Herceptin has improved survival for women with HER2-positive breast cancer. Now, scientists are exploring ways to mitigate the heart problems the drug can cause.
MARGARET ISLEY - PHOTO BY FIONA WILSON
When told by an oncologist that her breast cancer tested HER2-positive in June 2011, Margaret Isley didn’t quite understand the magnitude of such a diagnosis. And perhaps she partly wanted to keep it that way, for her own peace of mind. Normally, HER2 (human epidermal growth factor receptor 2) proteins play a key role in healthy breast cell development and repair. In about one in five patients with breast cancer, the cells make too many HER2 proteins, leading to uncontrolled growth and division. These HER2-positive breast cancers tend to be more aggressive, growing more quickly and spreading more rapidly than their HER2-negative counterparts.
Isley, a 65-year-old resident of Edmonton, Alberta, in Canada, found out about her HER2 status two months after an initial diagnosis of breast cancer. Her doctors broke the news to her, but also made it clear that she had a promising treatment option: Herceptin (trastuzumab), a monoclonal antibody that prevents the HER2 proteins from receiving growth signals.
“When my oncologist presented the whole HER2-positive information to me, he said it was fortunate that I didn’t have this before 2005, when Herceptin was first approved in Canada,” says Isley. “I’m thankful that the medical profession has progressed to such a level.”
At the same appointment, she decided to participate in a double-blind randomized trial headed by clinician scientist Edith Pituskin, Ph.D., of the University of Alberta, who described the risk of cardiac toxicity for patients treated with Herceptin and explained that she wanted to find a way to prevent this side effect.
As helpful as Herceptin is, it can cause decreases in the heart’s muscle function. While only 1 to 4 percent of patients experience symptoms from this, and while most patients recover, 10 to 15 percent may undergo a delay or halt in treatment due to this problem. Isley’s mother had died at 85 of an acute cardiac issue, and so the possibility of heart failure due to the drug remained a concern for her.
The clinical trial involved administration of generally safe and routine heart medications during Herceptin treatment to prevent cardiac side effects. Isley’s participation began in July 2011, when she received an echocardiogram and cardiac magnetic resonance imaging (MRI) to determine the baseline state of her cardiac function. Herceptin was given via intravenous infusion, with a total of 17 cycles for 51 weeks. With every dose, Isley also took capsules of the study medication, either a beta blocker, angiotensin-converting enzyme (ACE) inhibitor, or placebo.
“The only side effect I experienced was really a total and complete lack of energy,” she says. “There were some days I couldn’t even get off the couch, but I wasn’t sure if it was the Herceptin or the whole experience.” In fact, evidence shows that both treatment types can contribute to fatigue.
But once the treatment ended, she felt more or less normal again. No cardiac issues came up during the study or since — and Isley remains grateful to be cancer-free since August 2012.
TAKING THE GOOD WITH THE BAD
Ever since its fast-track approval by the U.S. Food and Drug Administration (FDA) in 1998 for advanced, and in 2006 for early-stage, breast cancer, Herceptin has changed the fate of patients diagnosed with HER2-positive breast cancer. Results of phase 3 clinical trials revealed that patients who were treated with Herceptin in addition to chemotherapy experienced slower disease progression than those treated with chemotherapy alone. As of 2013, 1.3 million had been treated with Herceptin, according to its developer, Roche.
Over 10 years ago, the results of four major adjuvant trials (studies done after initial surgery) showed that Herceptin reduced breast cancer recurrence by about 50 percent and risk of death by over 30 percent in patients with early-stage HER2-positive breast cancer who were receiving chemotherapy. With long-term follow-up out as far as 10 years post-treatment, 84 percent of women with early-stage disease who were treated with chemotherapy plus Herceptin were still alive, versus 75.2 percent of those who took chemotherapy alone. Overall, since it was introduced, Herceptin has dramatically improved survival rates for women with stages 1 to 3 HER2-positive breast cancer.
Unfortunately, early trials identified cardiotoxicity as a side effect of Herceptin. Specifically, initiation of Herceptin is associated with left ventricle cavity dilation and reduced ejection fraction that could lead to heart failure in a minority of patients. Asymptomatic cardiotoxicity affects as many as one in 10 of the women who take Herceptin, but most patients do not experience symptomatic heart failure.
