Abstract P5-07-25: “NAVIGATING THE NEXUS: OVERCOMING DOUBLE JEOPARDY OF EARLY HER2-POSITIVE BREAST CANCER PRESENTING AS AN ANTI-Yo POSITIVE PARANEOPLASTIC CEREBELLAR DEGENERATION IN A YOUNG WOMAN”

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Abstract Introduction: Anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) syndrome is a very rare condition that is most commonly associated with breast and gynaecologic cancers. Overall incidence of PCD in all cancer patients is approximately 1-3%. Percentage of breast cancer patients developing PCD is around 0.01% to 0.1%. Those cases associated with breast cancer tend to be human epidermal growth factor receptor 2 (HER2)-positive, though the reason for this correlation is unknown. Most commonly, the neurologic symptoms of the PCD syndrome predate the patient’s cancer diagnosis. Thus, prompt diagnosis of PCD is essential to allow for early treatment of the neurologic symptoms and the underlying malignancy. However, the prognosis is very poor for the anti-Yo-associated paraneoplastic syndrome, since neurologic damage is usually rapid and irreversible. Further progression may be stopped with appropriate treatment of cancer, but existing neurologic deficits at the time of diagnosis are usually permanent. Here we present a rare case of a young woman with early HER2 positive breast cancer diagnosed with PCD. Case Presentation: A 26-year-old woman with nil comorbidity and no family history of malignancy presented in February 2023 with progressive unsteadiness while walking with worsening truncal instability, slurring of speech, diplopia and increasing difficulty with fine motor tasks due to incoordination for 3 months. At this point, she needed the support of one person to walk. There were no constitutional symptoms, headaches, seizures, and hearing or visual disturbances. Her vitals and general physical examination (including breast) were normal. There was no lymphadenopathy. Neurological assessment revealed prominent cerebellar signs, including bilateral upper limb dysmetria, intention tremor, scanning speech, and gait and truncal ataxia. She had normal muscle tone, power, sensation, and symmetrical reflexes throughout her upper and lower limbs. Examination of the cranial nerves did not reveal any abnormalities. Gaze-evoked nystagmus was observed. Her routine laboratory tests were unremarkable. Brain and spine magnetic resonance imaging were normal, but her Nerve conduction studies (NCS) showed sensory peripheral neuropathy. Cerebrospinal fluid analysis revealed no cells, normal sugar levels, slightly increased protein level (77 mg/dl) with no oligoclonal bands, and it was negative for malignant cells. Serum was tested for onconeural antibodies, including anti-Yo, anti-Hu, anti-Ri, anti-CV2, anti-Ma2, and anti-amphiphysin. A high titre of anti-Yo antibodies (1:1,000) was detected in the serum and CSF samples using immunoblot assay with the dilution of 1:101. She underwent 2 cycles of plasmapheresis and 5 days of IVIG therapy leading to only minimal improvement. The presence of a characteristic anti-onconeural antibody led to the search of an underlying malignancy. A PETCT Scan was undertaken which showed a FDG avid enhancing lobulated soft tissue lesion involving retro areolar region of right breast, measuring 1.8 x 1.3cm, SUVmax 6.85 with no other sites of metastasis. A breast Biopsy was undertaken in which the histological report classified the tumour as a grade 3 infiltrating ductal carcinoma (IDC) with negative Estrogen receptors (ER), negative progesterone receptors (PR), Positive HER2 (3+) by immunohistochemistry. In addition, a panel of tumour susceptibility genes was performed, which did not show any mutations. Therefore, the patient was diagnosed of a unicentric IDC cT1cN0M0 HER2 positive of the right breast. With that information, she was initiated on Neoadjuvant therapy (NAT) completing 12 cycles of single agent weekly Trastuzumab from March 2023 to June 2023 with excellent tolerability. Paclitaxel was withheld due to pre-existing neuropathy on NCS. At this point, she had significant improvement in her symptoms to the tune that she could do her daily activities with minimal support. Following NAT, she underwent Breast conserving surgery with Axillary sampling in the month of July 2023 with post op Histopathology showing pathological complete response (pCR) (ypT0 and pN0 in sentinel nodes 0/6). Post Surgery in the month of July 2023 she had worsening of her ataxia with new onset sensorineural hearing loss (SNHL) which was moderate loss as per pure tone audiometric (PTA) test. She was given 5 days of High dose Methylprednisolone Pulse therapy following which she had good improvement with respect to her ataxia but not to SNHL. She completed 13 cycles of adjuvant three weekly single agent trastuzumab in the month of April 2024 and is on observation since then. On her first follow-up since completion of her treatment she observed improvement in her ataxia but only minimal improvement in her SNHL still requiring one person support for her activities of daily living with breast cancer being in remission. Conclusion: PCD remains a therapeutic challenge, based on the treatment of the neoplastic disease in conjunction with corticosteroid therapy and immunomodulators, such as immunoglobulins. It should be noted that neurological improvements have been described in patients with HER2 positive breast cancer under treatment with trastuzumab. In paraneoplastic conditions where the antigen is intracellular, as in the present case, the effectiveness of immunoglobulins is doubtful. Both positivity and titres of antibodies have not been shown to be predictors of evolution or response to treatment. Here, we present a novel case of a patient treated with only HER2 blockade, achieving a pathological complete response, which may impact the prognosis of the paraneoplastic syndrome. Citation Format: Vallish Shenoy, Sudeep Gupta, Seema Gulia, Prabhat Ghanshyam Bhargava, Sushmitha Rath, Shalaka Joshi, Tabassum Wadasadawala, Dileep Hoysal, Revathy Krishnamurthy. “NAVIGATING THE NEXUS: OVERCOMING DOUBLE JEOPARDY OF EARLY HER2-POSITIVE BREAST CANCER PRESENTING AS AN ANTI-Yo POSITIVE PARANEOPLASTIC CEREBELLAR DEGENERATION IN A YOUNG WOMAN” [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-07-25.

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