ASCO’s Early Breast Cancer Guidelines Updated to Include T-DM1

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The approval of adotrastuzumab emtansine prompted the American Society of Clinical Oncology to issue guidelines regarding the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer.

Amy Comander, MD

Amy Comander, MD

The approval of adotrastuzumab emtansine (T-DM1; Kadcyla) prompted the American Society of Clinical Oncology (ASCO) to issue guidelines regarding the selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer.1 ASCO’s multidisciplinary group of experts (Expert Panel) developed the previous guidelines based on the 2016 Cancer Care Ontario (CCO) guidelines.2 After releasing the findings from the KATHERINE trial (NCT01772472) in 2019, the panel reviewed and updated the guidelines to add 2 additional clinical recommendations. KATHERINE focused on patients with HER2-positive early breast cancer and residual disease after neoadjuvant chemotherapy. The update addressed 2 clinical questions regarding the administration of T-DM1 (FIGURE).3

Clinical question 1: Should adjuvant T-DM1 be administered after completion of standard preoperative chemotherapy and HER2-targeted therapy in all patients with HER2-positive breast cancer with residual invasive cancer in the breast or lymph nodes at surgery?

The short answer is yes. In an interview with Targeted Therapies in Oncology, Amy Comander, MD, an ASCO expert and hematologist-oncologist at Massachusetts General Hospital in Boston, discussed how KATHERINE’s results affected her approach to cancer care.

“The KATHERINE study demonstrated that for those patients with residual disease after neoadjuvant HER2-based therapy for HER2-positive breast cancer, the administration of postoperative T-DM1 compared with trastuzumab (Herceptin) for 14 cycles improved 3-year invasive disease-free survival. Thus, the introduction of the KATHERINE study has changed the way we treat patients with HER2-positive disease in the postoperative setting.”

Investigators found that adjuvant treatment with trastuzumab emtansine reduced the risk of invasive disease by 50% over the previously recommended treatment of trastuzumab.3 In the group who received T-DM1, 71.4% of patients finished all 14 cycles compared with the trastuzumab group, in which 81% of patients completed therapy. Although more patients completed therapy in the trastuzumab arm (77%), 3-year disease-free survival versus 88.3% for the T-DM1 group (HR, 0.50; 95% CI; 0.39-0.64; P < .001).

Moreover, the risk of recurrence for the T-DM1 group was 10.5% compared with the trastuzumab group at 15.9% (HR, 0.60; 95% CI, 0.45-0.79).4

In KATHERINE, 133 patients in the T-DM1 group had to discontinue the therapy, whereas only 15 had to discontinue because of adverse events. Of 133 patients in the T-DM1 group, 71 switched to the trastuzumab group, and as a result, 63 patients were able to finish all 14 treatment cycles.3 The most common adverse events were decreased platelet count (T-DM1 group, 28.5%; trastuzumab group, 2.4%), radiation-related skin injury (T-DM1 group, 27.6%; trastuzumab group, 25.4%), and peripheral sensory neuropathy (T-DM1 group, 6.9%; trastuzumab group, 18.6%).4

The Expert Panel determined that these data highlighted the need for multidisciplinary management of treatment for patients with HER2-positive breast cancer to ensure a more tailored approach to patient adjuvant therapy. The panel hopes that future studies focus on risk of recurrence to optimize outcomes for HER2-targeted therapies.3

They concluded: “Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity.”3

Clinical question 2: Among patients with HER2-positive breast cancer who receive adjuvant trastuzumab therapy, do trastuzumab, trastuzumab and hyaluronidaseoysk, and currently available FDA-approved biosimilars of trastuzumab differ regarding safety or efficacy?

Biosimilars, although potentially cheaper for patients, are not generic forms of name brand pharmaceuticals. For the FDA to consider it interchangeable, a biosimilar must be expected to produce the same clinical result as the reference product in any given patient and fulfill necessary safety requirements as outlined by the agency.5

Approved biosimilars for trastuzumab listed in the ASCO update include the following: trastuzumab-dkst (Ogivri), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dttb (Ontruzant), and trastuzumab- qyyp (Trazimera).

