Trastuzumab Beyond Progression

[alicem]

Trastuzumab Beyond Progression

Peter D. Beitsch, MD
June 19 2009

Peter D. Beitsch, MD is with Dallas Breast Center, Dallas, Texas

Heresy is a belief that rejects the orthodox tenets of a religion. In this case the religion is oncology, and the belief is that if a patient's disease progresses on a particular regimen, the priest (oncologist) must stop that regimen and change to a different one. However, the doctrine was written in stone prior to the advent of novel biologic agents such as trastuzumab and lapatinib. Evidence on continued use of trastuzumab beyond progression either alone or with a switch in concurrent chemotherapy is based on retrospective studies. However, a prospective randomized trial was recently published in the Journal of Clinical Oncology—Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study.1 In this study, women with locally advanced or metastatic HER2-positive breast cancer who had received no more than one chemotherapy drug for metastatic disease were assigned to receive either capecitabine or capecitabine plus trastuzumab. The capecitabine dose in the first group was 2.5 g/m2 on days 1-14 followed by 1 week off, and the other group received the same capecitabine dose plus trastuzumab 6 mg/kg every 3 weeks. Complex statistical methodology was used to arrive at accrual numbers (please see original paper if interested).

All patients had received at least 12 weeks of trastuzumab and had ended trastuzumab therapy no more than 6 weeks prior to entering this trial (this will be important in the discussion). There were 156 patients (78 in each arm) entered into the study, most with metastatic disease; 111 had received taxane plus trastuzumab, 42 had received trastuzumab alone or a nontaxane-containing chemotherapy plus trastuzumab, and 3 patients received taxane plus trastuzumab adjuvant therapy. Treatment interruptions occurred in <10% of cycles, but over half the patients had to have a dose reduction of capecitabine. Median follow-up was 15.6 months, with 65 events occurring in the capecitabine group and 62 in the capecitabine plus trastuzumab group. The median time to progressions were 5.6 months for the capecitabine group and 8.2 months for the capecitabine plus trastuzumab group (P = .0338). Combining complete, partial, and stable disease, the clinical benefit rates were 54% for the capecitabine group and 75% for the capecitabine plus trastuzumab group (P = .0068). Durations of response, 3.4 and 3.9 months, and overall survival, 20.4 and 25.5 months, for the capecitabine and capecitabine plus trastuzumab group, respectively, were not statistically significantly different. Grade 3/4 toxicities occurred in 66% of patients in the capecitabine group and 64% in the capecitabine plus trastuzumab group; however, anemia was seen more often in the capecitabine plus trastuzumab group. Four patients in the capecitabine plus trastuzumab group and 1 in the capecitabine group experienced cardiac events.

Discussion
This study has shown in a prospective randomized fashion that continued treatment with trastuzumab beyond progression improves activity of the next line of chemotherapy in patients with HER2-positive breast cancer. These improved response rates should ultimately translate into improved survival—the true goal for our patients. Trastuzumab has antiproliferative effects through inhibition of HER2 signaling leading to altered cell cycle regulation, altered DNA repair, and antiangiogenesis activity. However, it also has chemotherapy sensitizing activity and, under the continuous antibody exposure, breast cancer cells are able to bypass the antiproliferative action of trastuzumab, but the chemotherapy sensitizing mechanism remains intact. Whatever the mechanism, it also has translated to other noncytotoxic drugs like lapatinib, pertuzumab, tenispimycin, and DM1 in heavily pretreated patients. This trial does have an interesting note in that the curves do not separate until ~3 months into the study, and the capecitabine only arm has improved overall response rate compared with previously reported studies. This could be attributed to ongoing exposure to trastuzumab in the capecitabine only arm due to the long half-life of trastuzumab.

Conclusion
We are entering a new era in the treatment of metastatic breast cancer patients in which the logical next step may not be the most beneficial. We must constantly challenge the dogmas to elevate our religion and better take care of our parishioners (the patients). The dogma that metastatic breast cancer is the same as the primary tumor is falling by the wayside as rebiopsy of metastatic lesions has shown that clonal domination changes 20% to 40% of the time. Therapy will have to change accordingly. But not only are medical oncology dogmas falling. Pathologic dogma is changing as poor parameters such as size and histologic type become less important (irrelevant?) in the face of the genetic analysis of tumors (Oncotype, MammaPrint, Rotterdam 76 gene array, etc). As we further tease out the genetics of an individual's breast cancer, we will actually move into the individualization of therapy for that particular tumor and stop relying on large groups of patients to determine best available treatment.

Reference
von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:1999-2006.

[Jackie07]

Another Texan close by. Thanks, Alice, for this important article. Your family looks great.

[Rich66]

"Whatever the mechanism, it also has translated to other noncytotoxic drugs like lapatinib, pertuzumab, tenispimycin, and DM1 in heavily pretreated patients"

I have read that treatments that address cancer stem cells may take longer to show results. Imagine the immediate effects above ground when mowing, and the delayed results from weed killing.

[alicem]

I also found this particularly interesting . . .

"Pathologic dogma is changing as poor parameters such as size and histologic type become less important (irrelevant?) in the face of the genetic analysis of tumors (Oncotype, MammaPrint, Rotterdam 76 gene array, etc). As we further tease out the genetics of an individual's breast cancer, we will actually move into the individualization of therapy for that particular tumor and stop relying on large groups of patients to determine best available treatment."

This supports what Jean often says, that the size of the tumor is not necessarily that important.

Oh, and Hello Texan Jackie. Great state, isn't it

[Rich66]

"individualization of therapy for that particular tumor"

I think referencing "tumor" as singular may be found inaccurate too as the heterogeneities keep mounting.

[alicem]

Very possible.

By the way Rich, you are ALMOST TEN TIMES the poster that I am! I've got a looooooong way to go