a biggie: marker found which predicts who will suffer irreversible heart injury fr

[Lani]

om herceptin as well as those at greatest risk for cardiotoxicity (reversible or not)



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Troponin I elevation identified patients at risk for cardiotoxicity associated with trastuzumab therapy.

STUDY IN CONTEXT
Trastuzumab targets human epidermal growth factor receptor 2 (HER2), which is overexpressed in up to 30% of all breast cancers. However, cardiotoxicity, mainly asymptomatic left ventricular ejection fraction (LVEF) reduction or overt heart failure (HF), occurs in up to 34% of patients treated with trastuzumab, particularly when it is used with anthracyclines. Anthracyclines may also cause cardiotoxicity, but the pathologic changes and outcomes differ from those caused by trastuzumab. Unlike anthracycline-induced cardiotoxicity, trastuzumab-induced cardiotoxicity is not dose dependent and does not result in ultrastructural changes; in addition, cardiac function may recover after discontinuation of trastuzumab and initiation of HF therapy.

Tropinin I (TNI) is a well-established marker of myocardial injury resulting from other forms of chemotherapy, but it has not been investigated in trastuzumab-treated patients. This study demonstrated that TNI identifies patients at risk for cardiotoxicity and is a marker for response to HF treatment.

This prospective study enrolled patients with breast cancer who were treated with trastuzumab but did not at baseline have ischemic or valvular heart disease, LVEF <55%, severe hypertension, or abnormal renal or hepatic function. Patients underwent LVEF measurement before trastuzumab therapy, every 3 months during trastuzumab, and during the first year after drug discontinuation, and every 6 months thereafter. In patients exhibiting cardiotoxicity, trastuzumab was discontinued, HF therapy was initiated, and LVEF was measured every month for the first 3 months of HF therapy. TNI was assayed before and after each trastuzumab cycle and at each cardiologic check after completion of therapy. Elevated TNI (TNI+) was defined as TNI >0.08 ng/mL.

A total of 251 women were enrolled, of whom 123 (49%) received trastuzumab as adjuvant therapy and 128 (51%) received trastuzumab as treatment for metastatic disease. Median treatment time was 12 months (range, 1 to 24 months) for adjuvant therapy and 16 months (range, 1 to 72 months) for metastatic disease. In total, 62 patients died from cancer, and 4 patients were lost to follow-up.

Trastuzumab-induced cardiotoxicity occurred in 42 patients (17%), including 14 patients (11%) in the adjuvant group and 28 patients (22%) in the metastatic group (P =.005). Cardiotoxicity was associated with lower baseline LVEF, TNI+, metastatic disease, previous treatment with high-dose chemotherapy, and previous treatment with taxanes or anthracyclines. The relationship between the risk of cardiotoxicity and prior anthracycline use was dose related. Incidence of cardiotoxicity was lower in patients treated with trastuzumab alone than in those treated with trastuzumab in combination with other drugs.

Among the 36 patients (14%) who were TNI+, 7 patients were TNI+ at baseline, possibly as a consequence of previous chemotherapy. In most cases, TNI elevation appeared soon after the first trastuzumab cycle. TNI+ normalized within 3 months. Trastuzumab-induced cardiotoxicity occurred 1 to 8 months after TNI+ was first detected. On multivariate analysis, TNI+ was the strongest independent predictor of cardiotoxicity (hazard ratio [HR], 17.6; 95% CI, 8.85−35.0; P < .001). TNI+ was also a predictor of duration of positivity (HR, 16.5; 95% CI, 8.1−33.6; P < .001).

LVEF recovered in 25 patients (60%) after trastuzumab withdrawal and initiation of HF therapy. The relative risk for LVEF recovery in patients without TNI+ was 3.0 (95% CI, 1.85.1; P < .001). The positive predictive value for lack of LVEF recovery in TNI+ patients was 65%, and the negative predictive value was 100%.

There were 22 major adverse cardiac events. The incidence of these events was higher in patients with TNI+ (50% vs 2%; P < .001). Trastuzumab was reintroduced in 7 patients with trastuzumab-induced cardiotoxicity; 2 patients were TNI+ and developed LVEF <50%, following which trastuzumab was permanently discontinued.

In this study, TNI+ was the strongest independent predictor of cardiotoxicity, thus enabling identification of patients at greatest risk. Assessment of TNI also identified patients in whom trastuzumab-induced cardiac dysfunction may be irreversible even with adequate HF treatment.

[Lani]

moving up as doesn't seem to have been noticed

another article:


Troponin Identifies Those on Trastuzumab With Heart Risk

September 9, 2010 — The biomarker troponin I (TNI) can help clinicians identify which breast cancer patients receiving trastuzumab (Herceptin, Genentech/Roche) are at risk for heart damage and which of those patients who are unlikely recover from the damage, say Italian researchers.

The ability to identify these patients is "crucial," in part because various studies have shown that "many" patients who experience toxic effects will not recover, note the study authors, led by Daniela Cardinale, MD, PhD, from the Cardiology Unit at the European Institute of Oncology in Milan, Italy.

In a new study, TNI was the only independent predictor of trastuzumab-induced cardiotoxicity (hazard ratio [HR], 22.9; 95% confidence interval [CI], 11.6 - 45.5; P < .001) and of lack of recovery from that cardiotoxicity (HR, 2.88; 95% CI,1.78 - 4.65; P < .001).

The study appears in the September 1 issue of the Journal of Clinical Oncology.

