Skin/nail infections with the addition of pertuzumab to trastuzumab-based chemotherapy

The FDA approval of new agents is made on the basis of randomized clinical trials where the primary endpoints are tumor regression or improved PFS and overall survival. Toxicity is an important component of the approval process. However, the toxicity data are generally collected during the study conduct and are limited by the sample size. In response to patient demand, the approval process for new treatments of advanced cancers is shortening [14, 15]. As these agents become available to more patients, additional side effects become apparent. In fact, half of all serious adverse events are recognized more than seven years after FDA approval [16].

This is the first series to report the association of pertuzumab, trastuzumab, and chemotherapy with severe cutaneous staphylococcal infections. In CLEOPATRA, the median number of cycles of docetaxel administered was eight in both arms and the frequency of all adverse effects was noted to decrease once the docetaxel was discontinued. However diarrhea, rash, dry skin, neutropenic fever, pruritus, and mucosal inflammation appeared to be more common in patients assigned to pertuzumab [6]. Nail disorders were reported in 22.9 % of patients in both arms, but the incidence of grade 3/4 toxicity was higher in patients receiving pertuzumab, 1.2 % versus 0.3 % [10]. We believe that severe skin and nail infections with Staphylococcus species are unique side effects resulting from the addition of pertuzumab to trastuzumab-based chemotherapy. This toxicity may have gone unrecognized for a number of reasons. The pertuzumab safety data are derived from three large randomized clinical trials—CLEOPATRA, NEOSPHERE, and TRYPHAENA—that enrolled patients from many institutions worldwide (Table 3). The 808 patients in CLEOPATRA were enrolled from 205 sites and 25 countries. NEOSPHERE enrolled 417 patients from 59 sites and 16 countries, and TRYPHAENA enrolled 225 patients from 44 sites and 19 countries [5, 7, 8]. It would be difficult for an investigator to appreciate a safety signal with so few patients treated at any one site.

The clinical trial designs for the randomized trials are summarized in Table 3. Three of the four arms in the NEOSPHERE trial combined trastuzumab with pertuzumab, but each administered only four cycles of therapy. All three arms of the TRYPHAENA trial utilized pertuzumab and trastuzumab, but delivered only three cycles in one arm and six cycles in two arms. In our series, folliculitis was observed early, however, the more severe infections and nail infections developed after cycles 3 and 4. In total, the toxicity data for the combination of pertuzumab and trastuzumab are based on 846 patients, 556 of whom received six cycles, 215 four cycles, and 75 three cycles. Because the addition of lapatinib to trastuzumab results in a synergistic anti-tumor effect with predictable normal tissue toxicities, synergistic toxicities from adding pertuzumab to trastuzumab were not anticipated [3, 17, 18].

The majority of new agents are first tested in patients with metastatic disease, and it may be difficult to distinguish drug toxicity from symptoms of advanced disease. The musculoskeletal pains that occur with the aromatase inhibitors were only recognized as a toxicity of the drug class when they were used in the adjuvant setting [19]. Side effects that occur in the adjuvant versus neoadjuvant settings are less likely to be attributed to the underlying disease and safety signals are more apparent. The ongoing adjuvant APHINITY trial (Table 3) is likely to clarify new side effects related to the combined antibody therapy.

The development of pustular skin lesions may have been attributed to the steroid premedication routinely administered in patients receiving taxane-based therapies. The skin lesions described here are not typical of “steroid acne.” Steroid-induced acne generally presents as monomorphic papules distributed on the upper trunk, arms and less commonly on the face [20]. Although steroid use is generally immunosuppressive, the number and severity of these reactions are unlikely to be attributed to short-course steroid use alone. Additionally, the prevalence of staphylococcal infections in this population suggests that there is a specific underlying mechanism. Although the precise pathogenesis of these reactions is unknown, we propose several overlapping and synergistic mechanisms.

Both trastuzumab and pertuzumab target HER2, an epidermal growth factor receptor overexpressed in breast cancer cells and present in keratinocytes [21]. Although these agents do not induce the classic acneiform rash seen with other EGFR inhibitors such as cetuximab and erlotinib, the combination therapy is clearly disrupting epidermal differentiation in the patients who had biopsies [13]. These results suggest that the combination of trastuzumab and pertuzumab induces a reaction that is histologically similar to other EGFR inhibitors, though clinically distinct. The difference in the morphologies of the reactions is most likely due to the variability of HER kinase expression in the skin, nails, and follicles [22, 23]. Similar to other EGFR inhibitors, this altered epidermal differentiation predisposes to infection, primarily by staphylococcal species. In one study of 221 patients on EGFR inhibitor therapy, 38 % of the patients had clinical evidence of infection and over 50 % of these were culture positive for staphylococci [24]. The rash and infectious disease complications with these patients were managed prophylactically with oral antibiotics (usually doxycycline or minocycline) plus a topical steroid to treat the inflammatory component. It may be beneficial to treat breast cancer patients on combined therapy with prophylactic measures as well, especially if we can determine which patients are at the highest risk of developing infectious complications. Patients who develop rash with EGFR inhibitor therapy also tend to have better outcomes [25]. It will be interesting to determine if there is a similar correlation between pertuzumab and trastuzumab treatment. The complete pathologic response rate in this small series suggests that skin/nail infections were neither a favorable nor an unfavorable predictor or response.

Recent studies have demonstrated that the immunosuppressive effect of IVIG may be related to a small percentage of glycosylated IgG-Fc present in the preparations rather than a direct effect of antigen-specific binding [26]. It may be possible that the monoclonal antibodies themselves contribute to the immunosuppression seen in these patients. We did document hypoglobulinemia in six of the patients. However, many of the affected patients had normal immunoglobulins at the time of infection and other patients became hypoglobulinemic with continuation of therapy. Nonetheless, hypoglobulinemia alone does not explain the mechanism of infection.

The data presented here was derived from cases identified prospectively only after the patient developed an infection. We do not have data on the patients who did not experience any skin reaction. Amongst the group of physicians who identified the patients with skin infections reported here, the incidence was 30 %. To minimize any bias in assigning toxicity to pertuzumab and trastuzumab, we enlisted the help of specialists in Infectious Disease and Dermatology, and in three instances, the occurrence of a skin complication was deemed unrelated to treatment. Although this was not a prospective clinical trial, we are convinced that the occurrence of staphylococcal infections of the skin and nails is a unique toxicity observed when pertuzumab is added to trastuzumab. We are initiating a prospective trial to address cutaneous and immunologic changes in women undergoing treatment with this combined antibody therapy.