Younger women with breast cancer differ from their older counterparts in ways that should be appreciated by their clinicians, according to Ann H. Partridge, MD, MPH, FASCO, Vice Chair of Medical Oncology at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. At PER’s Miami Breast Cancer Conference, held virtually this year, Dr. Partridge discussed differences that ranged from predominant subtypes to treatment outcomes and treatment adherence.1
“Treatment principles should be similar for all patients with HER2-positive disease, regardless of age….”— Ann H. Partridge, MD, MPH, FASCO
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“Anyone who cares for these patients knows that life is harder for younger people when they’re diagnosed with breast cancer,” Dr. Partridge said. “They have to deal with chemotherapy, endocrine therapy, and local therapy decisions, which may be more difficult in younger patients, as they’re more likely to need or receive chemotherapy and to lean toward more aggressive local therapy. These patients are also dealing with issues that are unique to, or accentuated by, being younger.”
Outcomes Often, but Not Always, Worse in Younger Women
Generally speaking, younger age has long been associated with poorer survival after a breast cancer diagnosis. Older data show a 13% relative survival detriment at 5 years for patients between the ages of 30 and 40 vs those aged 45 to 49.2 More recently, better treatments are available, yet unpublished data from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 still indicate an absolute 5% difference in 5-year cancer-specific survival in patients younger than age 40 vs older.
One reason for this could be a greater proportion of aggressive disease, such as HER2-positive and triple-negative tumors. Of note, though, in an analysis from the National Comprehensive Cancer Network (NCCN), led by Dr. Partridge, women up to age 40 with HER2-positive or triple-negative disease did not experience worse breast cancer–related mortality than older women; young age was associated with significantly increased risks only in patients with luminal A breast cancer.3
The reason for poorer outcomes is multilayered, with one aspect probably related to lower rates of treatment adherence. Younger women may be more concerned about specific side effects of treatment, including infertility, and so perhaps may be more apprehensive about adherence. Efforts to help young women preserve fertility through treatment may help this problem and improve their outcomes.
Subtypes Differ
Much about breast cancer in younger women has been learned recently from the Young Women’s Breast Cancer Study (YWS), which is following a large population of patients grouped by age: ≤ 30, 31–35, and 36–40. Across these younger age ranges, luminal B subtypes outnumber luminal A subtypes, though luminal A tumors still account for about one-third of breast cancers.4
High genomic risk profiles do seem to be found in younger patients, she continued. In an analysis of 71 studies involving 561,188 patients (4.9% were “young”), most tumors deemed at high genomic risk were observed in patients up to age 40.5 “Just as you see a different mix of tumors, you tend to see higher-risk tumors in younger women,” Dr. Partridge commented.
In the YWS, genetic testing yielded useful information about BRCA mutational status within breast cancer subtypes. For example, young BRCA1-positive patients were most likely to develop triple-negative breast cancer, whereas BRCA2-positive patients tended to develop estrogen receptor–positive high-grade tumors—in other words, more of the luminal B subtypes—suggesting perhaps the need for chemotherapy. In the YWS patients who were either not tested or tested negative for the BRCA mutation, the mix of disease phenotypes appears comparable to what has been seen in older patients, she reported.
“It really speaks to tailoring therapy as we gain more clarity on breast cancer subtypes, better treatments for each subtype, as well as genetic testing and how that should impact our treatment decisions,” commented Dr. Partridge.
HER2-Positive Disease
Of note, with the HER2-positive disease population, the disparity in survival between younger and older patients seems to be narrowing. For example, the NCCN analysis examined HER2-positive patients according to estrogen receptor status.3 The data showed that “when you controlled for all of the other things that predict for risk, there wasn’t a clear disparity by age in terms of breast cancer mortality,” she noted. In the phase III HERA trial of adjuvant trastuzumab, which Dr. Partridge led, age was also not prognostic or predictive of early recurrence.6 These seemingly comparable outcomes in HER2-positive disease may stem from better anti-HER2 therapies over the past 2 decades.
According to Dr. Partridge, the data suggest that treatment principles should be similar for all patients with HER2-positive disease, regardless of age, and de-escalation should not be routinely dismissed. “This is really important information…. For a younger woman with HER2-positive disease, regardless of age, we should be treating the tumor…. We shouldn’t just be throwing more chemotherapy at our younger patients, especially in the era of trying to de-escalate,” Dr. Partridge maintained.
