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dlaxague · 12-03-2008, 10:31 AM

Hi all,

When the adjuvant AI data first started appearing, there was a lot of talk about AI's being better in HER2+ cancer because HER2+ cancer was Tamoxifen resistant. But I think that over the last few years the thinking has changed a bit. Yes, HER2+ cancers tend to derive less benefit from hormonal treatment. That is probably in part because the levels of hormone receptors tend to be lower, and in part because of resistance to hormonal treatment. But it's looking as if that resistance is similar for AI's. It's not just Tamoxifen.

And alas, the jury is still out on the whole issue. It's interesting to me that the garden-variety community oncs are the ones who'll tell us that they know these answers: "AI's are more effective for HER2+", or "Tamoxifen is fine for HER2+", or "Herceptin makes Tamoxifen work better". Any or all of these statements may be true, or not. We do not (yet) know enough to make such broad statements.

I think that these docs make these silly statements for several reasons. One, they know that we like to hear that it's all under control. They, too, like to feel that it's all under control. So they tend toward giving answers that sound more secure or absolute than they really are. Secondly, these busy community oncs probably do not read all there is to read about breast cancer. They may be hanging their hat on one or two studies, when there are 10 studies and the results are contradictory. You can find one or two studies to support almost anything you'd like to support. The experts in the field of hormone treatment and hormone resistance will be the first to say that they do not (yet) know enough to make such statements.

There's a lot of information going to appear next week at SABCS. In the meantime, here's a recent (2008), long, and complicated discussion:

http://www.medscape.com/viewarticle/580741_3

You may have to register to see this but Medscape registration is free. The link is to page 3 of 7, so scroll through it all. If you're like me, you'll skim the details of the complicated discussion of pathways and crosstalk but still be able to get the gist of it. I'll copy/paste some relevant snips (broken up for readability) below. Remember that they are talking about hormonal treatment in the absence of Herceptin or other HER2 targeted therapy (although if you follow the link, page 4 and 5 do bring in Herceptin and friends).

There was some initial enthusiasm that HER2+ tumors would be more sensitive to AIs than to tamoxifen.[76] Careful analysis of published data, however, suggests that even with AIs, patients with HER2+ disease have a poor response.[83,84,85,86,87,88]

For example, a phase III trial of 916 patients[17] with advanced breast tumors and an unknown HER2 status treated with first-line endocrine therapy showed superiority of letrozole over tamoxifen in terms of TTP (9.4 months versus 6.0 months; P <0.0001) and overall response rate (ORR; 32% versus 21%; P = 0.0002).

Nevertheless, subsequent analysis of HER2 status[83] revealed that in HER2+ patients there was no significant difference between those treated with letrozole and those treated with tamoxifen in terms of ORR (17% versus 13%; P = 0.45) or clinical benefit[89] (33% versus 26%; P = 0.31), although a strong trend towards a longer duration of response with letrozole was observed (6.1 months versus 3.3 months; P = 0.0596).[83] These poor results in the HER2+ subpopulation contrast with the median TTP observed in the HER2-negative subgroup (12.2 months in letrozole-treated patients and 8.5 months in tamoxifen-treated patients).

Finally, early preliminary reports from the Breast International Group 1-98 Study (BIG 1-98) and the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, which compared tamoxifen with either letrozole or anastrozole, revealed that HER2+ status is associated with a significantly higher relapse rate, regardless of whether an AI or tamoxifen is administered.[86,88]

Taken together, these studies strongly suggest that HR+/HER2+ breast cancer may be less responsive to tamoxifen and estrogen-deprivation therapies with AIs than cancer negative for HR and HER2 expression, which could be an indication than HER2 overexpression and/or amplification results in a dominant phenotype in ER+/HER2+ tumors.

Are you still reading? There's LOTS more - that's only a portion of page 3, and he goes on to discuss Herceptin and other targeted therapies in conjunction with hormonal treatment, etc. Let me know if you have trouble with the link.

