Treatment Options From 5 Experts on Neoadjuvant and Adjuvant Therapy for HER2-Positive Early Breast Cancer: An Online Tool

Frankie Ann Holmes, MD, FACP
Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Mark D. Pegram, MD
Denise A. Yardley, MD
Released: March 19, 2019

Additional Considerations

This Interactive Decision Support Tool for HER2-positive early breast cancer does not provide a comprehensive list of all potentially acceptable treatment regimens, as these can be found in other resources. It is beyond the scope of the tool to list and consider every potential neoadjuvant or adjuvant therapy option for breast cancer. As such, the faculty have narrowed the potential neoadjuvant and adjuvant therapy choices to the most common treatment options for patients with this disease.

Many factors can influence the choice of treatment for an individual. This Interactive Decision Support Tool assumes you are a “standard” patient with HER2-positive early breast cancer, who is medically fit enough to tolerate therapy and has no characteristics other than those specified within the tool that would affect treatment decisions.

Considerations for Age and Comorbidities
According to the St Gallen International Breast Cancer Consensus Guidelines, there is no specific age limit for the use of adjuvant chemotherapy for people with early breast cancer, and your oncologist should base his/her decision on your individual health status, risk of cancer recurrence, the likely benefit of therapy, and your preferences.[5] When considering treatment for older people, it is important to consider the risk of breast cancer recurrence or death compared with other causes of death or serious illness and weigh the impact of disease and possible treatment-related side effects with any other major health concerns.[6]

Some studies have suggested that patients older than 65 years of age who are receiving chemotherapy are more likely to experience grade 3 or higher side effects, more frequent hospitalization, and more cardiac side effects after trastuzumab (Herceptin®) therapy compared with younger patients.[7,8] Studies specific to patients with HER2-positive early breast cancer have also suggested that advanced age and preexisting heart disease are risk factors for cardiotoxicity.[9,10] However, after 11 years of follow-up, the HERA trial (N = 5102) did not show this association, possibly due to the trial design allowing for tailoring of chemotherapy to age and comorbidities.[11] In addition, the APT trial showed that “de-escalated” adjuvant therapy with paclitaxel (Taxol®) plus trastuzumab (Herceptin®) is efficacious (effective) for patients with small, node-negative HER2-positive early breast cancer and showed an incidence of heart failure of only 0.5%.[12]

If you are an older patient, your oncologist should consider using the Comprehensive Geriatric Assessment (CGA) to determine whether you can or cannot safely receive treatment for early breast cancer. The CGA may be preferable to the Eastern Cooperative Oncology Group performance status for reducing hospitalization and mortality in older patients receiving treatment for breast cancer.[6]

In addition to age and overall fitness, your specific comorbidities are an important factor that should be taken into consideration when choosing a neoadjuvant or adjuvant therapy regimen. Patients with comorbidities may require treatment regimens known to have a relatively good safety profile in order to diminish toxicity and stress.

This tool asks about diarrhea, rash/skin side effects, and LVEF changes (a measure of heart function), as these comorbidities can affect treatment choice. Additional comorbidities that are of particular concern with breast cancer treatment include osteopenia or osteoporosis, anemia, neutropenia, other heart conditions, neuropathy, and metabolic disorders such as diabetes.

Diarrhea has been associated with some HER2-targeted therapies, including pertuzumab (Perjeta®) and neratinib (Nerlynx®). It is more common with trastuzumab (Herceptin®)/pertuzumab (Perjeta®) vs trastuzumab (Herceptin®) alone (61% vs 34%, respectively). Data from the phase III APHINITY trial showed that rates of grade 3 diarrhea ranged from 8% to 18% with pertuzumab (Perjeta®), with more patients experiencing diarrhea on nonanthracycline-based chemotherapy.[13] Hydration, diet modifications, and antidiarrheal medication can all help manage pertuzumab (Perjeta®)-induced diarrhea, if you experience this while on trastuzumab (Herceptin®)/pertuzumab (Perjeta®) therapy. Delay or discontinuing (stopping) trastuzumab (Herceptin®)/pertuzumab (Perjeta®) therapy is generally not necessary for pertuzumab (Perjeta®)-associated diarrhea.