"We routinely use TNI evaluation in our clinical practice. We measure TNI before beginning both anthracycline-containing regimens and trastuzumab regimens in all patients. It's not an invasive test and it is a cheap way to detect cardiotoxicity early, long before echocardiographic changes. We use a common commercially available test (Siemens Healthcare Diagnostics; Eschborn, Germany)," Dr. Cardinale told Medscape Medical News.

Other research indicates that trastuzumab causes heart damage in as many as one third of treated patients who have received anthracycline treatment, according to Dr. Cardinale and her coauthors.

However, in their study of 251 women with breast cancer, the researchers observed trastuzumab-induced cardiotoxicity in only 42 patients (17%), and it was significantly more frequent in patients with TNI elevation (62% vs 5%; P < .001).

Of the 42 patients, 60% recovered from the cardiotoxicity after trastuzumab withdrawal and initiation of heart failure therapy. None of the patients who recovered had TNI elevation at baseline. However, 7 of 17 (41%) who did not recover had TNI elevation at baseline.

Patients who did not have elevated TNI at baseline were nearly 3 times as likely to recover from trastuzumab-induced cardiotoxicity as those who had elevated TNI (relative risk, 2.88).

Identifying the TNI-positive and TNI-negative patients can greatly aid clinicians, the authors explain.

"The early identification of patients at higher risk of [trastuzumab-induced cardiotoxicity], and of those who may recover from cardiac dysfunction, may allow us to reach 2 important therapeutic goals: first, trastuzumab should not be indiscriminately discontinued in all patients developing [trastuzumab-induced cardiotoxicity], depriving them of the drug's effectiveness; second, a prophylactic therapy should be started in selected high-risk patients."

Dr. Cardinale added: "We hope that this publication will spread this kind of approach among oncologists and cardiologists involved in this clinical setting."

Trastuzumab Not Only to Blame

In the study, the Italian researchers measured TNI in the women before and after each cycle of trastuzumab. TNI elevation was defined as >0.08 ng/mL.

They also measured left-ventricular ejection fraction (LVEF) at baseline, every 3 months during trastuzumab treatment, and every 6 months thereafter. Trastuzumab-induced cardiotoxicity is defined as a LVEF decrease of more than 10 units and below 50%. Recovery was defined as LVEF increase above 50%.

However, an editorial that accompanies the study suggests that the term trastuzumab-induced cardiotoxicity might be misleading

Michael S. Ewer, MD, from the University of Texas MD Anderson Cancer Center in Houston, and Steven M. Ewer, MD, from the University of Wisconsin, Madison, raise questions about the role trastuzumab actually played in the cardiotoxicity reported by Dr. Cardinale's group.

"First, prior anthracycline use was found to be a significant risk factor for the development of [trastuzumab-induced cardiotoxicity]. Second, the cumulative anthracycline dose was significantly higher in those who developed [trastuzumab-induced cardiotoxicity]. Third, elevation of troponin I (with all of its prognostic implications) was observed exclusively in patients with prior anthracycline exposure. Fourth, troponin I elevation was found in 7 patients prior to trastuzumab therapy, despite normal left-ventricular ejection fraction, suggesting ongoing anthracycline-mediated myocyte damage that would have otherwise gone unrecognized," the Drs. Ewer write.

They propose that anthracycline administration causes oxidative damage to cardiac myocytes, which is worsened by trastuzumab.

"As we move forward, we may well discover that trastuzumab aids and abets in the crime of cell death and amplifies the burden of the anthracycline; in this sense, trastuzumab is far from innocent. But when taken by itself and out of the context of the vulnerable and previously damaged anthracycline-exposed myocyte, we may ultimately discover that trastuzumab is not nearly as guilty for the death of the myocyte as has heretofore been suggested," they write.

Dr. Cardinale has disclosed no relevant financial relationships. Dr. Michael Ewer reports serving as a consultant for Roche, MethylGene, and Genentech, and receiving honoraria from Roche and Sanofi-Aventis.

J Clin Oncol. 2010;28:3901-3904, 3910-3916. Abstract, Abstract

[karen z]

Lani,
Thanks for posting.
Karen

[TriciaK]

Lani, thank you for posting this article. It has special significance for me because I have lung mets again after 5 years NED, and since an echocardiogram a month ago showed my ef at 45-50 my oncologist doesn't want to give me herceptin or tykerb. He did give me two rounds of navelbine, and then we discontinued while I went on a trip to Hawaii. I am back now and having a lot of trouble breathing, plus heaviness in my chest. It got so bad I had to go to the ER Wednesday where they ruled out pulmonary embolism but said my ekg did not look good so they did an angiogram which actually showed some improvement over an angiogram a year and a half ago. They also did echocardiograms on my heart and carotid arteries, but I won't know the ef they show until I see the cardiologist on Monday. I had told him previously and also in the cath lab that I wanted him to help me raise my ef so the onc would give me herceptin. He teased me that the whole ER thing was for that purpose, and I told him I'd just thought about it but it might be a good idea after all. I am hoping the improved angiogram and hoped-for rise in the ejection fraction will convince my oncologist to start herceptin. I had 15 rounds of it, plus 6 months navelbine, in 2004-2005 after a heart attack in 2004. A CT scan after the heart attack showed the BC was back after 15 years cancer NED. I had had BC twice before but the first two were not her2. The last two have been.
I would like to print these articles off to take with me when I see my oncologist on Tuesday. Would it be possible for you to send them directly to me by email? My email is pairadox1@q.com. Thank you so much for posting them! Hugs, Tricia

[Mary Anne in TX]

Yes, Lani, thanks so much.
And Tricia, you keep fighting to get the Herceptin.
Many prayers and much love to ya, ma

[Lani]

Articles forwarded on, fit to print!