PMC8716402_01
Response of the metastases to treatment of the patients in cases 1 and 2. (A) Photograph taken before treatment: The skin on the left chest wall is diffused with painless hard nodules, accompanied by redness and swelling. (B) Photograph taken after one cycle of treatment, at which point, the redness and hard nodules of the cutaneous had obviously subsided. (C) Photograph taken on the latest follow-up date showing hypertrophic scars formed by repeated shedding and new scabs. (D) H&E staining image of tumor samples taken from the left chest wall of the patient in case 1. (E) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the left chest wall of the patient in case 1. (F) Photograph of the patient in case 2 taken before treatment: The skin on the left chest wall is diffused with hard nodules, and the skin around the edge of the lesion is red and swollen. (G) Photograph taken after two cycles of treatment, at which point the redness and hard nodules of the cutaneous had obviously subsided. (H) Photograph showing the size of the pulmonary lesion before the initial treatment. (I) Photograph showing the shrinkage of the pulmonary lesion after two courses of treatment. (J) Photograph showing the progression of pulmonary lesion after she had stopped pyrotinib. (K) Photograph which shows that the pulmonary lesion was controlled again after pyrotinib was resumed. (L) Photograph showing the size of the intracranial lesion before the initial treatment. (M) Photograph showing the shrinkage of the intracranial lesion after two courses of treatment. (N) Photograph showing the progression of the intracranial lesion after she had stopped pyrotinib. (O) Photograph showing that the intracranial lesion was controlled again after pyrotinib was resumed. (P) H&E staining of the 2017 breast tissue specimen taken from the patient in case 2 (she refused to take a new tissue for pathological examination.) (Q) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples of the patient in case 2.
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Cutaneous manifestations of inflammatory breast cancer were also observed on the right breast ( Figure 1F ). At the time of admission, her brain, lung, and cutaneous metastases of breast cancer had a high tumor burden ( Figures 1H, L ), and her PS was 2. She was diagnosed with HER2 (+) BC ( Figures 1P, Q ) and treated at our hospital in February 2017; the specific treatment events and disease progressions are shown in  Supplementary Figure S2 . We treated her with vinorelbine combined with trastuzumab and pyrotinib regimen, which achieved good results ( Figures 1G, I, M ). However, she decided to discontinue pyrotinib after her cutaneous lesions improved, which led to the progression of her intracranial and pulmonary lesions ( Figures 1J, N ). Then, she resumed the standard dosage of pyrotinib and achieved good results again ( Figures 1K, O ).
PMC8716402_02
Response of the metastases to treatment of the patients in cases 1 and 2. (A) Photograph taken before treatment: The skin on the left chest wall is diffused with painless hard nodules, accompanied by redness and swelling. (B) Photograph taken after one cycle of treatment, at which point, the redness and hard nodules of the cutaneous had obviously subsided. (C) Photograph taken on the latest follow-up date showing hypertrophic scars formed by repeated shedding and new scabs. (D) H&E staining image of tumor samples taken from the left chest wall of the patient in case 1. (E) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the left chest wall of the patient in case 1. (F) Photograph of the patient in case 2 taken before treatment: The skin on the left chest wall is diffused with hard nodules, and the skin around the edge of the lesion is red and swollen. (G) Photograph taken after two cycles of treatment, at which point the redness and hard nodules of the cutaneous had obviously subsided. (H) Photograph showing the size of the pulmonary lesion before the initial treatment. (I) Photograph showing the shrinkage of the pulmonary lesion after two courses of treatment. (J) Photograph showing the progression of pulmonary lesion after she had stopped pyrotinib. (K) Photograph which shows that the pulmonary lesion was controlled again after pyrotinib was resumed. (L) Photograph showing the size of the intracranial lesion before the initial treatment. (M) Photograph showing the shrinkage of the intracranial lesion after two courses of treatment. (N) Photograph showing the progression of the intracranial lesion after she had stopped pyrotinib. (O) Photograph showing that the intracranial lesion was controlled again after pyrotinib was resumed. (P) H&E staining of the 2017 breast tissue specimen taken from the patient in case 2 (she refused to take a new tissue for pathological examination.) (Q) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples of the patient in case 2.
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Cutaneous manifestations of inflammatory breast cancer were also observed on the right breast ( Figure 1F ). At the time of admission, her brain, lung, and cutaneous metastases of breast cancer had a high tumor burden ( Figures 1H, L ), and her PS was 2. She was diagnosed with HER2 (+) BC ( Figures 1P, Q ) and treated at our hospital in February 2017; the specific treatment events and disease progressions are shown in  Supplementary Figure S2 . We treated her with vinorelbine combined with trastuzumab and pyrotinib regimen, which achieved good results ( Figures 1G, I, M ). However, she decided to discontinue pyrotinib after her cutaneous lesions improved, which led to the progression of her intracranial and pulmonary lesions ( Figures 1J, N ). Then, she resumed the standard dosage of pyrotinib and achieved good results again ( Figures 1K, O ).
