Metastatic breast cancer

Operated breast cancer with metastases
Short Summary

A 55 years old female was diagnosed with infiltrating ductal carcinoma of the right breast 7 years ago. The patient underwent a right quadrantectomy and axillary lymph nodes removal, adjuvant chemotherapy and radiation therapy. 5 years ago, after diagnostic finding of reappearance of infiltrating ductal carcinoma of the right breast, the patient underwent right mastectomy and revisional surgery of axillary armpit, and another adjuvant chemotherapy. 
One year ago appeared cerebral, hepatic, right suprarenal gland lymph nodes, and bone (L4) metastases. The patient underwent neurosurgery of cerebral metastasis and G-knife treatment for a further cerebellar lesion and boost on the surgical bed was performed. Histological examination of cerebral metastases was consistent with her known breast cancer. However, this examination also revealed that her tumor was c-erbB2 positive, and that the Ki-67 was equal to 25%. Since then the patient treated with Herceptin and Taxol and Zometa.
4 months after the neurosurgery, MRI was performed: the right frontoparietal lesions were reduced of 90% and there was no appearance of new lesions. At the PET/CAT scan examination was no more evidence of areas of high hepatic, skeletal, suprarenal glands and lymph nodes metabolic activity. 3 months later, a MRI of the brain and encephalic trunk was carried out to compare it to the previous examination, which was suggestive of tumor growth. A further PET scan examination has revealed new lesions.
 

Patient's Questions

1) What therapy do you suggest?
2) Any treatments under trial?
3) On the basis of the latest medical tests performed, do you think a disease resumption is ongoing?

Medical Background

A 55 years old female.
7 years ago, the patient was diagnosed with infiltrating ductal carcinoma of the right breast (ER negative, PgR negative, c-erbB2 not carried out, Ki-67 not carried out). The patient underwent a right quadrantectomy and axillary lymph nodes removal. Following IV CMF (Cyclophosphamide, Methotrexate and Fluorouracil) every 28 days for 6 cycles and radiation therapy.

5 years ago- diagnostic finding of reappearance of infiltrating ductal carcinoma of the right breast.
At histology examination: Infiltrating Ductal Carcinoma, G3. (ER negative, PgR negative, c-erbB2 not determined, Ki67 not determined). The patient, therefore, underwent right mastectomy and revisional surgery of axillary armpit, and then 4 cycles of AC (Adriamycin and Cyclophosphamide).

One year ago, appeared cerebral, hepatic, right suprarenal gland lymph nodes, and bone (L4) metastases. The patient underwent neurosurgery of cerebral metastasis, the histology examination of which is indicative of “friable nodular mass consistent with breast cancer ER 5%; PgR negative; c-erbB2 3+. Histological revisional surgery at IEO (European Institute of Oncology) referred to neoplasia of the right frontal region: metastasis of angioinvasive carcinoma consistent with breast primary tumour. The immunocytochemical assessment of the estrogen receptors is positive (5% of the neoplastic cells) and the progesterone receptors assessment is negative. Intense membrane complete immunoreactivity for Her-2/neu (Dako polyclonal antiserum) in 50% of the neoplastic cells. The proliferative fraction (Ki-67) is equal to 25%.
G-knife treatment for a further cerebellar lesion and boost on the surgical bed was performed. Since then, the patient treated with Herceptin and Taxol and Zometa.

4 months after the neurosurgery, MRI was performed: the right frontoparietal lesions were reduced of 90%, and there was no appearance of new lesions. At the PET/CAT scan examination that was performed on the same period, there was no more evidence of areas of high hepatic, skeletal, suprarenal glands and lymph nodes metabolic activity. Ca 15-3 not carried out. CEA altered.

During the oncologic visit, the following therapeutic schedule was outlined:
1- In consideration of the disease regression, continue with Trastuzumab (if the cardiac function makes it possible) with associated Paclitaxel until the maximum of response or tolerance, for no longer than 6 months following the principle of parsimony.
2- When the apex of the response or tolerance has been reached, suspend chemotherapy with Paclitaxel continuing with the maintenance therapy taking Trastuzumab (if the cardiac function makes it possible) in monotherapy.
3- In case the disease progresses, it would be advisable to consider a chemotherapy following the Cooper regimen (CMFVP) or Lapatinib plus capecitabine. If the disease progresses at brain level, take into consideration a panencephalic radiotherapy.
4- Reduce the intake of bisphosphonates after the 6th administration every 3-6 months in asymptomatic patient for the risk of avascular osteonecrosis of the jaw due to the extended use.

3 months later, a MRI of the brain and encephalic trunk was carried out to compare it to the previous same examination (that was performed 3 months ago), which shows that the findings, in the frontal region and at the top of the right side, are substantially unchanged, result of past operation of cerebral metastasectomy. Furthermore, appreciable marginal enhancement near the surgical cavity that currently shows a more irregular appearance with a small area of nodular enhancement on the anterior medial edge. At today’s examination a small doubtful area of slight nodular enhancement is appreciated, in anterior frontobasal region on the right side suspicious of further repeated localization. The remaining reports are unchanged.
A further PET scan examination has revealed:
- Lesions at D6 and D3 level consistent with repeated localizations.
- Right laterocervical lymphadenopathies that show a metabolic gradient at the limits of importance.