Being interchangeable is important. For example, Medicare part D plans and commercial payers provide coverage for oral biologics under their pharmacy benefit. These benefits dictate the out-of-pocket cost or cost sharing of preferred and nonpreferred drugs. If a biosimilar is defined as interchangeable, it falls under the generic drug pricing policies.4

However, if the biosimilar is not interchangeable, it could fall under a standalone, single-source product, which in turn could fall under nonpreferred policies. This may lead to it being denied by the insurance provider, leaving the patient to pay for it in full or seek another treatment option.5 Agreeing on a treatment option only to subsequently find out it is not covered wastes valuable time in initiating treatment. Although each price may be different depending on cost sharing, reimbursement rates, and other various factors, it is important to have different options available for patients. Proper education on which options are effective substitutions for more expensive treatments is also essential. High out-of-pocket costs can become a barrier in initiating or even finishing treatment plans. Biosimilars play a vital role in trying to mitigate that barrier.3

“Our patients are increasingly required to pay a larger proportion of their treatment costs through deductibles and coinsurance,” said Comander. “It is important to address our patients’ financial concerns as we make treatment recommendations.”

The Expert Panel concluded that, “Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.”3

The original 2016 ASCO guidelines provided numerous recommendations, including the use of trastuzumab in addition to chemotherapy in patients with higher-risk HER2-positive disease. Trastuzumab can be administered with any chemotherapy regimen, making it quite adaptable even before the option to use biosimilars became available.

For patients with HER2-negative breast cancer, the recommendations included the use of an anthracycline and taxane-based therapy.

So why not combine both approaches into 1 therapy regimen? The ASCO expert panel determined that the concurrent administration of trastuzumab with the anthracycline component of a chemotherapy regimen is not recommended due to the increased risk of cardiotoxicity. Instead, clinicians should only administer trastuzumab concurrently with a nonanthracycline chemotherapy regimen.2

If adverse events such as cardiotoxicity are a main concern, there is less cardiotoxicity with the 3-drug regimen of docetaxel, carboplatin, and trastuzumab than with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab, then docetaxel, carboplatin, trastuzumab. Docetaxel-cyclophosphamide for 4 cycles offers improved disease-free survival and overall survival when compared with doxorubicin for 4 cycles. However, as there is a higher risk of infection with docetaxel-cyclophosphamide for 4 cycles, the use of granulocyte colony stimulating factor is recommended.2 Although there is no strong evidence backing up this claim or efficacy data from trials, the Expert Panel concluded that an all-intravenous-based cyclophosphamide, methotrexate, and fluorouracil regimen delivered once every 21 days is very effective.2 This reasoning was based on the regimen’s accessibility and convenience, as patients could receive all their treatment at once in a much more tolerable avenue, which helped maintain patient compliance.

These recommendations will likely remain unless new biosimilars are developed. “The recommendation for use of T-DM1 in the postoperative setting for patients with residual disease after neoadjuvant treatment is unlikely to change, unless there is a different agent that is compared with T-DM1 in the postoperative setting and is shown to have greater benefit,” said Comander. Many patents for biologics expired in 2020, which is expected to spark a new wave of biosimilar development in the United States.5

Further Study

An area highlighted by the ASCO guidelines that needs further clarification concerns the roles of platinum salts in triple-negative breast cancers and the addition of pertuzumab (Perjeta) in HER2-positive disease. Investigators are awaiting the completion of trials to demonstrate survival benefits.2

“It would be useful to identify which patients with HER2-positive breast cancer can receive HER2-targeted therapies alone, and perhaps avoid chemotherapy. In addition, it would be useful to identify agents that can prevent CNS [central nervous system] recurrences in our patients with HER2-positive breast cancer.”

In conclusion, T-DM1 for the postoperative adjuvant treatment of HER2-positive breast cancers is promising. The guidelines also include approved biosimilars, as new agents have proved to be effective treatment options and can be cost effective for patients, depending on their insurance status. However, challenges regarding toxicity levels, drug-drug interactions, and cost-effective approaches to HER2-positive breast cancer treatment remain.


1. FDA approves ado-trastuzumab emtansine for early breast cancer. FDA. Updated May 6, 2019. Accessed January 21, 2021.

2. Denduluri N, Somerfield MR, Eisen A, et al. Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)-negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology Guideline adaptation of the Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. 2016;34(20):2416-2427. doi:10.1200/JCO.2016.67.0182

3. Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO Guideline update. J Clin Oncol. Published online October 20, 2020. doi:10.1200/JCO.20.02510

4. von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

5. Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: Biosimilars in Oncology. J Clin Oncol. 2018;36(12):1260-1265. doi:10.1200/JCO.2017.77.4893

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