Response of the tumor metastases to treatment. (A) Photograph taken before treatment: The skin on the left chest wall was diffused with nodules and ulcerated skin on the surface, accompanied by redness and swelling. (B) Photograph taken after 8 days of treatment: The redness and hard nodules of the skin had obviously subsided. (C-E) The skin lesions shrank quickly. (F) The ulcer on the chest wall continued to progress after she chose to reduce the dose of pyrotinib. (G) The skin lesions shrank rapidly after she resumed the standard dose of pyrotinib. (H) H&E staining image of tumor samples taken from the chest wall of the patient in case 3. (I) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the left chest wall of the patient in case 3.
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The lesion area was about 10 cm x 20 cm and extended to the neck ( Figure 2A ), and her PS was 2. The pathological result of the chest wall nodule was HER2-positive BC metastasis ( Figures 2H, I  ). After 8 days of treatment, the tumor lesions on her cutaneous showed scabs in the ulcer area and shrinkage of the lesion area ( Figure 2B ). After continuous treatment, the condition of the patient gradually improved ( Figures 2C-E ). After 30 days of dose reduction, the ulcer on her chest wall had progressed ( Figure 2F ). Then, she restored the dosage of pyrotinib to 400 mg/day and subsequently had significant therapeutic effects ( Figure 2G  ).
PMC8716402_03
Response of the tumor metastases to treatment. (A) Photograph taken before treatment: The skin on the left chest wall was diffused with nodules and ulcerated skin on the surface, accompanied by redness and swelling. (B) Photograph taken after 8 days of treatment: The redness and hard nodules of the skin had obviously subsided. (C-E) The skin lesions shrank quickly. (F) The ulcer on the chest wall continued to progress after she chose to reduce the dose of pyrotinib. (G) The skin lesions shrank rapidly after she resumed the standard dose of pyrotinib. (H) H&E staining image of tumor samples taken from the chest wall of the patient in case 3. (I) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the left chest wall of the patient in case 3.
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The lesion area was about 10 cm x 20 cm and extended to the neck ( Figure 2A ), and her PS was 2. The pathological result of the chest wall nodule was HER2-positive BC metastasis ( Figures 2H, I  ). After 8 days of treatment, the tumor lesions on her cutaneous showed scabs in the ulcer area and shrinkage of the lesion area ( Figure 2B ). After continuous treatment, the condition of the patient gradually improved ( Figures 2C-E ). After 30 days of dose reduction, the ulcer on her chest wall had progressed ( Figure 2F ). Then, she restored the dosage of pyrotinib to 400 mg/day and subsequently had significant therapeutic effects ( Figure 2G  ).
Response of the cutaneous and liver tumor metastases to the treatment. (A) Photograph taken on the day of pathological biopsy. The skin nodules marked are the tissues to be removed. (B) On the 3rd day after she received low-dose capecitabine and standard-dose pyrotinib; albumin paclitaxel and trastuzumab was increased at this point. (C-J) Gross changes in the tumor over time. (K) The chest wall that was once covered by a huge mass is now completely covered by skin. (L) Prior to primary treatment, the chest wall CT showed considerable soft tissue with necrotic cavities. (M) At this time, the chest wall CT showed that the tumor had disappeared and healed. (N-Q) Gross changes in the tumor over time. (R) H&E staining image of samples taken from the abdominal nodule of the patient in case 4. (S) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the samples taken from the abdominal nodule of the patient in case 4.
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Her whole left breast was enlarged and hard, covered with ulcers, nodules, and yellow-white pus, and the nipple-areola complex could not be clearly seen ( Figures 3A, L ); and her PS was 3. We performed a biopsy of her nodule in the thoracic and abdominal wall on April 1, 2020 (the nodule is marked in  Figure 3A ). She also had significant liver metastases ( Figure 3N ). BC ( Figures 3R, S ). Based on these findings combined with NCCN (V2020.1), her tumor (T), lymph node (N), and metastasis (M) staging is cT4N4M1 (stage IV). During the 2 days of treatment with only pyrotinib and low-dose capecitabine, the redness and swelling that had spread to the lesions on the left rib area and the contralateral breast disappeared, and the swollen tissue shrunk to obvious wrinkles ( Figure 3B ). On the fifth day of treatment, the patient's tumor further shrunk ( Figure 3C ). On the 10th day of treatment, the tumor of the patient had shrunk significantly ( Figure 3D ). On the 13th day, the left breast had become flat, and the nipple wrapped in the tumor was exposed ( Figure 3E ). In subsequent treatment, the patient's tumor continued to shrink ( Figures 3F-K, M ). The symptoms of the patient continuously improved as the treatment continued, including a reduction in liver metastases ( Figures 3N-Q ). On April 20, 2021, her significant tumor masses had been completely replaced by new skin and her liver lesions had shrunk significantly ( Figure 3Q ).
