A Case of Pathological Complete Response and Resolution of Dermatomyositis Following Neoadjuvant Chemotherapy in HER2-Positive Early Breast Cancer

Round 1

Reviewer 1 Report

This is a well written case report. The report is fascinating and I would like to congratulate the authors on these patient outcomes. Indeed we definitely need stronger data to better understand the ideal management of this small patient population but definitely these reports are helpful for now. The authors did a great job presenting the case and discussing it using the most up-to-date literature. 

Author Response

Dear reviewer, thanks for your words. Happy to contribute. In fact, we believe that case reports can also make an important scientific contribution. 

Reviewer 2 Report

General comments

Overall this paper is well written and presents an interesting case. 

However my major concern with this paper is it does not present any novel information about management of patients. As the authors point out, dermatomyositis has a known association with solid tumours. Management of the malignancy typically results in improvement of the symptoms. In this case the patient received standard treatment for her breast cancer, and as expected her symptoms improved. There was no novel biochemical or clinical information presented

Specific comments

Abstract: grammatical correction for pleurals (61 years should read 61 year, lymphadenopathy should not be pleural). Final sentence of case presentation needs grammatical review. Discussion and conclusion: Should include that this is a rare complication, ideally treated by management of the malignancy. I am not sure there is data presented here that would support neoadjuvant vs upfront surgery. 

Case presentation: 

• some spelling and grammar issues
• would be interesting to discuss what patients clinical response was after cycle 1 of treatment 
• authors should include her clinical stage (T2N2?) 
• authors may also include in patient history timing of breast mass in relation to clinical symptoms

Discussion

• In reading the case reports the concern re initiation of chemotherapy in these cases seems primarily related to risk of infection rather than risk of worsening neurologic symptoms. Immunosupression is treatment for DM
• Authors should note that pt received standard therapy for stage 3 her 2 positive breast cancer (neoadjuvant chemotherapy) 

Author Response

1. Overall this paper is well written and presents an interesting case.

Dear reviewer, thanks for your work and for your comment to paper.

2. However my major concern with this paper is it does not present any novel information about management of patients. As the authors point out, dermatomyositis has a known association with solid tumours. Management of the malignancy typically results in improvement of the symptoms. In this case the patient received standard treatment for her breast cancer, and as expected her symptoms improved. There was no novel biochemical or clinical information presented.

ANSWER Q2. The idea of our work arises from the finding in the literature about the management of “early breast cancer complicated by dermatomyositis”, almost totally based on upfront surgery. We therefore wanted to provide an example of a valid case management also using a pre-operative chemotherapy.

Specific comments

3. Abstract: grammatical correction for pleurals (61 years should read 61 year, lymphadenopathy should not be pleural). Final sentence of case presentation needs grammatical review. Discussion and conclusion: Should include that this is a rare complication, ideally treated by management of the malignancy. I am not sure there is data presented here that would support neoadjuvant vs upfront surgery.

ANSWER Q3. We modified “61 years” in “61 year” (line 3 page 1). We modified “lymphadenopaties” in “lymphadenopathy” (line 8 page 1). We modified the last sentence of the abstract as follow: “similar cases in literature are commonly referred to a fist line surgery and the role of neoadjuvant chemotherapy is debatable”.

Case presentation:

4. some spelling and grammar issues

would be interesting to discuss what patients clinical response was after cycle 1 of treatment

authors should include her clinical stage (T2N2?)

authors may also include in patient history timing of breast mass in relation to clinical symptoms

ANSWER Q4. Sorry, but we don’t have the data about the responde after one cycle of treatment because we usually do a radiological evaluation in the middle of the treatment. We added clinical stage (T2N2M0) in line 60 page 2

Discussion

5. In reading the case reports the concern re initiation of chemotherapy in these cases seems primarily related to risk of infection rather than risk of worsening neurologic symptoms. Immunosupression is treatment for DM.

ANSWER Q5. We have reviewed the literature on this. We confirm the absence of data about the use of neoadjuvant treatment in this setting, probably also related to the infectious risk. (Line 140)

6. Authors should note that pt received standard therapy for stage 3 her 2 positive breast cancer (neoadjuvant chemotherapy)

ANSWER Q6. I specified that the schedule we have used is the standard therapy for stage III HER2 positive breast cancer (line 136 page 3).

Author Response File: Author Response.docx

Reviewer 3 Report

The authors reported an interesting clinical of a woman with localized breast cancer, and a concurrent diagnosis of dermatomyositis – interpreted as paraneoplastic. The authors reported a work-up for autoimmunity, with evidence of biopsy-proven ANA, Ro52 and TIF1-γ antibodies dermatomyositis.

