re looking at probably a three or four percent risk of cardiomyopathy. A young woman who’s a jogger probably has normal cardiac function. If the husband brings that up, Andy, how would you respond?

DR SEIDMAN: I think the only meaningful data we have regarding trastuzumab’s role in patients with node-negative breast cancer come from the HERA trial, in which there were 1,100 such patients randomly assigned to trastuzumab or not (Piccart-Gebhart 2005). They had to have T1C or greater tumors; this woman clearly doesn’t fit that category. The incidence of cardiac events is probably very close to the potential benefit she would receive. It would be easy to defend not giving her trastuzumab.

DR LOVE: Aman, how would you approach the issue of chemotherapy and maybe even trastuzumab in this patient?

DR BUZDAR: I think the trastuzumab part is a little tricky, because she has a small tumor where 20 or 25 percent of the tumor is DCIS. I agree with John, that pathologists have to carefully look at and make sure that this overamplification of HER2 is indeed in the invasive component. Sometimes our pathologists at MD Anderson will say, “Yes, there is overamplification, but it is only confined in the DCIS area.” We should not be misguided and overtreat the patient.

What is interesting and intriguing about this patient is that she is young — she’s 45 — so she has a fairly long lifespan. But the tumor is very small and is strongly ER/PR-positive. The addition of chemotherapy in patients with strongly ER/PR-positive disease is marginal at best; most of the benefit in this patient would be from endocrine intervention.

DR RAVDIN: This case represents where molecular characterization comes into play in terms of treatment sensitivity. Even though this patient had a low-risk Oncotype DX score — seven percent rate of distant recurrence — that range includes patients with as low as two percent or as high as 10 percent risk. And a 10 percent risk of distant recurrence is — if you’re the one facing it — a substantial risk.

The Overview says chemotherapy adds to such patients about a 30 percent relative benefit. Now, a lot of that benefit — at least half of it — is probably an endocrine ablation type of benefit. But nonetheless, it is a benefit. So you could argue rationally that such a patient should be treated if you believe that she would get 30 percent of 10 percent, or a three percent net benefit.

However, a proportional benefit for this woman is likely to be less than that 30 percent benefit. In the future, I think if you look at it as a three percent possible benefit, that would be attractive to a number of people. So I don’t think you can discount the idea that such a patient would be treated even if all you know is the prognostic information.

DR LOVE: One final question for Aman. Does the fact that this patient has FISH-positive disease make you concerned about using just tamoxifen as opposed to an LHRH agonist or an LHRH agonist plus an aromatase inhibitor?

DR BUZDAR: There are small but definite data emerging that suggest that patients who have HER2-positive disease may have better disease-free survival when treated with an aromatase inhibitor — both in the metastatic and the adjuvant settings, or even in the neoadjuvant setting (Dowsett 2005, Smith 2005).

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