Expert's Opinion

A) Reconstruction of the medical data:
A 55 year old women diagnosed seven years ago with infiltrating ductal carcinoma of the right breast (ER negative, PgR negative, c-erbB2 not checked, Ki-67 not checked). She underwent right breast quadrantectomy and axillary lymph nodes dissection. There is no mentioning of her stage at diagnosis. Yet, she received adjuvant chemotherapy by six cycles of the CMF regimen and breast irradiation.

Two years later, her disease recurred locally. A repeated biopsy was consistent with infiltrating ductal carcinoma, G3. (ER negative, PgR negative, but the c-erbB2 status and the Ki67 were not determined). She then underwent right mastectomy and "again" received "adjuvant" chemotherapy, this time consisting on four cycles of AC.

Four years later, there was appearance of multiple organ metastases, including brain, liver, suprarenal gland, lymph nodes and bone(L4).

The patient underwent removal of a cerebral metastasis and the histological examination this time was consistent with her known breast cancer: ER 5%; PgR negative. However, this last examination also revealed that her tumor was c-erbB2 positive ( 3+), and that the Ki-67 was equal to 25%. The surgical bed received a boost of irradiation. Another lesion in the cerebellum was approached by G-knife treatment. Since then she is receiving Herceptin combined with Taxol and Zometa.
At MRI examination: the right frontoparietal lesions were reduced by 90% and there was no appearance of new lesions. In addition, PET/CAT scan examination was consistent with complete response elsewhere, including the metastases in liver, bone, lymph nodes and suprarenal gland. Ca 15-3 was not reported and CEA was "altered".

B) Questions and answers:

Question 3: On the basis of the latest medical tests performed, do you think disease resumption is ongoing?

I think that there is an accumulation of changes suggesting an imminent escape from disease control. Yet, this is still inconclusive.
- The PET scan has revealed "new lesions" at D6 and D3 level consistent with repeated localizations. Still, this conclusion seems to be weakened by the fact that the previous localization at L4 is not apparent this time.
- The new right laterocervical lymphoadenopathies showed a metabolic gradient although this was at "the limits of importance".
- Similarly, the brain MRI is suggestive of tumor growth, with a small doubtful area of slight nodular enhancement appreciated in anterior fronto-basal region on the right side. The brain condition deserves both close follow up and planning of the next therapeutic step, since progression in the brain may become the limiting factor of the disease.
- Practically, I would suggest a new comprehensive reevaluation of disease activity following two months interval from previous brain MRI and PET scan. Until substantiation of the present suspects I would not initiate any new line of treatment.
- Until then, and in agreement with the suggestions of the treating oncologist, I would continue with Trastuzumab (provided that the cardiac function makes it possible) with associated Paclitaxel until the maximum of response or tolerance, for no longer than 6 months following the principle of parsimony.

Question 1) What therapy do you suggest?
Question 2) Any treatments under trial?

-Since the tumor was found to be c-erb2 positive some anti HER-2 treatment should be continued. This could be either Trastuzumab beyond progression or Lapatinib as a new agent.
- If the progression is within the brain I would prefer switching to Lapatinib. This small molecule has proven better activity in the brain as compared with Trastuzumab which is a large molecular monoclonal antibody that does not cross the BBB.
- If progression is exclusively in the brain, with persistent control in the various other sites, the current chemotherapeutic agent should be considered to be active and should be continued, while changing only the anti HER-2 agent aimed at acting within the "sanctuary" of the brain.
- If progression is both in the brain and in other sites/organs, then I would suggest switching the whole treatment to Lapatinib+Capecitabine. This combination has been reported to induce regression of metastases both in the brain and in peripheral sites.
- If there is no progression in the brain, but disease progresses in other sites/organs then only the chemotherapeutic agent should be changed. In that case I would prefer Vinorelbine along with Trastuzumab.
- Learning from the lengths of disease free period following the two "lines of adjuvant treatment" it would seem that the disease was not sensitive to CMF, thus recurring within two years of diagnosis, while it was silent for four years following successive four cycles of AC. Therefore, I think this disease showed responsiveness to Doxorubicin, and I would consider Doxil as an additional option for latter treatment, so far as cardiac monitoring allows it.
- Additional optional chemotherapeutic agents in case of progression are Gemcitabine and Cisplatin.
- If and when disease progresses in the brain in spite of Lapatinib treatment there would be a role for additional radiotherapy. If there are multiple sites of activity within the brain then total brain irradiation is adviced. However if there are only one or two new sites of activity within the brain while systemic disease is still controlled, then a new G-knife treatment could be considered saving the whole brain irradiation to a latter time.
- Regarding the intake of bisphosphonates I agree with the treating oncologist, that Zometa administration should be reduced after the 6th monthly administration to once every 3-6 months, provided that the patient is still asymptomatic, aiming to reduce the risk of avascular osteonecrosis of the jaw due to the extended use.
- There is continuous development of new anti-cancer agents, tailored to specific characteristics of each case. For example, there is recent progress in the treatment of the aggressive and resistant triple negative tumors as well as that of the mutated BRCA cases, by the new PARP inhibitors. Accordingly, if and when the above listed interventions are exhausted, it is suggested to look over the literature for newly developed agents.
- I hope the remarkable response achieved so far by the first line of treatment can be repeated with a second line of treatment if and when disease progression is proven. 

""