An early phase 3 trial in the metastatic setting indicated a very high rate of heart problems associated with Herceptin; the rate of cardiac dysfunction was 27 percent among patients who took Herceptin combined with an anthracycline and cyclophosphamide, and 13 percent among patients who took Herceptin with paclitaxel. As a result of these alarming numbers, oncologists began monitoring heart function with echocardiogram, radionuclide ventriculography (multiple-gated acquisition [MUGA] scans), or cardiac MRI at baseline and at three-month intervals throughout therapy. This helps doctors to recognize high-risk patients before beginning treatment and document early signs of heart weakness. However, Herceptin added to chemotherapy did lead to improved survival, thus leading to its approval in 1998.
In later trials, incidence of left ventricular dysfunction, in particular a significant decline in asymptomatic left ventricular ejection fraction, ranged from 7.1 to 18.6 percent in HER2-positive patients who were taking regimens that included chemotherapy. Congestive heart failure appeared in only 0.4 to 4.1 percent of patients, in most cases not lethal.
Given this risk, Pituskin and her colleagues initiated the phase 2 clinical trial to give preventive heart medication to patients with metastatic HER2-positive breast cancer. The primary results of the trial — called Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research (MANTICORE) — were presented in December 2015 at the San Antonio Breast Cancer Symposium. While the trial didn’t meet its primary endpoint of significantly preventing changes to the heart's structure, it helped preserve the heart's pumping ability, ultimately preventing interruptions in Herceptin treatment for some patients.
“We found that both of the medications — beta blockers and ACE inhibitors, which are standard medications used for heart weakness due to heart attack or hypertension — were helpful for these patients in terms of preventing heart-pumping weakness,” says Pituskin. “And actually, beta blockers turned out to be a bit better than ACE inhibitors.” In earlier work, Pituskin and her colleagues had investigated the effect of aerobic exercise to mitigate the harmful changes that can occur in the left ventricle with Herceptin therapy. Unfortunately, this particular intervention wasn’t enough to prevent drops in left ventricular ejection fraction or remodeling.
Next, they decided to take the pharmacotherapy route via MANTICORE, a randomized, placebo-controlled trial of 99 patients with HER2-positive early breast cancer receiving a year of maintenance Herceptin following their initial therapy. MANTICORE was the first randomized trial to test preventive heart medication specifically for patients on Herceptin. The study found that, while traditional heart failure medications did not prevent left ventricular remodeling, subjects’ left ventricular ejection fraction was preserved, according to pre- and post-intervention cardiac MRI scans. The study medications (also available in the United States) included ACE inhibitor perindopril and beta blocker bisoprolol. The perindopril arm had a 3 percent decrease in left ventricular ejection fraction from baseline, the bisoprolol arm had a 1 percent decrease, and the placebo arm had a 5 percent decrease. Eight subjects on placebo had dose interruptions due to cardiotoxicity, as opposed to one in each of the other arms.
Chau T. Dang, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, has reservations about the study due to negative results for its primary endpoint — in other words, ACE inhibitors or beta blockers were not enough to prevent left ventricular remodeling in patients taking Herceptin. In her opinion, administering all patients heart failure pharmacotherapy is overtreatment.
“I would worry that we are making a lot about a small decline in left ventricular ejection fraction in asymptomatic patients that leads to stopping life-saving medication,” she says. “It’s a complicated subject, but I just want to drive home the point that trastuzumab is life-extending, and its benefits are significant, with very small rates of heart failure.”
Perindopril works by preventing angiotensin II production, a substance that narrows blood vessels and releases hormones that can raise blood pressure. ACE inhibitors often don’t cause side effects, but users could experience dry cough, increased blood-potassium level, fatigue, dizziness and headaches. Bisoprolol blocks the effects of adrenaline and causes the heart to beat more slowly. As with ACE inhibitors, many people who take beta blockers won’t experience side effects, but the drugs may cause fatigue, cold extremities or weight gain.
