Ado-trastuzumab emtansine: Avoiding side-effects of traditional HER2 positive breast cancer treatment

Clinical practice points

Importance of working with patient on finding treatment that is in line with their belief system

Introduction

HER2 positive breast cancer makes up approximately 15–20% of all breast cancers. ¹ Historically, HER2 positive breast cancer confers more aggressive clinical behavior and is associated with overall poor prognosis. ¹ Treatments targeted for HER2 have been noted to alter the natural course of the HER2-positive disease. ² This is why, it is important to understand and recognize the available treatment options. For treatment naïve patients, trastuzumab plus pertuzumab and a taxane are preferred. ³ Patients who are not appropriate candidates for taxane can be treated with trastuzumab and pertuzumab or ado-trastuzumab emtansine. ³ Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab, a thoether linker, and a microtubule inhibitor. ⁴ Ado-trastuzumab emtansine is now considered a second-line treatment agent for HER2 positive breast cancers. ⁵

We are going to use this case to illustrate approaches to HER2 positive breast cancer treatment and discuss possible alternatives to first-line therapies. Our patient chose to be on a second-line agent for multiple reasons explained in the case. She achieved significant improvement with minimal side effects.

Case presentation

A 70-year-old Russian-speaking female, former cardiologist trained in the former Soviet Union, was in her usual excellent state of health until early July of 2019 when she noticed bloody nipple discharge from her right breast. She palpated a mass, ipsilateral to the side of bleeding, and scheduled an appointment with her primary care physician. On initial presentation patient denied any pain, erythema or skin changes around the breast mass. On physical examination the right breast demonstrated that the nipple was erythematous with thinned epithelium, without overt evidence of skin retractions, edema or thickening. Patient had no evidence of lymphadenopathy, thyroid enlargement, nodularity or mass. There was a palpable mass in the right upper inner quadrant measuring at least two centimeters in size. Patient’s mammogram and ultrasound were graded as BI-RADS category five. Mammogram showed primary mass and satellite lesions in the two- to three-centimeter range, which were highly concerning for breast cancer (Figure 1). Patient’s MRI of bilateral breasts was graded as BI-RADS category six. Right breast showed enhancing mass 1.8 × 2.4 × 1.8 centimeters highly suspicious for cancerous lesion (Figure 2). Patient had no previous breast biopsies or surgical interventions. She had no family history of breast cancer or other malignancies. Given nipple involvement as well as rapid onset of her symptoms, patient was referred to a surgeon for high suspicion of HER2 or triple negative biology. Ultrasound guided biopsy was performed that revealed poorly differentiated histologic grade three and nuclear grade three invasive ductal carcinoma. The tumor was HER2 three plus positive, ER negative, and PR negative.

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Figure 1.

Bilateral diagnostic mammogram with CAD. In the right upper quadrant, there were two lobulated masses adjacent to each other, bother labeled with green. The larger lesion measured about 1.8 cm and the smaller about 0.9 cm. Entire area of involvement was over 3 cm, as marked. This film was a BI-RADS Category 5 and upon later biopsy has confirmed HER2/neu positive breast cancer.

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Figure 2.

MRI breast bilateral with and without contrast. Right breast: there was a 1.8 × 2.4 × 1.8 cm dominant enhancing mass. A smaller mass is seen just adjacent abutting the anterior margin of the dominant mass. Total AP dimension of the two masses combined is 5.4 cm. BI-RADS Category 6.

She remained otherwise symptom free but was complaining of moderate left hip pain, which on staging CT and bone scan (Figure 3) turned out to be a left pubic ramus metastatic disease. A bone biopsy of the pubic ramus was positive for metastatic breast cancer. Patient tested negative for BRCA1 and BRCA2.

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Figure 3.

NM Bone Image Scan demonstrated a probable healed/healing fracture involving the left superior pubic ramus. In the inferior pubic ramus was an extensive destructive process which is worrisome for a neoplastic lesion. This could be an unusual metastasis or possibly a primary bone tumor. When biopsies, turned out to be metastatic HER2 disease.

Patient was resistant to neoadjuvant chemotherapy and anti-HER2 therapy and had rather preferred bilateral radical mastectomies. She stated it was a common practice of managing breast cancer back when she was in training and that’s what she believed to be the most effective therapy. Another reservation she had with chemotherapy was hair loss that she wanted to avoid at all costs.