In the ExteNet trial with neratinib (Nerlynx®), most patients experienced diarrhea, with 40% of patients reporting grade 3 events.[14] Antidiarrheal prophylaxis (medication given before symptoms begin) helps reduce the rate of grade 3 diarrhea associated with neratinib (Nerlynx®). With loperamide (Imodium®) alone, the risk of grade 3 events was reduced from 40% to 31%, and the addition of a second antidiarrheal medication, either budesonide (Entocort EC® or Uceris®) or colestipol (Colestid®), further reduced the rate of grade 3 diarrhea to 25% or 11%, respectively.[15]

Hydration, diet modifications, and prophylactic antidiarrheal medication should be discussed with your oncologist if you are considering treatment with neratinib (Nerlynx®). Currently, loperamide (Imodium®) is recommended as an initial prophylactic antidiarrheal and can be started with the first full dose of neratinib (Nerlynx®).

Timing and dosing frequency of antidiarrheal medication can be adjusted as your risk for diarrhea subsides or if you experience constipation. If you do experience diarrhea, you should tell your oncologist and discuss the best way to manage your symptoms. In general, antidiarrheal medication should be taken after each diarrhea episode and a second antidiarrheal medication can be added as needed.

If you experience grade 2 diarrhea (4-6 bowel movements per day) lasting 5 days or more, grade 3 diarrhea (7 or more bowel movements per day) lasting 2 days or more, or any-grade diarrhea with complicated features, your oncologist may recommend stopping neratinib (Nerlynx®) until diarrhea resolves to grade 1 or better (fewer than 4 stools per day). If diarrhea resolves in 1 week or less, neratinib (Nerlynx®) can be resumed at the current dose. If diarrhea resolves in 8-21 days, neratinib (Nerlynx®) can be resumed at a reduced dose of 120 mg/day. Neratinib (Nerlynx®) should be permanently discontinued if you experience grade 4 diarrhea or grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Your oncologist may ask you about bowel function before initiating therapy with pertuzumab (Perjeta®) or neratinib (Nerlynx®), as many patients will not initiate this discussion. In addition to diarrhea, constipation can also occur while receiving antidiarrheal medication, particularly when using a prophylactic antidiarrheal with neratinib (Nerlynx®) therapy, since diarrhea typically begins on approximately Day 5. Close monitoring and discussion with your oncologists and other physicians are important to ensure that you are feeling well, particularly during the first few weeks of therapy.

Rash and/or Skin Side Effects
You may experience rash and other skin-related side effects while receiving pertuzumab (Perjeta®) and trastuzumab (Herceptin®). In the phase III APHINITY trial, rash occurred in 26% of patients receiving anthracycline-based chemotherapy plus trastuzumab (Herceptin®)/pertuzumab (Perjeta®), 25% of patients receiving nonanthracycline-based chemotherapy plus trastuzumab (Herceptin®)/pertuzumab (Perjeta®), and 21% of patients receiving anthracycline-based chemotherapy plus trastuzumab (Herceptin®) alone.

Pertuzumab (Perjeta®)-associated skin side effects (rash, nail disease, pruritus/itching, and dry skin) is usually grade 1 or 2 and typically resolves after treatment with systemic or topical medication (medication applied directly to the affected area). Topical steroids can be used for patients experiencing rash, antibiotics can help manage nail disease, and antihistamines can be used for patients who have itching.

Acneiform rash is an acne-like rash that can occur and should be managed appropriately. If you have grade 1 or 2 acneiform rash, your oncologist may recommend topical treatment with clindamycin and hydrocortisone ointment. If you have grade 2 acneiform rash, your oncologist may recommend oral doxycycline for at least 4 weeks or until rash improves along with topical treatment. Antihistamines can also be added for any associated pruritus (itching). If you experience grade 3 acneiform rash, your oncologist may recommend holding your therapy with pertuzumab (Perjeta®) (and trastuzumab [Herceptin®]) and treat as for grade 2. If your rash improves, therapy can resume.

