The Lobular Breast Cancer Alliance (LBCA) collected questions about hormone therapy from women with lobular breast cancer, also known as invasive lobular carcinoma (ILC), and posed them to LBCA Scientific Advisory Board Member Rachel Jankowitz, MD. Dr. Jankowitz is associate professor of Clinical Medicine in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania, and director of the Rena Rowan Breast Center at the Penn Abramson Cancer Center. Read what she has to say about where things stand in terms of the understanding of hormone therapy and efficacy with lobular breast cancer.

LBCA: Dr. Jankowitz, what questions remain and is there further research happening regarding hormone therapy and ILC treatment?

RJ: Many questions remain and in fact have only begun to be asked. We still do not have any ILC targeted therapies. Research about mechanisms response and resistance to hormonal therapy in ILC tumors is early and preclinical at this point. We have learned that not all ILC is the same, and that there may be different approaches needed for different patient subsets.

LBCA: What might be controversial or lacking consensus regarding the use of hormone therapy in treating ILC? What are the hot topics?

RJ: When making decisions about extended adjuvant hormonal therapy beyond five years, I consider the fact that patients with ILC potentially have increased risk of late recurrence compared to those with invasive ductal carcinoma (IDC) based on existing data. However, there is no ILC-specific way to prognosticate late recurrence risk or predict the potential benefit of extended hormonal therapy to lower that risk.

Certain molecular assays, such as the Breast Cancer Index (BCI) and Mammaprint assays, can support that decision-making process for patients with ILC and IDC, but they need to be interpreted in the context of clinical risk and patient tolerance/intolerance of hormonal therapies.

Many patients with ILC have grown concerned that tamoxifen may be less effective for their cancers. This stems from the Metzger Filho BIG 1-98 analysis that showed a higher proportional advantage of aromatase inhibitors over tamoxifen for postmenopausal patients with ILC compared to those with IDC. This was a retrospective analysis performed on a large clinical trial that only included postmenopausal patients.

Tamoxifen is still the standard of care for many premenopausal women with early-stage breast cancer. We should not be extrapolating from the BIG 1-98 trial analysis that all women with ILC are somehow resistant to tamoxifen. In general, there is an advantage to aromatase inhibitors over tamoxifen for postmenopausal patients with hormone receptor positive breast cancer; there was just a higher proportional advantage for those with ILC on the BIG 1-98 study. Further research is needed in the context of prospective clinical trials to study response to hormonal therapies in patients with ILC and to understand mechanisms of resistance to these therapies.

LBCA: What is the most current recommendation for duration of hormone therapy after diagnosis? Is a prescribed duration of hormonal therapy dependent on risk factors? If so, what are those risk factors and how are they best assessed?

RJ: There is not a universal recommendation. It is important to base decisions about the duration of hormone therapy on an individualized discussion between the patient and their oncologist. I can provide some information about general approaches based on existing guidelines:

Premenopausal:
Many women who are diagnosed at a premenopausal age are encouraged to complete more than five years of therapy. The initial upfront approach to hormonal therapy in premenopausal patients depends on the level of risk. Patients with low-risk disease are often prescribed tamoxifen, and at year five, they can continue on tamoxifen for another five years if they are still premenopausal. Or, if they become clearly postmenopausal while on tamoxifen and/or are postmenopausal at year five, they have the option to switch to an aromatase inhibitor. For those women with higher risk cancers, oncologists sometimes prescribe ovarian suppression in combination with tamoxifen or an aromatase inhibitor upfront.

Postmenopausal:
Most women who are postmenopausal at diagnosis are prescribed an aromatase inhibitor. Occasionally, oncologists will prescribe tamoxifen if there are contraindications to aromatase inhibitors such as osteoporosis and/or intolerance. The decision to extend beyond five years of an aromatase inhibitor is an individualized one based on risk assessment, patient preference, and/or the use of certain molecular assays as I previously discussed.

LBCA: Is there any evidence to support switching between aromatase inhibitors or from tamoxifen to an aromatase inhibitor after several years of therapy to avoid resistance/mutation?

RJ: No. Not to my knowledge in the setting of early-stage breast cancer. In patients with metastatic disease, treatment-emergent resistance to aromatase inhibitors has been described, such as ESR1 mutations. I do not believe anyone has demonstrated this in the adjuvant setting.

LBCA: Side effects are a big reason some women stop their hormone therapy. Do drug “holidays” or breaks increase risk of recurrence? If so, how long of a break is okay?

RJ: I am going to knock on wood here. I have never had a patient experience a recurrence during a brief “drug holiday.” I am not advocating taking multiple drug holidays a year or anything, but I sometimes do encourage my patients who are having significant side effects to take a three-week break from whatever pill they are on. Anecdotally, it helps reset things for some patients. It also allows the patient to examine how they feel off of their therapy before embarking on a new therapy. I feel like this is an important exercise to know what proportion of their symptoms are from the pill verses menopause and/or other factors.

If I have a patient with higher risk of recurrence, such as positive lymph nodes, I am admittedly less inclined to tell them to take treatment breaks, but I have never seen any publication or research on this topic. It would be impossible given the low recurrence rate in patients with early-stage breast cancer to study this in a meaningful way.