When early-stage breast cancer regimens are based on an individual patient’s risk, there may be an opportunity to improve outcomes while mitigating severe side effects, too.
Patients with early-stage breast cancer may be able to have their treatment personalized to their individual level of risks now that there are four HER2-targeted treatments in the space: Herceptin (trastuzumab), Perjeta (pertuzumab), Kadcyla (ado-trastuzumab emtansine; T-DM1) and Nerlynx (neratinib).
In doing so, outcomes will continue to improve for this patient population, and some patients may have an opportunity to be on a regimen that causes fewer side effects, explained Dr. Sara A. Hurvitz in a presentation at the 39th Annual Miami Breast Cancer Conference®.
“Despite successes (in the Herceptin era), it’s important to note that recurrences do happen, and they may occur late. Up to 20% of patients will experience a disease recurrence by year 10 despite (having received) Herceptin-based therapy,” Hurvitz, an associate professor at the David Geffen School of Medicine at University of California, Los Angeles (UCLA) and director of the Breast Cancer Clinical Trials Program at UCLA, said during the presentation. “The question is: How do we identify patients who need more (therapy) and how do we know when enough is enough?”
Response Over Size
Hurvitz explained that the size of a patient’s tumor, as well as the timing of systemic therapy (those that travel the blood stream, reaching cells all over the body), either in the pre-surgical or post-surgical setting does not appear to be a contributing factor for determining treatment outcomes.
“We know that giving systemic therapy before surgery yields the same long-term outcomes as giving it after surgery. Even (those with) very small tumors benefit from a HER2-targeted therapy approach,” Hurvitz said.
What does matter, according to Hurvitz, is use of response-guided approaches for these patients.
“A response-type approach allows us to start with a less toxic therapy and switch to a severe regimen if the tumor does not respond appropriately,” she said. “We now know that residual cancer after (pre-surgical) systemic therapy is prognostic and predictive and predictive of benefit from (post-surgical Kadcyla).”
For example, Hurvitz pointed to the practice-changing data from the KATHERINE trial (NCT01772472), which showed that patients with HER2-positive disease who had residual disease following pre-surgical therapy and received Kadcyla after surgery had a 50% reduction in the risk of death compared with those who received post-surgical Herceptin.
Specifically, the estimated three-year invasive disease-free survival (iDFS; defined as how long a patient lives after therapy without developing invasive disease) rate among the 743 patients who received Kadcyla after surgery was 88.3% compared with 77% among those who received Herceptin after surgery. At three years, 89.7% of patients who received Kadcyla did not have distant recurrences, compared with 83% of those on Herceptin.
The benefit extended to those patients with clinically small tumors. Those with stage ct1 tumors, which can’t be seen on imaging or felt by a clinician, who received Kadcyla (99 patients) had a three-year iDFS rate of 94.8% compared with 83.4% for those treated with Herceptin (81 patients).
Among those with stage ct2 tumors, which are slightly larger, those who received Kadcyla (365 patients) had a three-year iDFS rate of 90.4% compared with 82% among those who received Herceptin (389 patients). Further, an improved benefit was observed with Kadcyla over Herceptin among those whose disease did not spread to the lymph nodes.
In contrast, data from other trials that included patients with both high-risk and low-risk disease, such as the APHINITY trial (NCT01358877), demonstrate the importance of selecting populations who would benefit from additional treatment. A small benefit was observed among those treated with the HER2-directed therapy Perjeta versus placebo, which Hurvitz noted might not be enough to justify the side effects associated with Perjeta in this patient population.
The pre-surgical setting is also where clinicians can omit the use of riskier regimens, such as the use of anthracycline-based therapy, Hurvitz said. For patients with stage 2 or stage 3 tumors, pathological complete response (pCR; where there are no detectable cancer cells in a tissue sample) has become a standard measure to individualizing therapy before a patient undergoes surgery. For patients with early-stage disease, Hurvitz highlighted that a similar tactic can be applied to mitigate risk.
“Some of the first data suggesting a benefit from the use on nonanthracycline-based regimen came from TRYPHAENA (NCT00976989), a phase 2, randomized trial which (evaluated) the cardiac safety of regimens including the TCHP (docetaxel, carboplatin, Herceptin, Perjeta) regimen versus the anthracycline-based regimen FEC/HP (5-fluorouracil, epirubicin, cyclophosphamide/Herceptin plus Perjeta) followed by THP (docetaxel, Herceptin, Perjeta),” Hurvitz said.
The pCR rate was higher among those who received the nonanthracycline regimen when compared with those who did not, and the disease-free and progression-free survival rates were similar between the two groups.
Results of several studies in the pre-surgical setting using adaptative strategies with Herceptin/Perjeta as a backbone showed that pCR rates were above 50% for patients with early-stage disease.
Recommendations in the National Comprehensive Cancer Network Guidelines reflect the trend in comparable data with fewer adverse effects listing nonanthracycline regimens — paclitaxel plus Herceptin, TCH or TCHP — as preferred treatment options for patients with HER2-positive disease in the preoperative and adjuvant settings.
“The anthracycline-based regimens were moved to the ‘useful in certain circumstances’ category,” Hurvitz noted.
Is Less More?
In terms of moving the needle toward less treatment, Hurvitz reviewed data from trials evaluating the adjuvant use of Herceptin in patients with stage 1 disease to de-escalate chemotherapy therapy and preserve patient quality of life.
The APT trial (NCT00542451) evaluated Herceptin plus paclitaxel for 12 weeks followed by single-agent Herceptin for nine months in 410 patients with HER2-positive tumors measuring 3 cm or less. At a median follow-up of 7.5 years, the seven-year DFS rate was 93.3%.
Despite the success at seven years, Hurvitz noted that recurrences are still occurring, but that this treatment may be useful in the neoadjuvant setting to help patients who might be at a higher risk for recurrence.
In patients with estrogen receptor–positive, HER2-positive breast cancer, decreasing chemotherapy versus endocrine therapy plus Perjeta plus Herceptin was evaluated in the phase 2 WSG TP-II trial. A pCR was observed in 24% of patients who received endocrine therapy (96 patients) compared with 57% of those treated with de-escalated paclitaxel (102 patients).
A similar study was designed and executed for patients with hormone receptor–negative, HER2-positive disease. In the phase 2 WSG-ADAPT HER2+/HR− trial (NCT01779206), investigators evaluated the efficacy of Herceptin plus Perjeta with or without paclitaxel in the pre-surgical setting. The pCR rate among 42 treated patients in either group was 90.5% with the addition of paclitaxel compared with 36.3% with Herceptin and Perjeta alone.
As for whether chemotherapy can be omitted entirely, Hurvitz said, “Yes, (providers) can do it and achieve CRs without the use of chemotherapy although the pCR rates are fairly low.”
Hurvitz added that she would not advocate for this approach outside of a clinical trial.
“I do advocate for trials that continue to push the envelope and do de-escalation for lower-risk patients perhaps those with hormone receptor–positive, node-negative tumors,” she concluded
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A version of this article was originally published on OncLive as, “Risk-Adaptive Approaches Offer Safer, Effective Strategies for Early-Stage HER2+ Breast Cancer.”