In the MANTICORE trial, no subjects had to stop the preventive heart medication due to adverse side effects. Even one subject with low blood pressure did not have an issue, says Pituskin. While many patients being treated with Herceptin could theoretically be given concurrent beta blockers or ACE inhibitors, not all doctors believe that this should become standard of care.
“Do we give them a beta blocker or ACE inhibitor from the get-go when they’re getting their cancer treatment? I would say that’s over-treating, because you’re really treating to prevent a problem that may not ever occur in the majority of patients,” says Dang. “I’m hoping that maybe we’ll be able to tailor this more precisely instead of giving beta blockers or ACE inhibitors across the board.”
Dang suggests that preventive heart medications could be given to select individuals predicted to have a higher risk of heart problems, such as those who have hypertension, are age 50 years or older, have low baseline left ventricular injection fraction, and have previously been treated with anthracycline chemotherapy.
“It’s important for oncologists to work with cardiologists to find a way to maximize on oncologic care — meaning to not interrupt curative therapy unnecessarily — and also to maximize cardiac care,” Dang says.
Similar studies to MANTICORE have explored preventive heart medications, with similar results. Recently, the European PRADA trial randomized 120 breast cancer patients to an angiotensin II receptor antagonist (candesartan), a beta blocker (metoprolol) and placebo. The patients had early breast cancer and, after surgery, were taking anthracycline-containing regimens with or without Herceptin and radiation; they took the heart-protecting medications simultaneously. Results demonstrated a 0.8 percent decline in left ventricular ejection fraction in the angiotensin II receptor antagonist arm, as compared to a 2.6 percent decline in the placebo arm. However, when comparing the decline in left ventricular ejection fraction between the beta blocker arm and the placebo arm, there was no difference.
In 2013, a systematic review and meta-analysis gathered evidence for a prophylactic intervention to treat cardiotoxicity associated with anthracycline chemotherapy and/ or Herceptin versus a control arm. Fourteen published articles comprising 12 randomized trials and two observational studies used dexrazoxane (an agent approved to prevent Adriamycin [doxorubicin]- related heart failure), statins, beta blockers and angiotensin antagonists. The prophylaxis arm had 83 cardiac events such as heart failure or a drop in ejection fraction, while the control arm had 304 events. Overall, the rate of cardiac events was reduced with all of the study medication types tested.
Besides cardiotoxicity, Herceptin can cause other side effects, such as fever, chills, muscle aches and nausea. Alternatives to Herceptin do exist for patients with HER2- positive breast cancer; they include Tykerb (lapatinib), a dual tyrosine kinase inhibitor available for the treatment of advanced HER2-positive breast cancer that has stopped responding to anthracyclines, taxanes and Herceptin. It very rarely causes mild heart damage — much less severe than that seen with Herceptin — but patients should still be screened for pre-existing heart conditions and monitored carefully during treatment. Tykerb can also cause nausea, rash, mouth sores, hair loss and diarrhea.
However, in the recent phase 3 clinical trial known as MA.31, exploring what makes the best firstline treatment for metastatic HER2-positive breast cancer, Tykerb plus a taxane in first-line treatment failed to improve progressionfree survival when compared to Herceptin plus a taxane, so this drug is only used in later lines of therapy. In fact, in that study, the best progression-free survival results for this group of patients came with the addition of the monoclonal antibody Perjeta (pertuzumab) — which blocks the ability of HER2-positive cancer cells to grow — to Herceptin and a taxane.
In 2015, the phase 3 CLEOPATRA STUDY found that the addition of Perjeta to Herceptin and the taxane Taxotere (docetaxel) as first-line therapy for metastatic HER2- positive breast cancer improved overall survival by almost 16 months. Also, rates of heart failure and left ventricular dysfunction were not increased in the Perjeta group.
The FDA has approved the Perjeta-Herceptin-taxane combination in patients not previously treated with an anti-HER2 or chemotherapy drug.
All in all, the issue of cardiotoxicity as a result of cancer treatment still remains a concern that ideally requires input from both cardiologists and oncologists.
“Some scientists say Herceptinrelated heart effects only exist during the time the drug is being given, but that is not true,” says Pituskin. “There are longer-term effects, so we need to be very careful about giving a medication effectively in the way we want, but not damaging in the ways that we don’t want.”