Response of extensive breast cancer skin metastases to rechallenge with trastuzumab together with low-dose chemotherapy and insulin



Cutaneous metastasis occurs in about 29% of breast cancer patients and has a deep impact on patient quality of life.


A 60-year-old woman with cutaneous metastases from heavily pretreated HER2-positive breast cancer received CMFVP (oral cyclophosphamide 100 mg daily; oral prednisone 12.5 mg daily for 2 weeks, then 7.5 mg daily; intravenous weekly methotrexate 25 mg/m2, 5-5-fluorouracil 400 mg/m2 and vincristine 0.5 mg) with weekly trastuzumab and subcutaneous insulin until disease progression.


From March 2009 to November 2009 the patient was treated with the described regimen. At the best response, we observed the disappearance of some lesions and cessation of bleeding and thoracic pain. Time to progression was 8 months.


Our patient had clinical benefit from reintroduction of trastuzumab, low-dose chemotherapy and insulin. The explanation of this prolonged response is only speculative and requires further clinical confirmation in the treatment strategy of HER2-positive breast cancer.

Tumori 2016; 102(Suppl. 2): e26 - e28

Article Type: CASE REPORT



Laura Orlando, Paola Schiavone, Nicola Calvani, Palma Fedele, Aron Goldhirsch, Saverio Cinieri

Article History


Financial support: No financial support was received for this paper.
Conflict of interest: None of the authors has any financial interest related to this paper to disclose.

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Skin metastasis occurs in about 29% of breast cancer patients (1). Usually it is a manifestation of systemic disease and is associated with lesions in other nonvisceral or visceral sites. However, in some cases skin is the only involved site, thus allowing prolonged survival and multiple lines of systemic therapy. Cutaneous metastases from breast cancer have varying presentations and can appear as skin nodules, ulcers, plaques, erythematous annular patches and verrucous masses, extending to scar sites, chest wall, back, head and neck, arms, and abdomen (1). In a recent cohort study, skin metastases were reported in 8.3% of patients with HER2-positive breast cancer (2).

Case presentation

A 60-year-old woman with cutaneous and lymph node metastases from HER2-positive breast cancer, heavily pretreated with chemotherapy and anti-HER2 targeted therapies, experienced a surprisingly prolonged response to CMFVP (Cooper regimen) (3) combined with trastuzumab and low-dose insulin.

The patient was first diagnosed with locally advanced breast cancer in 2005, when a total left mastectomy was performed. The pathological features revealed non-endocrine-responsive disease and HER2 overexpression. She received trastuzumab plus vinorelbine, followed by trastuzumab alone. The first relapse occurred in the contralateral axilla, which was dissected. Systemic therapy with trastuzumab and capecitabine was started upon further disease progression with diffuse cutaneous metastases and involvement of the right breast. Subsequent therapies included paclitaxel, gemcitabine, metronomic chemotherapy with cyclophosphamide and methotrexate, liposomal anthracyclines, and carboplatin. All treatments were given in combination with trastuzumab. The patient also received bevacizumab in a clinical trial and lapatinib in combination with capecitabine. Progression of disease after the last lapatinib-containing regimen was characterized by bleeding and painful skin lesions on the chest wall, breast, abdomen and back (Fig. 1).

Pretreatment skin lesions.

In March 2009 the patient started treatment with the CMFVP regimen (oral cyclophosphamide 100 mg daily; oral prednisone 12.5 mg daily for 2 weeks and then 7.5 mg daily; intravenous weekly methotrexate 25 mg/m2, 5-fluorouracil 400 mg/m2; vincristine 0.5 mg on days 1 and 8 in the first month, then once a month). The regimen was administered for 6 consecutive weeks followed by a 2-week treatment-free interval. Our patient received also weekly trastuzumab and weekly low-dose regular insulin, 5 units subcutaneously if the glycemic index was ≥95 mg/dL. After the first course (6 weekly administrations), physical examination revealed the disappearance of some lesions and complete cessation of bleeding accompanied by a progressive reduction of opioid intake. After 3 courses the extent of all lesions was clearly reduced, tumor markers decreased progressively and performance status improved (Fig. 2). Due to the surprising disease response and the good tolerability, the patient continued treatment until November 2009, when progression of disease occurred.

Posttreatment skin lesions.


Cutaneous metastases from breast cancer are devastating for patients and represent a challenge for the oncologist. Our patient had been heavily pretreated, since she received 10 trastuzumab-based lines of treatment before starting the CMFVP-trastuzumab combination, achieving a clinical benefit of almost 8 months. This regimen was developed by Cooper (3) and subsequently adopted by Ayre et al (4) in association with insulin as a putative biological response modifier to enhance the anticancer drug effects. Moreover, the CMFVP regimen might be considered a metronomic schedule. In our previous small series of patients, low-dose oral metronomic cyclophosphamide and methotrexate combined with trastuzumab showed substantial activity in pretreated HER2-positive patients, also in trastuzumab-resistant disease (5).

The inclusion of low-dose insulin in our schedule was justified by its initial empiric use in chronic and oncological disease as so-called potentiation therapy (4). Intravenous administration of insulin has been shown to increase the permeability of cell membranes, allowing an increased intracellular amount of antitumor agents. The antitumor efficacy of cell entry offered by insulin-receptor-mediated endocytosis has already been tested in vitro by cross-linking methotrexate to insulin (6). Epidemiological data reported the association of diabetes and obesity with an increased risk of developing cancer through hyperinsulinemia and/or high insulin growth factor 1 (IGF-1) levels. Moreover, observational studies involving individuals with diabetes reported an increased risk of developing cancer in patients treated with insulin compared with those taking metformin (7). However, in nondiabetic cancer patients, hyperinsulinemia is uncommon and the action of low-dose exogenous insulin is actually unknown. Recent advances in the understanding of HER family pathways and their correlation with different growth factors may support the hypothesis of a more active and targeted role of insulin. Insulin and IGF-1 have been identified as autocrine and paracrine mitogenic factors for breast cancer cells and put forward as possible mechanisms of resistance to anti-HER2 targeted therapies (8). These data, however, might suggest a role of insulin in enhancing the cytotoxic effects of chemotherapy by increasing the fraction of proliferating cells. The role of low-dose insulin in association with chemotherapy and anti-HER2 agents may be even more complex and intriguing and should be further investigated.

Some innovative drugs were not yet available when our patient was treated. Impressive data with pertuzumab as first-line therapy (9) and trastuzumab emtansine (T-DM1) in subsequent lines (10) have changed the therapeutic strategy for advanced HER2-positive breast cancer; however, treatment options after progression to multiple anti-HER2 therapies are still needed. The role of old drugs, delivered as weekly metronomic schedules in association with anti-HER2 therapy, should be taken into account for patients with advanced breast cancer.

In conclusion, our patient had significant clinical benefit from the rechallenge with trastuzumab together with low-dose chemotherapy and insulin despite progression after multiple previous lines of treatment. The role of this multimodal approach in breast cancer is only speculative and requires further clinical confirmation in the treatment sequence of HER2-positive breast cancer.


Financial support: No financial support was received for this paper.
Conflict of interest: None of the authors has any financial interest related to this paper to disclose.
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  •  Medical Oncology Division and Breast Unit, Antonio Perrino Hospital, Brindisi - Italy
  •  Department of Medicine, European Institute of Oncology, Milan - Italy

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