Prophylactic management (before you have symptoms) can also be helpful and includes showering with warm water and avoidance of prolonged hot bathing causing softened or “wrinkled” skin (maceration); frequent use of oil, hypoallergenic lotion, and/or emulsions to prevent dry skin and irritation; and avoidance of injury or damage to the nail bed, including procedures such as manicures or pedicures.

Cardiac Dysfunction
Some of the chemotherapeutic agents used for patients with early breast cancer have the potential to cause acute and chronic cardiovascular complications. For example, anthracyclines, like doxorubicin (Adriamycin®), can increase risk of developing of heart disease such as congestive heart failure and cardiomyopathy (diseased heart muscles). The addition of trastuzumab (Herceptin®) may increase that risk further. Alkylating agents, such as cyclophosphamide (Cytoxan®), can also cause cardiac damage. Treatment with taxanes, such as paclitaxel (Taxol®) or docetaxel (Taxotere®), may increase risk for arrhythmias (irregular heartbeat), particularly bradycardia and, more rarely, myocardial ischemia. Overall, the risk of cardiotoxicity increases with higher doses of chemotherapy, prior anthracycline therapy, a history of mediastinal (chest) radiation, and older age.

As mentioned, trastuzumab (Herceptin®) and, to some extent, pertuzumab (Perjeta®) can also increase risk for cardiotoxicity and this risk is increased when additional cardiovascular risk factors are already present.

Of importance, the cardiotoxic effects of trastuzumab (Herceptin®) can be reversible if identified early through close monitoring during administration. Cardiotoxicity typically occurs in fewer than 3% of patients, but baseline left ventricular ejection fraction (LVEF) assessment should be performed on all patients who are planning treatment with trastuzumab (Herceptin®) with or without pertuzumab (Perjeta®) therapy. LVEF is a measure of heart function, specifically the amount of blood pumped out of the left ventricle of your heart. There are several ways your oncologist can measure this, including an echocardiogram. These routine tests are used to take a closer look at heart function, and there are specific guidelines that your doctors should follow to catch heart problems caused by cancer treatment in the years following treatment.

Pretreatment LVEF levels should be at least 55% (or at least 50% after anthracyclines) to safely begin trastuzumab (Herceptin®) with or without pertuzumab (Perjeta®). LVEF should also be monitored every 12 weeks during therapy, and if LVEF decreases to less than 50% with at least 10% decrease from baseline, trastuzumab (Herceptin®)/pertuzumab (Perjeta®) therapy should be held for at least 3 weeks until LVEF values improve.

Managing Bone Health
Because this tool is only addressing efficacy endpoints and not supportive care issues, it should be acknowledged that guidelines suggest that a bone mineral density scan should be conducted and bisphosphonate treatment implemented when appropriate. Bone mineral density testing can help diagnose osteoporosis and assess the risk of fractures. Patients with a low bone mineral density may have a higher risk of fractures whereas patients with normal bone mineral density likely have a lower risk of fractures. However, some data suggests that hormonal and other factors that can lead to higher bone mineral density can also lead to higher risk of breast cancer over a woman’s lifetime.

Bisphosphonates are a drug class that prevent, reduce, and delay skeletal complications in patients with cancer. Clinical trial data have demonstrated that without treatment to prevent skeletal-related events (such as pathologic fractures, spinal cord compression, and the need for bone irradiation or surgery), 64% of women with breast cancer and bone metastases will experience a skeletal-related event.[16]

In addition to preserving and rebuilding bones, bisphosphonates may also have a direct antitumor effect for some patients. In one study, the use of bisphosphonates in the adjuvant setting reduced the risk of recurrence by 14%, distant recurrence by 18%, and the risk of breast cancer death by 18% in postmenopausal women with early breast cancer.[17] These results were similar regardless of ER status, nodal status, and whether or not they received chemotherapy. However, no effects on disease outcome were observed in premenopausal women.