The patient is described to present with a ‘mastitis’ – and was investigated initially for inflammation. However, it is unclear if this tumor is an inflammatory cancer (IBC). IBC is a clinical diagnosis: despite the CT scan images being quite suggestive, there is evidence of a nodular mass, not gross interstitial lymph vessels thickening and only slight skin induration. Still, the diagnosis cannot be confirmed. IBC can present with or without a nodule, with rapid onset of erythema, edema, peau d'orange and/or abnormal breast warmth. These elements of the physical exam are important to acknowledge, and the title should be amended, if this is an IBC. Per definition, IBC is a locally advanced presentation. In this specific case, the disease is ≥IIB stage, and the indication for neoadjuvant treatment is quite stringent – more, for HER2 positivity. Also, TNM stage at diagnosis should be specified, as reported before neoadjuvant treatments.

The post-NACT restaging should be reported as: ypT0, ypN0; ypMx is not applicable, and could be reported as yM0 or ycM0 (a metastatic work-up had been performed with CT scan, so it is not Mx but M0).

The authors report a curious finding, of 3 nodules in the breast (multifocal disease?) and locoregional lymph nodes visible at CT scan,  and not reported at mammography and ultrasound.

This is uncommon, as the resolution of the CT scan is enhanced in the transversal slices – not really with MRP – so that the mass is better described in the 3D (shape, anatomic contacts) through dedicated techniques. Therefore, please consider reporting the findings from breast imaging.

Though outside the scope of this research, it is interesting that the patients utilized a dose-dense schedule for AC, in the HER2-positive setting. Was this decision related to the need to maintain better immune-suppression, and tackle both the cancer and the autoimmune disorder? In the HER2 setting ddAC is essentially investigational.

The decision to provide a triple-immune suppression is quite unique (high dose endoxan, Ig, low dose steroids).

• This patient has received an oral steroid at low dose (25mg) – that is unclear if was provided for symptom control (antiemetic?) or in combination with IV IGs per local practice. While IGs are steroid sparing, 25mg is still roughly lower to the recommended dose, at least the starting doses (1mg/kg prednisone equivalent).

(i) The patient was scheduled and actually received cyclophosphamide, high dose. The clinical use of cyclophosphamide for autoimmunity is quite consolidated in the clinical practice, especially for resistant autoimmune disorders, in doses ranging between 200 and 800 mg/m2:

• doi: 14397595.2018.1521185
• doi: 10.1177/1179547619855370
• doi: 10.1100/tsw.2002.863
• DOI: 1002/art.40418
• PMID: 18021522.
• PMID: 23358715
• doi: 10.1093/rheumatology/kel112 (in this setting).

(ii) The authors should comment on the decisional process and the elements accounted to provide a quite unique immune-suppressive combination treatment.

Also, the decision to pursue with taxanes (agents that can be myotoxic and induce myositis-like reactions) may deserve attention.

Then, considerations on the choice and compliance of adjuvant endocrine treatments may be accounted. It is demonstrated that patients with autoimmune disorders (mostly, arthritis) are more reluctant to adjuvant endocrine therapy, and this can have an impact on the outcome. Therefore, the authors could comment on the residual articular- muscular symptoms, beyond the serological markers of resolution of myonecrosis, or comorbid fibromyalgia.

The authors state that a “recent meta-analysis showed that patients with high levels of anti-TF1 have a 27-fold higher odds ratio of developing malignancy”. It is unclear if the authors willed to address a possible correlation of high anti-TF1 with a diagnosis of an underlying (including pre-clinical) malignancy – in the context of a paraneoplastic phenomenon.

The authors well report that surgical approach is preferred for eBC; if they confirm this was an IBC, they could legitimate the decision for primary systemic treatment – as the best option in this setting, and not surgery.

The statement “Immunoglobulins represent a second-line treatment for refractory myositis and contraindications for immunosuppressants, as paraneoplastic cases” is unclear. Same controversy for “previous case reports surgery is preferred to neoadjuvant treatment, because of possible clinical worsening of neurological symptoms due to the immunosuppression induced by chemotherapy”. The patient received the best anticancer treatments, with high chances to reach pCR – thus, to destroy the source of antigens nurturing the autoimmunity (in the hypothesis of paraneoplastic syndrome). The treatment per se is based on cyclophosphamide, that has recognized properties to tackle immune effectors of dysregulated responses, including in this setting. Accordingly, primary highly-efficacy standard treatments should be preferred, unless a risk to worsen other conditions (e.g., neuropathies) is tangibly reported.

The treatment- decision for radiotherapy after surgery must be also reported. RT-decision in autoimmunity setting is commonly controversial. RT-induced Köebner has also been reported, with resistant dermatitis and ulcerations in the context of dermatomyositis (doi: 10.1111/ijd.14466).

Author Response

please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Corrections noted thank you