Patient had multiple discussions with her oncologist regarding need for systemic chemotherapy prior to surgery. Patient was informed that cytotoxic chemotherapy with anti-HER therapy, trastuzumab and pertuzumab would significantly decrease her risk of recurrence and improve her chances of survival. She was also informed that chemotherapy when given before the surgery can lead to significant downstaging of the primary tumor with improvement in chances of obtaining clear margins. As part of treatment option discussions, patient was informed of KATHERINE study. ⁶ The study showed that patients with residual breast cancer following neoadjuvant chemotherapy with anti-HER2 therapy had significant improvement in their disease-free survival when treated with T-DM1 versus continuing the same anti-HER2 therapy. ⁶ Although our patient did not meet the KATHERINE study criteria of having residual breast cancer following first-line therapies, she felt like it was the most appropriate treatment as she believed it did not involve cytotoxic chemotherapy. It is unclear if patient was aware that T-DM1 is a potent chemotherapeutic agent connected via stable linker to the anti-HER2 antibody, trastuzumab. Because her insurance would not cover a second-line treatment, patient went directly to the pharmaceutical company and was able to obtain a full course of T-DM1. Given the patient’s aversion to cytotoxic chemotherapy, radiation therapy to the left pubic ramus was offered to prevent a fracture and to control her metastatic disease. It was decided to proceed with T-DM1 as well as radiation therapy to the left pubic ramus.

Patient completed eleven cycles of T-DM1 treatment, which she tolerated remarkably well. She noticed decreased size of the right breast mass and denied any new masses, lymphadenopathy, neurological deficit or focal bone pain. Repeat MRI of the breast showed complete treatment response (Figure 4.) and lack of visualization of previously contrast enhanced lesion. Energy level was good, as was her appetite. The patient denied having fevers, chills, headaches, chest pain, palpitations, dyspnea, abdominal pain, nausea, edema, and peripheral neuropathy. CEA as well as CA-27.29 remain normal.

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Figure 4.

MRI breast bilateral with and without contrast. Right breast: Known, biopsy-proven malignancy. Non-visualization for the enhancing masses consistent with biopsy-proven carcinoma at 2:00 posterior depth. Findings are consistent with complete treatment response. BI-RADS Category 6.

Discussion

There are a number of target HER2 receptor therapies. Trastuzumab is a monoclonal antibody that binds the extracellular domain of HER2. ⁷ Pertuzumab is a monoclonal antibody that binds the extracellular dimerization domain of HER2 and is usually administered together with trastuzumab rather than as a single agent. ⁸ T-DM1 is an antibody-drug conjugate composed of trastuzumab and the antimicrotubule agent, DM1. ⁴ Lastly, there is Lapatinib – a tyrosine kinase inhibitor against EGFR1, 3 and 4 as well as HER2 that results in inhibition of signaling pathways downstream of HER2. ⁹

In patients with metastatic HER2-positive disease, HER2-directed therapy is essential. For most patients HER2-targeter therapy is combined with chemotherapy. We will specifically discuss treatment of HER2-positive, hormone receptor-negative metastatic breast cancer, as it was the one our patient presented with. This treatment is divided into previously treated versus previously untreated patients. For previously untreated patients, trastuzumab plus pertuzumab and taxane is preferred. ³ For patients who are not taxane candidates for any reason, there is limited data on alternative treatment options. These patients usually receive a different chemotherapy with trastuzumab and pertuzumab or T-DM1. ³ Currently T-DM1 is considered second-line treatment. ⁵ There was a phase III MARIANNE trial, however, in 2019 that re-evaluated the role of T-DM1 as a first-line treatment of advanced or metastatic HER2-positive breast cancer. ¹⁰ This trial enrolled over 1000 women with progressive or recurrent locally advanced breast or previously untreated metastatic breast cancer. ¹⁰ Patients were randomly assigned to trastuzumab plus a taxane (arm 1), T-DM1 plus placebo (arm two), or T-DM1 plus pertuzumab (arm three). ¹⁰ Based on the collected data, there was no significant difference in progression free survival in arm one (HR 0.91, 97.5% CI 0.73–1.13), arm three compared with arm one (HR 0.87, 97.5% CI 0.69–1.08), or between arm three and arm two (HR 0.91, 97.5% CI 0.73-1.13). ¹⁰ The objective response rate (ORR) in the three arms was 68, 60, and 64%, respectively. ¹⁰ Side effects and toxicities such as neutropenia, neuropathy, and peripheral edema were reported less frequently in the non-taxane arms. ¹⁰ In particular, alopecia was much less common in the non-taxane arms (60% with taxane versus 7% with T-DM1 and 9% in T-DM1 plus pertuzumab). ¹⁰ Liver function test abnormalities, however, were much more commonly reported in the T-DM1 arms. ¹⁰

Conclusions

We presented a case of a patient who had specific reservations to first-line therapies for HER2 positive breast cancer. Her medical team worked on finding alternative treatment that would be feasible with patient’s overall goals. Recent studies discussed in this case showed that first-line therapies don’t have significant progression free survival advantage when compared to the second-line therapy that our patient received. Patient’s personal beliefs led her to choose a therapy that would have otherwise been a second-line treatment, but results showed that her disease responded appropriately to the treatment and had minimal side effects. More studies need to be done to further investigate positive result presented in this case and whether this could be considered an alternative to current first-line therapy.