Denosumab (XGEVA®) is an antibody to RANKL that is also used to improve bone mineral density and thereby reduce the risk of fractures or other skeletal-related events in patients with breast cancer.

Both zoledronic acid (Zometa®) and denosumab (XGEVA®) have been shown to reduce the incidence of skeletal-related events and delay progression of bone pain, which helps minimize the need for pain medication.[18] However, bone pain is often underreported in patients with breast cancer and some patients with breast cancer do not receive bone-targeted therapy early enough to prevent skeletal-related events and minimize pain.

In large studies of patients with metastatic breast cancer, denosumab (XGEVA®) has been demonstrated to be superior to zoledronic acid (Zometa®) for preventing skeletal-related events.[19] The phase III D-CARE study evaluated the addition of denosumab (XGEVA®) vs placebo to neoadjuvant or adjuvant therapy for patients with high-risk early breast cancer (N = 4509) and showed a reduced risk of first recurrence in bone and a reduced risk of fracture or skeletal-related events (both secondary endpoints). However, the primary endpoint of bone metastasis–free survival (defined as the first bone metastatic event confirmed by central imaging or death) was not significantly different with denosumab (XGEVA®) vs placebo.

Ki-67 Consideration
Ki-67 expression can measure breast cancer cell proliferation (growth) and has become an important biomarker oncologists can use to help guide treatment choices in patients with early breast cancer.

Patients with high histologic grade and high Ki-67 expression are more likely to have tumor present in their lymph nodes and experience other changes in their breast cancer tumor cells (eg, gain of HER2 or hormone receptor expression).[20] In addition, a high amount of Ki-67 in tumor cells has been shown to be predictive of pathologic CR to neoadjuvant chemotherapy and of shorter relapse-free survival in a recent meta-analysis (N = 6793 patients in 36 studies).[21] Likewise, a 10-study meta-analysis showed that Ki-67 expression was significantly predictive of recurrence of invasive and noninvasive breast ductal carcinoma in situ.[22] Some experts also take Ki-67 expression into consideration during treatment decisions for their patients with HER2-positive early breast cancer, but that discussion is beyond the scope of this tool.


Disclaimer: Access to and use of this Interactive Decision Support Tool titled, “Treatment Options From 5 Experts on Neoadjuvant and Adjuvant Therapy for HER2-Positive Early Breast Cancer,” is provided subject to the following terms and conditions. PLEASE READ THESE TERMS CAREFULLY.

The “Treatment Options From 5 Experts on Neoadjuvant and Adjuvant Therapy for HER2-Positive Early Breast Cancer” Interactive Decision Support Tool is designed to educate patients on optimal regimens for HER2+ early breast cancer, based on specific patient and disease characteristics. The information provided is based on the expert guidance of breast cancer experts Frankie Ann Holmes, MD, FACP; Sara Hurvitz, MD, FACP; Joyce O’Shaughnessy, MD; Mark D. Pegram, MD; and Denise A. Yardley, MD.

Although the information contained in the “Treatment Options From 5 Experts on Neoadjuvant and Adjuvant Therapy for HER2-Positive Early Breast Cancer” Interactive Decision Support Tool has been produced and processed from sources believed to be reliable, no warranty, expressed or implied, is made regarding the accuracy, adequacy, completeness, legality, reliability, or usefulness of any information. Patients should always discuss their healthcare decisions with their oncology care team. This disclaimer applies to both the isolated and aggregate uses of the information. Clinical Care Options provides this information on an as-is basis. This disclaimer applies to all data on the Clinical Care Options Web site including but not limited to medical information or opinions. All warranties of any kind, expressed or implied, including but not limited to the implied warranties of merchantability, fitness for a particular purpose, freedom from contamination by computer viruses, and noninfringement of proprietary rights are disclaimed.

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