Hormone Receptor–Positive, HER2-Negative Disease
Although younger patients with HER2-positive disease are enjoying the same benefits of treatment as older patients, the gap in disparities is not necessarily closing as much for other subtypes. In particular, cancer-specific survival data from SEER 2010 and 2015 (unpublished) demonstrated that the youngest patients with triple-negative or hormone receptor–positive, HER2-negative disease continue to have worse survival than older patients with these subtypes.
“The question is … should we be giving chemotherapy to all of our patients with luminal A or luminal B disease?” Dr. Partridge asked. “We now have more information to inform these decisions.”
Data from the phase III TAILORx trial did not show a clear benefit with chemotherapy in node-negative women older than age 50 with a recurrence score (RS) of between 11 and 25.7 In contrast, in node-negative premenopausal women up to age 50, some chemotherapy benefit was observed in women with an RS between 16 and 25. A subsequent analysis further broke down the younger population; it reported no clear chemotherapy benefit for patients younger than age 40, some benefit for patients between the ages of 41 and 45, and the most benefit for patients between the ages of 46 and 50.8
“That flies in the face of what we’ve known about chemotherapy historically,” Dr. Partridge noted. “I think this dose-response curve suggests that many of the benefits of chemotherapy in the premenopausal group are happening from ovarian suppression or are a chemo-endocrine effect. Therefore, it makes sense that the youngest women—the ones least likely to be sent into menopause—would be the ones to derive the least benefit from adjuvant chemotherapy.”
More recently, results from the phase III RxPONDER trial in women with one to three positive nodes again showed little benefit with chemotherapy in postmenopausal women. However, premenopausal women with an RS ≤ 25 experienced an absolute improvement of 5.2% in 5-year invasive disease–free survival,9 though the dose-response curve seen in TAILORx was not observed, she added, although they did not look at the youngest patient subgroup—those less than 40—on their own.
It is now known that ovarian function suppression clearly benefits the youngest patients with breast cancer who have higher-risk tumors, as demonstrated in a subanalysis of the phase III SOFT trial.10 This is also the population most likely to discontinue hormonal therapy.11 Thus, special efforts should be made to educate and support patients in this situation, and further research will be important to tailor treatment for this vulnerable group, Dr. Partridge added.
DISCLOSURE: Dr. Partridge has received royalties for coauthoring the breast cancer survivorship section of UpToDate and has been reimbursed for travel, accommodations, or other expenses by Novartis.
REFERENCES
2. Adami HO, Malker B, Holmberg L, et al: The relation between survival and age at diagnosis in breast cancer. N Engl J Med 315:559-563, 1986.
3. Partridge AH, Hughes ME, Warner ET, et al: Subtype-dependent relationship between young age at diagnosis and breast cancer survival. J Clin Oncol 34:3308-3314, 2016.
4. Guzman-Arocho YD, Rosenberg SM, Poorvu P, et al: Breast cancer subtypes in Young Women’s Breast Cancer study. 2019 San Antonio Breast Cancer Symposium. Abstract P4-07-02. Presented December 13, 2019.
5. Villarreal-Garza C, Ferrigno AS, De la Garza-Ramos C, et al: Clinical utility of genomic signatures in young breast cancer patients: A systematic review. NPJ Breast Cancer 6:46, 2020.
6. Partridge AH, Gelber S, Piccart-Gebhart MJ, et al: Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: Results from a Herceptin adjuvant trial. J Clin Oncol 31:2692-2698, 2013.
7. Sparano JA, Gray RJ, Makower DF, et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018.
8. 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.
9. Kalinsky K, Barlow WE, Meric-Bernstam F, et al: First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy ± chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence scores ≤ 25: SWOG S1007 (RxPONDER). 2020 San Antonio Breast Cancer Symposium. Abstract GS3-00. Presented December 10, 2020.
10. Saha P, Regan MM, Pagani O, et al: Treatment efficacy, adherence, and quality of life among women younger than 35 years in the International Breast Cancer Study Group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol 35:3113-3122, 2017.
11. Hershman DL, Kushi LH, Shao T, et al: Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 28:4120-4128, 2010.
