Joyce O’Shaughnessy, MD
The individualization and optimization of adjuvant endocrine therapy for breast cancer are important and not always simple. Guidance on this issue was offered at the 2020 Miami Breast Cancer Conference by Joyce O’Shaughnessy, MD, the Celebrating Woman Chair in Breast Cancer Research at Baylor University and Chair of the Breast Cancer Research Program at Texas Oncology and the US Oncology Network, Dallas.1
Dr. O’Shaughnessy addressed several important questions in the selection of treatment:
- How do you choose between aromatase inhibitors and tamoxifen for postmenopausal women?
- Which patients fare well with just 5 years of endocrine therapy?
- Does ovarian suppression improve outcomes in premenopausal women, and, if so, do all women need it?
Which Endocrine Therapy to Start With?
Which postmenopausal women do better by starting with an aromatase inhibitor as opposed to switching from tamoxifen after 2 to 5 years? Is there a group that needs to start with an aromatase inhibitor?
Compilation of data from seven clinical trials of upfront “early switch” (2–3 years of tamoxifen first) and sequencing of endocrine therapy indicates that the absolute disease-free survival events reduction at 3 to 6 years is between 2% and 4% for an upfront aromatase inhibitor; between 3% and 5% for early switching from tamoxifen to an aromatase inhibitor; and 1.5% for sequencing—“outcomes that look more or less the same,” Dr. O’Shaughnessy noted. However, in the 9-year follow-up of the head-to-head ATAC trial, anastrozole was associated with a 2.5% difference in disease-free survival events and a 4% difference at 9 years.2
It appears there are patients who will experience recurrence early on tamoxifen, she said, “so who might they be?” Data from the BIG 1-98 trial of tamoxifen vs letrozole have been informative.
Endocrine Therapy by Subgroup
In the BIG 1-98 trial, measurement of the Ki67 labeling index showed that 4-year disease-free survival was best among the lower Ki67 cohorts and trended downward as Ki67 levels rose. There was no notable difference between upfront tamoxifen and upfront letrozole until patients’ Ki67 levels exceeded 30%, in which case letrozole was superior.3
“It’s fair to say that, as we get up into the really high levels of Ki67, we want to be using aromatase inhibitors.”— Joyce O’Shaughnessy, MD
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This high-Ki67 subgroup has aggressive cancer and therefore is at higher risk for early recurrence, stated Dr. O’Shaughnessy. “It’s fair to say that, as we get up into the really high levels of Ki67, we want to be using aromatase inhibitors.”
Is the subtype of breast cancer relevant? The BIG 1-98 study also looked at this question by comparing 2,923 patients with invasive ductal carcinoma and classic invasive lobular carcinoma. Patients were additionally classified as having hormone receptor–positive disease with high (luminal B–like) or low (luminal A–like) proliferative activity by Ki67.4
The magnitude of benefit of adjuvant letrozole varied by histologic subtype. Letrozole significantly reduced the risk of disease-free survival events vs tamoxifen in women with lobular cancer, regardless of whether the tumor was luminal A–like or luminal B–like. By contrast, in the ductal carcinoma subset, letrozole significantly reduced disease-free survival events in the luminal B–like subtype, but there appeared to be no differences between letrozole and tamoxifen in the luminal A–like subtype.
“So, if you have a slowly growing ductal carcinoma, starting with tamoxifen is okay, but if you have a slowly growing lobular tumor, you may do poorly on tamoxifen,” commented Dr. O’Shaughnessy. “Also, the patients with lobular cancer who had the fastest growing tumors did particularly poorly with tamoxifen, so introducing tamoxifen in these patients was not in their best interest.”
For Which Patients Is 5 Years Enough?
“We have emerging data showing us that there is a group of patients that have little metastatic potential and do well with just 5 years of endocrine therapy,” Dr. O’Shaughnessy continued.
One of these groups consists of patients with node-negative, HER2-negative tumors, and a 21-gene recurrence score (RS) < 11, according to findings from the 9-year follow-up of TAILORx.5 For this group, 5 years of endocrine therapy led to a distant recurrence–free survival exceeding 99%. Excellent long-term benefits were seen for those aged 50 and younger, for women between the ages of 41 and 50, and for the premenopausal cohort. The TAILORx findings have been corroborated by those from the nonrandomized Young Women’s Breast Cancer Study.
“Endocrine therapy would probably be a more appropriate way to go [than chemotherapy] for patients with a low recurrence score and a low clinical risk.”— Joyce O’Shaughnessy, MD
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Do Clinical Factors Influence Outcomes?
TAILORx subsequently examined how clinical factors impacted outcomes.6 For patients deemed to be at low clinical risk who were younger than age 50 and had a recurrence score of between 16 and 20, the distant recurrence rate was less than 5%, whether they also received chemotherapy or not.
“This group is doing very well, and there was absolutely no benefit to chemotherapy,” she said. “Endocrine therapy would probably be a more appropriate way to go for patients with a low recurrence score and a low clinical risk.”
Conversely, for patients who have a recurrence score of between 21 and 25 and a low clinical risk, chemotherapy conveyed an absolute 6.4% benefit in distant relapse–free survival. “This group really needs more than tamoxifen,” Dr. O’Shaughnessy maintained. Also, premenopausal patients with high clinical risk and a recurrence score of 16 or greater also benefited from chemotherapy.
Lastly, data from the 20-year follow-up of the Stockholm STO-3 randomized trial of 1,780 node-negative, postmenopausal women deemed to be at “ultra-low” risk by the 70-gene signature, two-thirds had just 2 years of tamoxifen; and their breast cancer–specific survival was 97% (it was 94% for patients receiving no treatment at all).7
Does Ovarian Suppression Improve Outcomes?
