Impact of Age on Clinical Outcomes and Efficacy of Adjuvant Dual Anti-HER2 Targeted Therapy

Matteo Lambertini, MD, PhD; Shona Fielding, MSc, PhD; Sibylle Loibl, MD; Wolfgang Janni, MD; Emma Clark, MD; Maria Alice Franzoi, MD; Debora Fumagalli, MD, PhD; Carmela Caballero, MD; Luca Arecco, MD; Sharon Salomoni, MD; Noam F. Ponde, MD; Francesca Poggio, MD; Hee Jeong Kim, MD; Cynthia Villarreal-Garza, MD; Olivia Pagani, MD; Shani Paluch-Shimon, MD; Alberto Ballestrero, MD; Lucia Del Mastro, MD; Martine Piccart, MD, PhD; Jose Bines, MD; Ann H. Partridge, MD, MPH; Evandro de Azambuja, MD, PhD


J Natl Cancer Inst. 2022;114(8):1117-1126. 

In This Article

Abstract and Introduction


Background: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients.

Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor.

Results: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62–75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (P interaction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations.

Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status.


Breast cancer is the most frequent malignancy among young women,[1] defined according to international guidelines as age at diagnosis of 40 years or younger.[2] Young women are more likely to die of breast cancer than older women, in part because of higher risk to develop biologically aggressive breast cancer phenotypes including the HER2-positive subtype.[3]

Several prior studies have demonstrated that young age is an independent poor prognostic factor.[3] More recently, it has been shown that the effect of age on patients' outcomes may vary by breast cancer subtype, with a poor prognostic impact pertaining specifically to hormone receptor–positive disease.[4–9] However, in these studies, HER2 status was either not available or assessed only in a minority of patients, and modern anti-HER2 therapy was not routinely administered. Therefore, the numbers were too small to specifically evaluate the prognostic effect of age in patients with HER2-positive disease and if this can vary according to the co-expression of hormone receptors. Further, although current guidelines state that the use of anti-HER2 therapies should be the same regardless of age,[2] little evidence exists on their benefit in the specific cohort of young women.[10]

The largest prior analysis investigating the prognostic and predictive value of age in HER2-positive disease was conducted in the Herceptin Adjuvant (HERA) trial including 722 patients aged 40 years or younger at enrollment who received chemotherapy with or without trastuzumab.[11] At 2-year median follow-up, young age was not associated with worse survival outcomes regardless of trastuzumab administration, nor age was predictive of benefit from anti-HER2 therapy.[11] Nevertheless, follow-up was short, and no information was reported about a possible different effect of age according to the co-expression of hormone receptors.

Considering that treating young women with breast cancer is particularly complex with the risk of overtreatment based solely on age considerations, further research efforts to better investigate the prognostic and predictive value of age are urgently needed.[2] In the era of personalized medicine, the impact of age on outcomes and treatment effect should be controlled for biological features such as tumor subtype including, within the HER2-positive disease, the co-expression of hormone receptors.

The large phase III Adjuvant Perjeta and Herceptin IN Initial TherapY in Breast Cancer (APHINITY) trial led to the approval of adjuvant dual anti-HER2 blockade with trastuzumab and pertuzumab in patients with HER2-positive breast cancer at high risk of recurrence.[12,13] At a median follow-up of 74 months, the benefit of adding pertuzumab to trastuzumab was restricted to the cohort of patients with node-positive disease.[13] With 4805 randomly assigned patients, more than 6 years of median follow-up and central assessment of HER2 and hormone receptor status, APHINITY represented a unique opportunity to conduct the present analysis aiming to investigate the prognostic and predictive value of age in patients with HER2-positive disease treated with modern adjuvant chemotherapy and concurrent anti-HER2 targeted treatment.