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Answers to Burning Questions in Breast Cancer - Part 1: Early Breast Cancer

Presentation by Dr Lee Schwartzberg, Renown Cancer Institute

At the 2023 Total Health Spring Oncology Review and Renew Conference, Dr Lee Schwartzberg from Renown Cancer Institute provided an update on treatment for early-stage breast cancers, with answers to some key questions in the field and practice-changing findings, mainly as presented at the 2022 San Antonio Breast Cancer Symposium (SABCS).

Should patients having a moderate to high increased hereditary breast cancer risk be offered a contralateral prophylactic mastectomy?

The first question which Dr Schwartzberg addressed was whether patients who have a moderate to high hereditary risk for breast cancer, based on genetic testing results, should be offered a contralateral (opposite breast) mastectomy as a preventative (prophylactic) measure. He reviewed findings from the CARRIERS study, a population-based case control study which enrolled 65,000 women who either had breast cancer (the “cases”) or were unaffected matched “controls”. Results of the study identified 5 genes that were associated with significantly increased breast cancer risk, specifically, BRCA1 and BRCA2 (as expected), but also ATM, CHEK2, and PALB2.

One of the main questions which the study could address was what the chance of developing a contralateral breast cancer (CBC) was if you have already developed a breast cancer and have alteration in one of these genes. The results showed a very high risk for CBC for BRCA1 and BRCA2 (23% and 17% at 10 years, respectively) versus 4.3% for the normal population. Owing to this risk, as Dr Schwartzberg noted, a contralateral prophylactic mastectomy is a standard practice recommendation for all patients with breast cancer having a BRCA1 or BRCA2 mutation. By comparison, there was no increased risk for patients with ATM mutation (4%), and the CBC risk was about doubled with CHEK2 (8%). For PALB2, Dr Schwartzberg noted the CBC risk was overall low, except for patients who had estrogen receptor negative (ER-) tumors, in whom the risk was about 3-fold increased. Based on these findings, contralateral prophylactic mastectomy should be offered to patients with BRCA1 or BRCA2 mutation, and could perhaps be discussed for patients with CHEK2 mutation. Another important finding which Dr Schwartzberg noted was that, if patients were first diagnosed with breast cancer over the age of 65 and have a mutation in any of these genes, the overall risk of CBC was overall very low, suggesting there would be limited benefit of a contralateral prophylactic mastectomy.

What is the optimal preventive strategy for pre-invasive breast lesions?

Breast cancers are most commonly classified as “invasive”, such as invasive ductal carcinomas, but some breast lesions are classified as “pre-invasive”, such as ductal carcinoma in situ (DCIS) which, by definition does not spread, and the optimal preventative treatment in these patients, once they have undergone their surgery, is unclear. To this point, Dr Schwartzberg reviewed 10-year follow up data from a phase III study of low dose tamoxifen, an endocrine treatment, for patients under 75 years who were diagnosed with pre-invasive breast cancers. The patients were randomized to either placebo or to tamoxifen at one quarter of the normal dose (“Babytam”) for 3 years of treatment, and had at least 7 years of follow up. The results showed a significant preventive benefit for all breast events (breast cancer or DCIS) with Babytam versus placebo (hazard ratio [HR]=0.58; P=0.028), and interestingly, there was a continuing “carry over” effect of Babytam after the first 3 years, that persisted and continued to improve out to 10 years. Dr Schwartzberg noted that the carry over effect of tamoxifen is well known, and has previously been seen in preventive trials of tamoxifen at higher doses. There was also a similar benefit of Babytam in the important subgroup of DCIS patients (HR=0.50; P=0.02). Dr Schwartzberg suggested that, while the strategy has not yet been tested in patients with invasive breast cancer, the data provide an option of using low dose tamoxifen for patients with pre-invasive breast lesions who are seeking a preventive treatment after surgery.

Can we safely stop endocrine therapy for a time to allow premenopausal women with breast cancer to get pregnant and give birth?

A third question which Dr Schwartzberg addressed was the important issue of whether younger patients who develop breast cancer can safely interrupt their endocrine therapy (ET) for a time in order to get pregnant and have a child. He noted this is a frequent issue that arises with premenopausal women and creates a difficult choice for patients between treating their cancer and having a child; in addition, there has been little data available to reliably inform patients about the risks and benefits of interrupting their ET for this purpose. Dr Schwartzberg described results from the POSITIVE trial, a prospective, observational trial of premenopausal patients (<42 years old) interested in getting pregnant who had received between 18 and 30 months of prior ET for Stage I – III, hormone receptor positive (HR+) breast cancer with no evidence of a recurrence, and who, once enrolled in the trial, were allowed to stop their ET with careful follow up. Outcomes for this group of patients were compared to a historical cohort of patients from the SOFT/TEXT study, who had received optimal ET without any interruption of their therapy.

Results from the trial showed that, for patients who discontinued their ET for approximately 1 year to get pregnant and give birth, the main outcomes of breast cancer-free interval (BCFI), and distant recurrence free interval (DRFI) were similar as compared to those who did not. Moreover, patients who did get pregnant actually had a lower risk for recurrence than those who did not get pregnant following interruption of their ET, indicating there was no adverse impact of getting pregnant on breast cancer recurrence. He also noted that the majority of patients (76%) did resume their ET after having a child and completing their nursing (if done). Summarizing, Dr Schwartzberg noted “this is the best data we’re going to see” with regard to advising women whether they can safely interrupt ET to get pregnant, and he noted that, based on the data, “women can feel comforted” to know that their risk for recurrence is not elevated by interrupting treatment and then resuming their therapy.