Data from the TEXT and SOFT trials, which included premenopausal patients with hormone receptor–positive/HER2-negative disease, were compiled into a 2019 joint analysis; it examined recurrence risk among 4,891 patients.8 In TEXT, patients received tamoxifen or exemestane plus ovarian suppression for 5 years. In SOFT, patients received tamoxifen alone, ovarian suppression plus tamoxifen, or ovarian suppression plus exemestane for 5 years.
After 6 years of follow-up, outcomes were determined according to age, nodal status, tumor size, and estrogen receptor expression, with the following conclusions:
- Premenopausal patients with node-negative disease that lacks the high-risk features of age younger than 40, high-grade/high Ki67 levels, low estrogen and/or progesterone receptor expression, or T2 tumors can be treated with 5 years of tamoxifen alone; their 8-year outcomes are excellent.
- Patients with node-positive disease and those who require systemic chemotherapy benefit from the addition of a luteinizing hormone-releasing hormone agonist to either tamoxifen (if at moderate risk) or an aromatase inhibitor (if at higher risk).
- A total of 5 years of ovarian function suppression is recommended, and patients at higher risk can then complete 10 years of endocrine therapy with tamoxifen, according to the most recent ASCO guidelines.9
- It is unclear whether high-risk patients benefit from oophorectomy or a longer duration of ovarian suppression.
Interestingly, in the ABCSG-12 trial of premenopausal patients who received the gonadotropin-releasing hormone agonist goserelin, patients with a normal body mass index (BMI) derived similar benefit from 3 years of anastrozole and tamoxifen, but those with a BMI ≥ 25 kg/m2 had a significant detriment in disease-free survival with anastrozole. The difference emerged after therapy was stopped.10
“I think the data are cautionary…. We need to wait for data from SOFT and TEXT looking at BMI to get a better feel for the efficacy of ovarian suppression and aromatase inhibitors in overweight and obese patients,” Dr. O’Shaughnessy commented.
KEY POINTS
- Patients with node-negative early breast cancer, a recurrence score (RS) less than 11, or ultra-low–risk 70-gene signatures have excellent outcomes with adjuvant endocrine therapy alone (perhaps even with less than 5 years’ duration).
- Women younger than age 35 (and perhaps younger than age 40) benefit from the addition of a luteinizing hormone-releasing hormone agonist.
- Premenopausal patients with a low clinical risk and an RS ≤ 20 and postmenopausal patients with any clinical risk and an RS ≤ 25 have a 95% distant disease–free survival at 9 years with 5 years of endocrine therapy.
- Patients with higher-risk, virulent breast cancers, regardless of stage and age, benefit from an aromatase inhibitor (and ovarian function suppression if they are pre/perimenopausal) more than tamoxifen.
Ovarian Suppression for All Premenopausal Women?
Ovarian suppression is clearly important for women younger than age 35 who do “exceptionally poorly” with tamoxifen alone, according to data from the SOFT trial.11 This group had a 5-year disease-free survival of 68%, compared with 79% with tamoxifen and ovarian suppression, and 83% with exemestane and ovarian suppression.
A composite risk and STEPP (subpopulation treatment effect pattern plot) analysis of SOFT and TEXT data found that patients at high risk for recurrence benefit greatly from ovarian suppression: their 8-year disease-free survival was improved by 10% to 15% with exemestane plus ovarian suppression vs tamoxifen/ovarian suppression or tamoxifen alone.12 In the intermediate-risk group (most of whom also received chemotherapy), exemestane plus ovarian suppression conveyed a benefit of 4% to 5%. For patients at low risk, however, the potential benefit of escalating endocrine therapy from tamoxifen alone was minimal, since 97% were without distant recurrence at 8 years, Dr. O’Shaughnessy said.
DISCLOSURE: Dr. O’Shaughnessy has served as a consultant for G1 Therapeutics, AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Ondonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, and Syndax Pharmaceuticals.
REFERENCES
1. O’Shaughnessy J: Age- and risk-adapted adjuvant endocrine therapy. 2020 Miami Breast Cancer Conference. Invited Lecture. Presented March 7, 2020.
2. ATAC Trialists’ Group, Forbes JF, Cuzick J, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45-53, 2008.
3. Viale G, Giobbie-Hurder A, Regan MM, et al: Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: Results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 26:5569-5575, 2008.
4. Filho OM, Giobbie-Hurder A, Mallon E, et al: Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1-98 trial. J Clin Oncol 33:2772-2779, 2015.
5. Sparano JA, Gray RJ, Makower DF, et al: Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 373:2005-2014, 2015.
6. Sparano JA, Gray RJ, Ravdin PM, et al: Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. N Engl J Med 380:2395-2405, 2019.
7. van ‘t Veer LJ, Yau C, Yu NY, et al: Tamoxifen therapy benefit for patients with 70-gene signature high and low risk. Breast Cancer Res Treat 166:593-601, 2017.
8. Pagani O, Francis PA, Fleming GF, et al: Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies for premenopausal women: Results from TEXT and SOFT. J Clin Oncol. October 16, 2019 (early release online).
9. Burstein HJ, Lacchetti C, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol 34:1689-1701, 2016.
10. Pfeiler G, Königsberg R, Fesl C, et al: Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: An analysis of the prospective ABCSG-12 trial. J Clin Oncol 29:2653-2659, 2011.
11. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.
12. Regan MM, Francis PA, Pagani O, et al: Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive HER2-negative breast cancer: Results from TEXT and SOFT. 2018 ASCO Annual Meeting. Abstract 503. Presented June 4, 2018.
