Age, Subtype Impact Outcomes More Than Surgical Extent in Breast Cancer

Tari A. King, MD

The influence of age and the molecular subtype of breast cancer on surgical decision-making is complex. Although both impact the risk of local-regional recurrence and overall survival (OS), the increased risk seen with younger age at diagnosis differs among breast cancer subtypes, and a favorable interaction exists between older age at diagnosis and molecular subtype, according to a lecture given at the 15th St. Gallen International Breast Cancer Conference.

Tari A. King, MD, chief of Breast Surgery at the Dana Farber/Brigham Women’s Cancer Center, and Harvard Medical School, began her discussion by listing the biology and pathology features that occur more commonly in young women, putting them at higher risk of local recurrence and poorer survival: Younger women are more likely to have larger, higher-risk tumors that are poorly differentiated, and to also be both hormone receptor (HR) and HER2 negative.

One analysis of the effect of age on tumor subtype showed that the incidence of luminal tumors increases with age from 30% to 71% (P <.001), while the incidence of basal tumors decreases with age by 44% to 9% (P <.001). For example, among HR+/HER2- patients, younger women are less likely to have luminal A/B tumors compared to older women, 67% versus 86%, respectively (P = .006). In addition, among patients with triple-negative breast cancer (TNBC), younger patients were more likely than older patients to have basal-like tumors, 80% versus 57%, respectively (P = .003; Jenkins et al. Oncologist. 2014).

“This begs the question, is age an independent prognostic factor or is age simply a reflection of biology?” King asked.

In answer to this, King referred to a population-based analysis of 3046 patients younger than 50 years old. When the women were stratified into subgroups of <40 years and 40 to 49 years and evaluated according to molecular subtype, the survival curves showed a distinct relapse-free (RFS) and OS advantage in the older cohort for both HER2+ and HR+/HER2-negative subtypes. However, when women with TNBC were stratified into the same age groups, the RFS and OS curves were superimposed and showed no survival advantage to either age group.

In another analysis of 1915 patients younger than 40 years with luminal A, luminal B, HER2+, or TNBC, the risk of death by breast cancer subtype was determined as HR 2.1, 1.4, 1.2, and 1.4, respectively, in the same age groupv (Partridge et al. J Clin Oncol. 2016).

The incidence of local recurrence following breast-conserving treatment (BCT) was also seen to be dependent both upon age and molecular subtype. An analysis of local recurrence using data from the MD Anderson Cancer Center (MDACC) showed that over 27 years beginning in 1970, the rates of local recurrence decreased from 9.1% to 1.4% in patient ≤50 years old and from 2.6% to 1.2% in patients older than 50 years (P = .001; MDACC data base).

A multivariate analysis of 8-year local recurrence rates following BCT in 2233 patients revealed that recurrence was associated with subtypes luminal B (HR, 2.16), HER2 (HR, 5.42), TNBC (HR, 4.33), age ≤50 years (HR, 0.56) and increasing number of lymph nodes involved (HR, 1.06 per involved node). Recurrence rates were highest in the 23 to 46 year age groups for luminal A and B, luminal/HER2, and HER2 subtypes but local recurrence rates were highest for TNBC in the 64 to 88 year age group (Braunstein et al. BCRT. 2017).

This observation led King to discuss the relationship between TNBC and age that revealed distant recurrence rates in TNBC were highest in patients aged <40 years compared to those aged older than 40 years (P <.01). Neither disease-free survival (DFS) nor local recurrence was associated significantly with age (Radosa et al. Ann Sur Oncol. 2017).

“Bigger surgery did not result in better RFS outcomes in any subtype,” King remarked. When local recurrence in patients undergoing mastectomy was compared to BCT, the risk of recurrence was HR, 0.82; HR, 1.08; HR, 1.54; and HR, 0.87 for subtypes HR+/HER2-; HR+/HER2+; TNBC; and HR-/HER2+; respectively. This was supported by an analysis done by the British Columbia Cancer Agency in 965 patients aged 20 to 39 years that revealed similar outcomes following BCT and mastectomy (Cao et al. Int J Rad Oncol. 2014). “BCT was not associated with reduced survival,” King commented, “Only tumor location associated with poorer breast cancer specific survival and overall survival.

“Escalating therapy with bigger surgery does not beat bad biology,” King said, pointing out that neoadjuvant therapy may be a consideration in TNBC and HER2+ subsets, but not more extensive surgery.

On the contrary, findings from the CALGB 9343 trial indicate that treatment de-escalation may be possible. Comparisons of lumpectomy plus tamoxifen with or without radiotherapy in women aged >70 years with early breast cancer showed 5-year mastectomy-free survival and distant DFS rates above 98% in patients receiving tamoxifen plus radiotherapy versus tamoxifen monotherapy, with no statistically significant different between treatment groups (Jenkins et al. N Engl J Med. 2004.). Consistent findings were revealed in a 12-year update (Huges. J Clin Oncol. 2013).

“Opportunities exist for further treatment de-escalation in patients with favorable disease characteristics, based on traditional clinic-pathologic features or by molecular profiling,” King commented.

“Appropriate patient selection is necessary for decision making in BCT that includes referral for genetic testing and counseling,” King advised, “There is no evidence that mastectomy or bilateral mastectomy improves survival in women of any age or with breast cancer of any subtype.”

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“In fact, the 2013 SSO/ASTRO guidelines on margins for BCS with whole breast radiotherapy in stages I and II invasive breast cancer recommend that positive margins associate with a 2-fold increase and negative margins minimize the risk of ipsilateral breast tumor recurrence,” King said. “The guidelines further state that there is no evidence that wider margins are warranted in younger patients or in more aggressive subtypes (Moran et al. J Clin Oncol. 2014).