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Young women account for a relatively small proportion of breast cancer patients, but they are more likely to present with aggressive subtypes, including HER2-positive and advanced disease.

Independent predictive factors for overall survival in young (usually defined as under age 40) female breast cancer patients include tumor size, hormone receptor (HR) status, surgery, adjuvant therapies, lymph node status, and race.

Controlling for those known prognostic factors, young women with HER2-positive breast cancer merit similar treatments and experience similar outcomes as older women once diagnosed. "There is no adverse effect on prognosis in HER2-positive early breast cancer, when treated with current standard regimens, based on age," said Charles E. Geyer Jr., MD, of the University of Pittsburgh School of Medicine.

A recent using the Surveillance, Epidemiology, and End Results (SEER) database indicated younger women have the same benefits from therapy as older women for HER2-positive and triple-negative early breast cancer. Researchers led by Ann Partridge, MD, of Dana-Farber Cancer Institute in Boston, examined data for 271,173 women with stage I-III breast cancer from 2010 through 2015, including 14,109 women who were under age 40. Using regression models to account for competing risks, they examined the risk of breast cancer-specific death by age and clinical subtypes and considering grade, hormone receptor, and HER2 status, with adjustment for demographic, clinical, and treatment variables.

After controlling for those variables, young age was significantly associated with an increased risk of breast cancer mortality among women with HR-positive, lower grade disease (HR 1.7, 95% CI 1.4-2.1) but not for women with HR-positive/high-grade, HER2-positive, or triple-negative disease. The researchers confirmed that in women with HER2-positive or triple-negative breast cancer, there was no clear increased risk of breast cancer mortality among women under age 40 years compared with middle-age women.

In terms of treatment, the introduction of trastuzumab (Herceptin) revolutionized the way oncologists treat patients with HER2-amplified breast cancer. "Its use in the neoadjuvant and adjuvant setting has dramatically improved the survival of women with this disease subtype," said Julie Fisher, MD, of Atrium Health Levine Cancer Institute in Charlotte, North Carolina. Combined with chemotherapy, it has substantially reduced risk for recurrence and death in women of all ages with early HER2-positive breast cancer.

"The majority of women who develop HER2-positive early breast cancer can be cured of their disease with HER2-targeted therapies. Trastuzumab is a core component of therapy, with benefit from adding pertuzumab [Perjeta] in patients with involvement of axillary and other regional lymph nodes at presentation," said Geyer.

Young patients with small (less than 1 cm) node-negative, HER2-positive primary disease are treated with surgery and adjuvant paclitaxel and trastuzumab. Patients with tumors 2 cm or greater or positive lymph nodes at presentation receive neoadjuvant therapy with trastuzumab and pertuzumab in combination with chemotherapy, most commonly carboplatin with docetaxel. "If there is no residual cancer found at surgery, they complete a year of trastuzumab with pertuzumab," said Geyer.

Patients with tumors 1 to 2 cm in size can undergo initial surgery or receive neoadjuvant therapy using the above regimens. "This offers us the opportunity to minimize the surgical intervention in the breast and downstage the axilla. Most importantly, it allows us to assess the response to treatment," said Fisher.

A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (Phesgo) was approved by the FDA in 2020. This subcutaneous formulation has demonstrated as the IV formulations of these therapies when combined with chemotherapy in the neoadjuvant setting.

"Cancer treatment can feel like an all-consuming endeavor for women going through it. Younger patients are often juggling their cancer treatment with active careers and childcare responsibilities," said Fisher. "Subcutaneous formulations of HER-2 targeted treatments allow them to reclaim some of their time. I want patients living their fullest lives and spending as little time as possible in the infusion suite. Subcutaneous delivery of medication helps make that possible."

If young women have residual invasive cancer, they receive 14 doses of the antibody-drug conjugate trastuzumab emtansine (T-DM1, Kadcyla), said Geyer. The trial in invasive HER2-positive breast cancer found that young women with residual disease after neoadjuvant therapy who received adjuvant T-DM1 had superior 3-year invasive disease-free survival as compared with trastuzumab alone (86.5% vs 74.9%) among the 296 patients younger than age 40.

"The bottom line on the KATHERINE study was the benefits of administration of T-DM1 were essentially a 50% reduction in risk of cancer recurrence or death," Geyer said. "The improvement in invasive disease-free survival with T-DM1 for the older groups was very similar to the younger group."

Factors other than age alone impact an individual patient's degree of risk for recurrence, such as extent of disease at diagnosis and presence of positive axillary nodes at surgery. "Groups with these risk factors have a higher risk for recurrence than other groups, both with standard therapy and with T-DM1," said Geyer, who emphasized that age is not considered an independent risk factor for outcomes with HER2 targeted therapy or T-DM1.

"This is an exciting time to be treating young patients with HER2-positive breast cancer. New drugs and regimens continue to benefit patients," said Fisher. "Now we also find ourselves in the position of fine-tuning existing therapies in a way that improves outcomes and maximizes patients' quality of life. Our goal is for patients to live long, fulfilling lives despite their cancer diagnoses."

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