Which LN-/HR+/HER2- patients benefit from chemotherapy?

A fourth question which Dr Schwartzberg addressed was which patients with lymph-node negative (LN-), hormone-receptor positive (HR+) breast tumors that are human epidermal growth factor receptor 2 negative (HER2-) benefit from the use of chemotherapy. The challenge with these patients, he noted, is that recurrences with this specific type of breast cancer (LN-/HR+/HER2-) tend to occur late (after 5 years), and as such, at least 10 years of follow up is needed to determine if treatments completed early on have any significant benefit in terms of preventing later recurrence. In this regard, he noted that some answers have already emerged to this question, based on results of trials such as TailoRx, which show that the use of genomic profiling tests such as Oncotype Dx can provide not only prognostic information (meaning what is the risk for breast cancer recurrence), but also predictive information (meaning, is there a benefit for using chemotherapy in this setting).

The twelve-year results of TailoRx, presented at SABCS 2022 continue to show that the OncotypeDx recurrence score (RS) is prognostic for all RS numbers, and for all endpoints, meaning that if the RS score is low, the risk for recurrence is low, and if RS score is high, recurrence risk is high, regardless of what treatment is given, and this is true for all measures of efficacy, including invasive disease-free survival (IDFS), distant recurrence free interval (DRFI) as well as overall survival (OS). In TailoRx, patients with intermediate RS values of 16 through 25 were randomized to receive chemotherapy along with endocrine treatment or not, and the results showed, specifically in the subgroup of women under 50 with an RS of 16 – 20, there was an apparent benefit of chemotherapy for patients with high clinical risk, but not for those with low clinical risk. These results allow for a more accurate assessment of chemotherapy benefit, such that chemotherapy could be safely avoided for a patient with an RS of 16 and a small (T1) tumor, while chemotherapy might be more strongly considered for a patient with an RS of 16 with a Grade III or a 3 cm tumor. By comparison, in the same group there was a benefit of chemotherapy for patients with RS of 21 – 25 regardless of their clinical risk factors, and as such, Dr Schwartzberg noted that based on the data, for any woman under 50, if their RS score is 21 or greater, he would recommend chemotherapy. As a final note on this data, Dr Schwartzberg highlighted the unanswered question of whether the benefit of chemotherapy in this younger pre-menopausal population is related to a direct cytotoxic impact of the chemotherapy or an indirect impact of the chemotherapy causing the patients to become essentially post-menopausal by shutting down their ovaries (ovarian function suppression); he noted that trials are currently being designed/ongoing to answer this important question.

Does the benefit of the CDK4/6i abemaciclib in high-risk breast cancer persist after cessation of treatment?

The final question which Dr Schwartzberg addressed on the topic of early breast cancer was whether there is a persisting benefit of abemaciclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) following initial treatment in patients who have higher risk early breast cancer. He noted previous results from the monarchE trial, which showed that, for patients with HR+, LN+ breast cancer with a high risk for recurrence, there was a benefit in invasive disease-free survival (IDFS) for patients who received abemaciclib in addition to endocrine therapy, as compared to those receiving endocrine therapy alone.

The now updated results from monarchE, however, addressed the important question of whether there was a persistent benefit of abemaciclib in this setting, or whether the benefit was limited only to the duration of time the patients were actually receiving the drug (2 years). Dr Schwartzberg noted that, reassuringly, there was, in fact, a continued benefit of having added abemaciclib after four years, with the survival curves continuing to widen, even though the drug had been discontinued 2 years earlier. At 4 years, the benefit in IDFS was approximately 6% (85.8% vs. 79.4%), with a significant hazard ratio (HR) of 0.664 (P<0.0001). There was a similar ~6% benefit in distant recurrence free survival (88.4% vs. 82.5%; HR=0.659; P<0.0001).

Quick Summary

· Prophylactic contralateral mastectomy should be offered to select patients with moderate to high hereditary breast cancer risk, particularly those with BRCA1 or BRCA2 germline mutations.

· Low dose tamoxifen (“Babytam”) is an effective preventive therapy option for those patients with pre-invasive breast lesions such as ductal carcinoma in situ (DCIS).

· Following an initial 18 – 30-month course of endocrine therapy (ET), premenopausal women wishing to get pregnant and give birth can safely interrupt their ET for a period, with little to no impact on their recurrence risk.

· Genomic classifiers such as the OncotypeDx recurrence score (RS) can be used both to determine recurrence risk as well as predict the benefit of chemotherapy for patients with LN-/HR+/HER2- early breast cancer.

· The benefit of an initial 2-year treatment with abemaciclib in combination with endocrine therapy persists for at least up to 4 years in patients with LN+/HR+ high risk breast cancer.

Speaker Disclosure Information: Dr Schwartzberg lists his disclosures as follows: Consultant: AstraZeneca, Daiichi Sankyo, Genentech, Novartis, Pfizer, Seagen, Spectrum, Coherus. Speaker Bureau: AstraZeneca, Seagen, Merck.

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