struggling with my AI's(i hate them)

[R.B.]

Hi All

I sadly do not have time to do lots of reading on this at the moment, but a quick google found the paper cited below - your onc may not have seen it or know more. I have not read the paper, and only bring it to your attention in case of interest.

I have some information I dug out a while ago and will try and find it see if it is still relevant.







The Predictive Value of HER2 in Breast Cancer
Martine Piccart, Caroline Lohrisch, Angelo Di Leo, Denis Larsimont

Institut Jules Bordet, Brussels, Belgium

Oncology 2001;61:73-82 (DOI: 10.1159/000055405)


Measurement of molecular markers predictive of response to therapy should enable more selective and effective utilization of anticancer agents. The predictive value of HER2 remains a complex and inconclusive subject. In metastatic breast cancer, HER2-positive, ER-positive patients can show responses to endocrine treatment, but experience shorter time to progression and survival than HER2-negative patients. In the adjuvant setting, weak, retrospective evidence suggests that tamoxifen is potentially harmful in HER2-positive patients and that there is no benefit from prolonged tamoxifen therapy. It has not yet been demonstrated conclusively that HER2 positivity increases resistance to adjuvant cyclophosphamide, methotrexate, 5-FU (CMF), but there are indications that HER2-positive patients benefit more from adequately dosed anthracyclines than from CMF. The greatest value of HER2 as a predictive marker lies in the prediction of response to therapies that target HER2, such as Herceptin®. Patients with strongly HER2-positive breast cancer derive significant clinical benefit from single-agent and combined Herceptin therapy. HER2 testing has become an integral part of the optimal management of the breast cancer patient. Best current practice in adjuvant breast cancer therapy based on the current knowledge of the potential predictive power of HER2 constitutes not denying tamoxifen to HER2-positive, ER-positive patients or CMF to HER2-positive patients. Outside of clinical trials, adequately dosed anthracycline-based chemotherapy is the current preferred adjuvant treatment option for HER2-positive patients.

[R.B.]

It seems the answers as usual are far form straight forward.


Understanding Resistance to Tamoxifen in Hormone Receptor–Positive Breast Cancer
Michaela J. Higgins1 and Vered Stearns1,a

1 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD.

aAddress correspondence to this author at: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., CRB I, Rm. 145, Baltimore, MD 21231-1000. Fax 410-955-0125; e-mail vstearn1@jhmi.edu.

The first 300 words of the full text of this article appear below.

The selective estrogen receptor (ER)1 modulator tamoxifen has been used for more than 30 years to treat and, more recently, to prevent breast cancer. Unfortunately, even among patients with ER-positive tumors, the response achieved with tamoxifen treatment is variable. Recent years have seen a sharp increase in the number of studies suggesting that the efficacy and safety of anticancer therapies such as tamoxifen depend not only on tumor characteristics but also on characteristics of the host. It is probable that future prescribing of truly "personalized" treatment approaches for our patients will be determined after analysis of both sets of traits. This Perspective summarizes recent basic and translational studies of putative mechanisms of tamoxifen resistance.


Tumor Characteristics

Resistance to tamoxifen therapy may be intrinsic or acquired. Breast cancers that produce either ER or progesterone receptor (PR) have the potential to respond to tamoxifen; however, a proportion of ER-positive tumors are intrinsically resistant to the drug. Historically, metastatic breast cancer that is both ER and PR positive (suggesting that the ER is functional) has an approximately 80% rate of response to antihormonal therapy, whereas tumors that are ER positive but PR negative have lower response rates, approximately 40%. Tumors that do not produce ER or PR are not expected to respond to tamoxifen.

Investigators have proposed several mechanisms of intrinsic resistance, including cross talk with growth factor–signaling pathways and a balance of ER coregulators. In addition, alterations in epigenetic regulation may cause a lack of ER production or lead to the acquisition of resistance to hormone therapy.

Recently, breast tumor phenotypes have been further characterized with DNA microarrays, and such studies have identified 5 clinically distinct subtypes: luminal A, luminal B, ERBB2-amplified, basal-like, and normal breast-like. So-called luminal B breast cancers that are classically associated with amplification of ERBB22 [v-erb-b2 erythroblastic leukemia viral . . . [Full Text of this Article]

[MJo]

I hate them too. But my doctor and his nurse practicioner strongly urge me to continue. I have seven more months of Femara and I'm counting the days. My life is tolerable with them. If your life is intolerable, maybe you could ask for a lower dose before you go off completely.

[Debbie L.]

Suzanne, you're not alone. The side effects seem to vary a lot from one woman to the next, both in what they are and how severe they are. I hope that the recent studies showing poor adherence to endocrine treatment will serve as a heads-up for researchers to find ways to help women tolerate the AI's, or maybe just find better drugs.

It's possible that you will eventually decide to stop all endocrine therapy in exchange for better quality of life. But you have many things to try first!

I know women whose AI-related pains have been helped by:

1. Vitamin D supplementation - get your levels above 30 or even 40.

2. Try another AI, either aromasin/exemestane or femara/letrazole. They do basically the same thing but one study showed that about 50% of women who try a different one get some relief from the side effects.

3. Go back to Tamoxifen. The AI's offer only an incremental benefit over Tamoxifen and if the other option is nothing, then Tamoxifen offers a big benefit. The studies that initially seemed to show that AI's might be better for certain subgroups like HER2+ don't seem to have played out -- it seems to be more that some ER+ cancer is resistant to all endocrine therapies, and HER2+ is more likely than most to be resistant (but no way to know for any one individual, if her ER+ cancer is resistant).

I think that there IS a big question needing an answer about duration of endocrine therapies. This is true for all ER+ cancers but especially for HER2+ ones where the synergy with Herceptin (and/or Lapatinib) seems to be a factor in sensitivity/resistance. It seems like the smaller a subgroup is, the less we know about it because few studies have been large enough to tease it out to such details, or the studies were done before we even knew the markers to see the subgroups.

We hear a lot nowadays about triple negative breast cancer being understudied and unaddressed but the same could be said for triple positive, in my opinion.

Keep us posted - what your onc says, what you try, and what works.

Debbie Laxague