Debbie Laxague

12-03-2008, 10:31 AM	#10
dlaxague Senior Member Join Date: May 2006 Posts: 221	relatively resistant to hormonal therapy - not just Tamoxifen Hi all, When the adjuvant AI data first started appearing, there was a lot of talk about AI's being better in HER2+ cancer because HER2+ cancer was Tamoxifen resistant. But I think that over the last few years the thinking has changed a bit. Yes, HER2+ cancers tend to derive less benefit from hormonal treatment. That is probably in part because the levels of hormone receptors tend to be lower, and in part because of resistance to hormonal treatment. But it's looking as if that resistance is similar for AI's. It's not just Tamoxifen. And alas, the jury is still out on the whole issue. It's interesting to me that the garden-variety community oncs are the ones who'll tell us that they know these answers: "AI's are more effective for HER2+", or "Tamoxifen is fine for HER2+", or "Herceptin makes Tamoxifen work better". Any or all of these statements may be true, or not. We do not (yet) know enough to make such broad statements. I think that these docs make these silly statements for several reasons. One, they know that we like to hear that it's all under control. They, too, like to feel that it's all under control. So they tend toward giving answers that sound more secure or absolute than they really are. Secondly, these busy community oncs probably do not read all there is to read about breast cancer. They may be hanging their hat on one or two studies, when there are 10 studies and the results are contradictory. You can find one or two studies to support almost anything you'd like to support. The experts in the field of hormone treatment and hormone resistance will be the first to say that they do not (yet) know enough to make such statements. There's a lot of information going to appear next week at SABCS. In the meantime, here's a recent (2008), long, and complicated discussion: http://www.medscape.com/viewarticle/580741_3 You may have to register to see this but Medscape registration is free. The link is to page 3 of 7, so scroll through it all. If you're like me, you'll skim the details of the complicated discussion of pathways and crosstalk but still be able to get the gist of it. I'll copy/paste some relevant snips (broken up for readability) below. Remember that they are talking about hormonal treatment in the absence of Herceptin or other HER2 targeted therapy (although if you follow the link, page 4 and 5 do bring in Herceptin and friends). There was some initial enthusiasm that HER2+ tumors would be more sensitive to AIs than to tamoxifen.[76] Careful analysis of published data, however, suggests that even with AIs, patients with HER2+ disease have a poor response.[83,84,85,86,87,88] For example, a phase III trial of 916 patients[17] with advanced breast tumors and an unknown HER2 status treated with first-line endocrine therapy showed superiority of letrozole over tamoxifen in terms of TTP (9.4 months versus 6.0 months; P <0.0001) and overall response rate (ORR; 32% versus 21%; P = 0.0002). Nevertheless, subsequent analysis of HER2 status[83] revealed that in HER2+ patients there was no significant difference between those treated with letrozole and those treated with tamoxifen in terms of ORR (17% versus 13%; P = 0.45) or clinical benefit[89] (33% versus 26%; P = 0.31), although a strong trend towards a longer duration of response with letrozole was observed (6.1 months versus 3.3 months; P = 0.0596).[83] These poor results in the HER2+ subpopulation contrast with the median TTP observed in the HER2-negative subgroup (12.2 months in letrozole-treated patients and 8.5 months in tamoxifen-treated patients). Finally, early preliminary reports from the Breast International Group 1-98 Study (BIG 1-98) and the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, which compared tamoxifen with either letrozole or anastrozole, revealed that HER2+ status is associated with a significantly higher relapse rate, regardless of whether an AI or tamoxifen is administered.[86,88] Taken together, these studies strongly suggest that HR+/HER2+ breast cancer may be less responsive to tamoxifen and estrogen-deprivation therapies with AIs than cancer negative for HR and HER2 expression, which could be an indication than HER2 overexpression and/or amplification results in a dominant phenotype in ER+/HER2+ tumors. Are you still reading? There's LOTS more - that's only a portion of page 3, and he goes on to discuss Herceptin and other targeted therapies in conjunction with hormonal treatment, etc. Let me know if you have trouble with the link. Debbie Laxague