PMC8716402_04
Response of the cutaneous and liver tumor metastases to the treatment. (A) Photograph taken on the day of pathological biopsy. The skin nodules marked are the tissues to be removed. (B) On the 3rd day after she received low-dose capecitabine and standard-dose pyrotinib; albumin paclitaxel and trastuzumab was increased at this point. (C-J) Gross changes in the tumor over time. (K) The chest wall that was once covered by a huge mass is now completely covered by skin. (L) Prior to primary treatment, the chest wall CT showed considerable soft tissue with necrotic cavities. (M) At this time, the chest wall CT showed that the tumor had disappeared and healed. (N-Q) Gross changes in the tumor over time. (R) H&E staining image of samples taken from the abdominal nodule of the patient in case 4. (S) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the samples taken from the abdominal nodule of the patient in case 4.
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Her whole left breast was enlarged and hard, covered with ulcers, nodules, and yellow-white pus, and the nipple-areola complex could not be clearly seen ( Figures 3A, L ); and her PS was 3. We performed a biopsy of her nodule in the thoracic and abdominal wall on April 1, 2020 (the nodule is marked in  Figure 3A ). She also had significant liver metastases ( Figure 3N ). BC ( Figures 3R, S ). Based on these findings combined with NCCN (V2020.1), her tumor (T), lymph node (N), and metastasis (M) staging is cT4N4M1 (stage IV). During the 2 days of treatment with only pyrotinib and low-dose capecitabine, the redness and swelling that had spread to the lesions on the left rib area and the contralateral breast disappeared, and the swollen tissue shrunk to obvious wrinkles ( Figure 3B ). On the fifth day of treatment, the patient's tumor further shrunk ( Figure 3C ). On the 10th day of treatment, the tumor of the patient had shrunk significantly ( Figure 3D ). On the 13th day, the left breast had become flat, and the nipple wrapped in the tumor was exposed ( Figure 3E ). In subsequent treatment, the patient's tumor continued to shrink ( Figures 3F-K, M ). The symptoms of the patient continuously improved as the treatment continued, including a reduction in liver metastases ( Figures 3N-Q ). On April 20, 2021, her significant tumor masses had been completely replaced by new skin and her liver lesions had shrunk significantly ( Figure 3Q ).
PMC8716402_05
Partial response to capecitabine combined with trastuzumab and pyrotinib treatment. (A) Photograph taken before treatment: The skin on the left chest wall was diffused with erosion and exuding hard nodules, and the skin around the edge of the lesion was red and swollen. (B) Photograph taken on the 4th day during the 1st cycle of treatment: The exudation had completely disappeared, the erosional area had healed, and the redness and swelling of the skin had obviously subsided. (C) The skin on the left chest wall had completely healed. (D) Chest CT scans before treatment. (E) CT scans taken on September 15, 2020 showed that the liver lesions had shrunk significantly. (F) CT scans showed that the liver lesions had been further reduced. (G) H&E staining image of tumor samples taken from the liver of the patient in case 5. (H) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the liver of the patient in case 5. (I) H&E staining image of tumor samples taken from the left chest wall of the patient in case 5. (J) Very strong immunohistochemical staining (IHC 3+) of HER2 was observed in the tumor samples taken from the left chest wall of the patient in case 5.
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The treatment process, the time of disease progression, and the factors that impact our decision-making process are shown in  Supplementary Figure S4 . After admission, we found that her left chest wall was diffused with erosions companied by exudation, and the surrounding skin was red and swollen ( Figure 4A ); her performance status was 2. The results of a further examination revealed abnormal enlargement of the right axillary lymph nodes and a suspected tumor in the liver ( Figure 4D ). The results of a pathological examination demonstrated that her HER2-positive BC metastasized ( Figures 4G-J ). Her cutaneous metastases quickly healed after receiving treatment ( Figures 4B, C ). Her liver metastases were also gradually shrinking during treatment ( Figure 4E ). An examination of the liver lesions in January 2021 revealed that the liver metastases had almost disappeared ( Figure 4F ).